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Sample records for carcinogenesis przeglad teorii

  1. [Carcinogenesis].

    Science.gov (United States)

    Martín de Civetta, María Teresa; Civetta, Julio Domingo

    2011-01-01

    Cell division is controlled by stimulatory and inhibitory systems.The origin of cancer is monoclonal, and in order that a normal cell switches its phenotype and becomes a neoplastic cell, genetic mutations must occur on it.These genetic mutations modify the products that in normal conditions the gene would codify and, finally, cause cancer. Cancer may be hereditary (due to mutations in one or both of germinal cells alleles) or sporadic (due to action of environmental mutagenic agents).The mechanisms that may cause alterations on genes may be genetic or epigenetic. Genetic mechanisms occur when structural alterations of genome are present and the epigenetic processes occur due to enzymatic alterations or alterations on its substrates. Carcinogenesis has three stages: initiation, promotion and progression.The last of these stages, progression, is exclusive of malignant transformation and implies the capacity to invade surrounding or distant tissues. For metastasis to take place, many mechanisms are required: angiogenesis, matrix degradation, cell migration, evasion of host immune response and metastatic colonization. This article presents a partial review of current bibliography about concepts related to carcinogenesis and conveys the minimum necessary information to achieve an understanding of this complex process.

  2. Chemical carcinogenesis

    Directory of Open Access Journals (Sweden)

    Paula A. Oliveira

    2007-12-01

    Full Text Available The use of chemical compounds benefits society in a number of ways. Pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. There are three stages involved in chemical carcinogenesis. These are defined as initiation, promotion and progression. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair - i.e. mutations in proto-oncogenes and tumour suppressing genes. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals.A sociedade obtém numerosos benefícios da utilização de compostos químicos. A aplicação dos pesticidas, por exemplo, permitiu obter alimento em quantidade suficiente para satisfazer as necessidades alimentares de milhões de pessoas, condição relacionada com o aumento da esperança de vida. Os benefícios estão, por

  3. Gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Ismail Gomceli; Baris Demiriz; Mesut Tez

    2012-01-01

    Gastric cancer is the second most common cancer worldwide and the second most common cause of cancer-related deaths.Despite complete resection of gastric cancer and lymph node dissection,as well as improvements in chemotherapy and radiotherapy,there are still 700 000 gastric cancer-related deaths per year worldwide and more than 80% of patients with advanced gastric cancer die of the disease or recurrent disease within 1 year after diagnosis.None of the treatment modalities we have been applying today can influence the overall survival rates:at present,the overall 5-year relative survival rate for gastric cancer is about 28%.Cellular metaplasia due to chronic inflammation,injury and repair are the most documented processes for neoplasia.It appears that chronic inflammation stimulates tumor development and plays a critical role in initiating,sustaining and advancing tumor growth.It is also evident that not all inflammation is tumorigenic.Additional mutations can be acquired,and this leads to the cancer cell gaining a further growth advantage and acquiring a more malignant phenotype.Intestinalization of gastric units,which is called "intestinal metaplasia";phenotypic antralization of fundic units,which is called "spasmolytic polypeptide-expressing metaplasia"; and the development directly from the stem/progenitor cell zone are three pathways that have been described for gastric carcinogenesis.Also,an important factor for the development of gastrointestinal cancers is peritumoral stroma.However,the initiating cellular event in gastric metaplasia is still controversial.Understanding gastric carcinogenesis and its precursor lesions has been under intense investigation,and our paper attempts to high-light recent progress in this field of cancer research.

  4. Oxidative damage and carcinogenesis

    OpenAIRE

    2012-01-01

    Oxygen is an essential element to conduct life processes but some of the metabolic byproducts e.g. reactive oxygen species (ROS), are toxic for living organisms. Endogenous ROS are produced e.g. reduction of dioxygen; some exogenous sources of radicals also exist, including nicotine and ionizing radiation. Reactive oxygen species include superoxide anion, hydroxyl radical, singlet oxygen, hydrogen peroxide and hypochlorous acid. Carcinogenesis is a multistep process. The exact reasons for the...

  5. Sawmill chemicals and carcinogenesis.

    OpenAIRE

    Huff, J

    2001-01-01

    Workers in wood industries are exposed to variable medleys of chemicals, both natural and synthetic. Additional exposures include fungi, bacteria, bark and wood dusts, solvents, paints, and various other wood coatings. These individual and conglomerate exposures have been associated with diverse occupational illnesses and hazards, including cancers. In this commentary, I summarize both experimental and epidemiologic carcinogenesis results for several chemicals used in the wood industry, as we...

  6. [Cyclooxygenase 2 and carcinogenesis].

    Science.gov (United States)

    Rodrigues, Sylvie; Bruyneel, Erik; Rodrigue, Christelle M; Shahin, Emami; Gespach, Christian

    2004-05-01

    The membrane glycoprotein Cox2 is regulated at transcriptional and post-transcriptional levels by pro-inflammatory agents, cytokines, growth factors, oncogenes, and tumor-promoters. Cox2 is expressed during early stages of colorectal carcinogenesis from the premalignant adenoma stage, and adenocarcinomas of stomach, colon, breast, lung and prostate. Its expression is detected in neoplastic, inflammatory, endothelial and stromal cells. Cox2 is involved in the conversion of arachidonic acid into prostaglandins and thromboxanes, as well as the synthesis of malonaldehyde (MDA, a mutagen) and the production of hydrogen peroxide, which promotes carcinogenesis. The Cox2 products act in turn on serpentine receptors coupled to heterotrimeric G-proteins (R-TXA2, R-PG) that are connected to signaling elements implicated in oncogenesis. Thus, Cox2 plays a key role in early stages of carcinogenesis by promoting the proliferation of tumoral cells and their resistance to apoptosis, as well as angiogenesis, tumor cell invasion and setting up of the metastatic process. These mechanisms establish the rationale behind the therapeutic targeting of Cox2 in human solid tumors.

  7. Oxidants, antioxidants and carcinogenesis.

    Science.gov (United States)

    Ray, Gibanananda; Husain, Syed Akhtar

    2002-11-01

    Reactive oxygen metabolites (ROMs), such as superoxide anions (O2*-) hydrogen peroxide (H2O2), and hydroxyl radical (*OH), malondialdehyde (MDA) and nitric oxide (NO) are directly or indirectly involved in multistage process of carcinogenesis. They are mainly involved in DNA damage leading sometimes to mutations in tumour suppressor genes. They also act as initiator and/or promotor in carcinogenesis. Some of them are mutagenic in mammalian systems. O2*-, H2O2 and *OH are reported to be involved in higher frequencies of sister chromatid exchanges (SCEs) and chromosome breaks and gaps (CBGs). MDA, a bi-product of lipid peroxidation (LPO), is said to be involved in DNA adduct formations, which are believed to be responsible for carcinogenesis. NO, on the other hand, plays a duel role in cancer. At high concentration it kills tumour cells, but at low concentration it promotes tumour growth and metastasis. It causes DNA single and double strand breaks. The metabolites of NO such as peroxynitrite (OONO-) is a potent mutagen that can induce transversion mutations. NO can stimulate O2*-/H2O2/*OH-induced LPO. These deleterious actions of oxidants can be countered by antioxidant defence system in humans. There are first line defense antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). SOD converts O2*- to H2O2, which is further converted to H2O with the help of GPx and CAT. SOD inhibits *OH production. SOD also act as antipoliferative agent, anticarcinogens, and inhibitor at initiation and promotion/transformation stage in carcinogenesis. GPx is another antioxidative enzyme which catalyses to convert H2O2, to H2O. The most potent enzyme is CAT. GPx and CAT are important in the inactivation of many environmental mutagens. CAT is also found to reduce the SCE levels and chromosomal aberrations. Antioxidative vitamins such as vitamin A, E, and C have a number of biological activities such as immune stimulation, inhibition of

  8. Simulation modeling of carcinogenesis.

    Science.gov (United States)

    Ellwein, L B; Cohen, S M

    1992-03-01

    A discrete-time simulation model of carcinogenesis is described mathematically using recursive relationships between time-varying model variables. The dynamics of cellular behavior is represented within a biological framework that encompasses two irreversible and heritable genetic changes. Empirical data and biological supposition dealing with both control and experimental animal groups are used together to establish values for model input variables. The estimation of these variables is integral to the simulation process as described in step-by-step detail. Hepatocarcinogenesis in male F344 rats provides the basis for seven modeling scenarios which illustrate the complexity of relationships among cell proliferation, genotoxicity, and tumor risk.

  9. BOOK REVIEW - Adrian Liviu Ivan, Teorii și practice ale integrării europene [Theories and Practices of European Integration

    Directory of Open Access Journals (Sweden)

    Adrian Daniel STAN

    2016-06-01

    Full Text Available Teorii și practice ale integrării europene [Theories and Practices of European Integration] is a genuine contribution to understanding how the European Union’s particular character has been adjusted in more than half of century of institutional growth and development. Professor Ivan`s key argument for this book is that the European Union has been shaped as a functional project taking into consideration the diverse heritage and traditions of its Member States. The opening chapter of this book focuses on the particularities of international relations discipline after the Second World War in order to introduce the theme of European Integration Process. This chapter must be analysed in a series of contributions dedicated to the European Integration process and to the theories that made this integration possible because professor Ivan has previously published books such as: Statele Unite ale Europei [The United States of Europe], Sub zodia Statelor Unite ale Europei [Under the Sign of the United States of Europe], in which he debates the origins of the European construction and brings forward arguments to support the importance of each theoretical and functional pillar of this “Common European Project”.

  10. [Iron function and carcinogenesis].

    Science.gov (United States)

    Akatsuka, Shinya; Toyokuni, Shinya

    2016-07-01

    Though iron is an essential micronutrient for humans, the excess state is acknowledged to be associated with oncogenesis. For example, iron overload in the liver of the patients with hereditary hemocromatosis highly increases the risk of hepatocellular carcinoma. Also, as to asbestos-related mesothelioma, such kinds of asbestos with a higher iron content are considered to be more carcinogenic. Iron is a useful element, which enables fundamental functions for life such as oxygen carrying and electron transport. However, in the situation where organisms are unable to have good control of it, iron turns into a dangerous element which catalyzes generation of reactive oxygen. In this review, I first outline the relationships between iron and cancer in general, then give an explanation about iron-related animal carcinogenesis models.

  11. Methylation in esophageal carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Da-Long Wu; Feng-Ying Sui; Xiao-Ming Jiang; Xiao-Hong Jiang

    2006-01-01

    Genetic abnormalities of proto-oncogenes and tumor suppressor genes have been demonstrated to be changes that are frequently involved in esophageal cancer pathogenesis. However, hypermethylation of CpG islands, an epigenetic event, is coming more and more into focus in carcinogenesis of the esophagus. Recent studies have proved that promoter hypermethylation of tumor suppressor genes is frequently observed in esophageal carcinomas and seems to play an important role in the pathogenesis of this tumor type. In this review, we will discuss current research on genes that are hypermethylated in human esophageal cancer and precancerous lesions of the esophagus. We will also discuss the potential use of hypermethylated genes as targets for detection, prognosis and treatment of esophageal cancer.

  12. MYC and gastric adenocarcinoma carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Danielle Queiroz Calcagno; Mariana Ferreira Leal; Paulo Pimentel Assumpcao; Marilia de Arruda Cardoso Smith; Rommel Rodriguez Burbano

    2008-01-01

    MYC is an oncogene involved in cell cycle regulation, cell growth arrest, cell adhesion, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function. It has been described as a key element of several carcinogenesis processes in humans. Many studies have shown an association between MYC deregulation and gastric cancer. MYC deregulation is also seen in gastric preneoplastic lesions and thus it may have a role in early gastric carcinogenesis. Several studies have suggested that amplification is the main mechanism of MYC deregulation in gastric cancer. In the present review, we focus on the deregulation of the MYC oncogene in gastric adenocarcinoma carcinogenesis, including its association with Helicobacter pylori (H pylori) and clinical applications.

  13. Gene amplification in carcinogenesis

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    Lucimari Bizari

    2006-01-01

    Full Text Available Gene amplification increases the number of genes in a genome and can give rise to karyotype abnormalities called double minutes (DM and homogeneously staining regions (HSR, both of which have been widely observed in human tumors but are also known to play a major role during embryonic development due to the fact that they are responsible for the programmed increase of gene expression. The etiology of gene amplification during carcinogenesis is not yet completely understood but can be considered a result of genetic instability. Gene amplification leads to an increase in protein expression and provides a selective advantage during cell growth. Oncogenes such as CCND1, c-MET, c-MYC, ERBB2, EGFR and MDM2 are amplified in human tumors and can be associated with increased expression of their respective proteins or not. In general, gene amplification is associated with more aggressive tumors, metastases, resistance to chemotherapy and a decrease in the period during which the patient stays free of the disease. This review discusses the major role of gene amplification in the progression of carcinomas, formation of genetic markers and as possible therapeutic targets for the development of drugs for the treatment of some types of tumors.

  14. DNA methylation and carcinogenesis.

    Science.gov (United States)

    Lichtenstein, A V; Kisseljova, N P

    2001-03-01

    In the world of easy things truth is opposed to lie; in the world of complicated things one profound truth is opposed to another not less profound than the first. Neils Bohr The hypothesis of the exclusively genetic origin of cancer ("cancer is a disease of genes, a tumor without any damage to the genome does not exist") dominated in the oncology until recently. A considerable amount of data confirming this hypothesis was accumulated during the last quarter of the last century. It was demonstrated that the accumulation of damage of specific genes lies at the origin of a tumor and its following progression. The damage gives rise to structural changes in the respective proteins and, consequently, to inappropriate mitogenic stimulation of cells (activation of oncogenes) or to the inactivation of tumor suppressor genes that inhibit cell division, or to the combination of both (in most cases). According to an alternative (epigenetic) hypothesis that was extremely unpopular until recently, a tumor is caused not by a gene damage, but by an inappropriate function of genes ("cancer is a disease of gene regulation and differentiation"). However, recent studies led to the convergence of these hypotheses that initially seemed to be contradictory. It was established that both factors--genetic and epigenetic--lie at the origin of carcinogenesis. The relative contribution of each varies significantly in different human tumors. Suppressor genes and genes of repair are inactivated in tumors due to their damage or methylation of their promoters (in the latter case an "epimutation", an epigenetic equivalent of a mutation, occurs, producing the same functional consequences). It is becoming evident that not only the mutagens, but various factors influencing cell metabolism, notably methylation, should be considered as carcinogens.

  15. Helicobacter pylori in gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Hyo; Jun; Ahn; Dong; Soo; Lee

    2015-01-01

    Gastric cancer still is a major concern as the third most common cancer worldwide, despite declining rates of incidence in many Western countries. Helicobacter pylori(H. pylori) is the major cause of gastric carcinogenesis, and its infection insults gastric mucosa leading to theoccurrence of atrophic gastritis which progress to intestinal metaplasia, dysplasia, early gastric cancer, and advanced gastric cancer consequently. This review focuses on multiple factors including microbial virulence factors, host genetic factors, and environmental factors, which can heighten the chance of occurrence of gastric adenocarcinoma due to H. pylori infection. Bacterial virulence factors are key components in controlling the immune response associated with the induction of carcinogenesis, and cag A and vac A are the most well-known pathogenic factors. Host genetic polymorphisms contribute to regulating the inflammatory response to H. pylori and will become increasingly important with advancing techniques. Environmental factors such as high salt and smoking may also play a role in gastric carcinogenesis. It is important to understand the virulence factors, host genetic factors, and environmental factors interacting in the multistep process of gastric carcinogenesis. To conclude, prevention via H. pylori eradication and controlling environmental factors such as diet, smoking, and alcohol is an important strategy to avoid H. pylori-associated gastric carcinogenesis.

  16. Carcinogenesis mechanisms of Fusobacterium nucleatum.

    Science.gov (United States)

    Gholizadeh, Pourya; Eslami, Hosein; Kafil, Hossein Samadi

    2017-03-07

    Transformed cells of cancers may be related to stromal cells, immune cells, and some bacteria such as Fusobacterium nucleatum. This review aimed to evaluate carcinogenesis mechanisms of Fusobacterium spp. in the oral cavity, pancreatic and colorectal cancers. These cancers are the three of the ten most prevalence cancer in the worldwide. Recent findings demonstrated that F. nucleatum could be considered as the risk factor for these cancers. The most important carcinogenesis mechanisms of F. nucleatum are chronic infection, interaction of cell surface molecules of these bacteria with immune system and stromal cells, immune evasion and immune suppression. However, there are some uncertainty carcinogenesis mechanisms about these bacteria, but this review evaluates almost all the known mechanisms. Well-characterized virulence factors of F. nucleatum such as FadA, Fap2, LPS and cell wall extracts may act as effector molecules in the shift of normal epithelial cells to tumor cells. These molecules may provide new targets, drugs, and strategies for therapeutic intervention.

  17. Epigenetic alterations in gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    In-Seon CHOI; Tsung-Teh WU

    2005-01-01

    Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.

  18. Environmental and chemical carcinogenesis.

    Science.gov (United States)

    Wogan, Gerald N; Hecht, Stephen S; Felton, James S; Conney, Allan H; Loeb, Lawrence A

    2004-12-01

    People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic or mutagenic properties in experimental systems. Exposure can occur exogenously when these agents are present in food, air or water, and also endogenously when they are products of metabolism or pathophysiologic states such as inflammation. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers, when exposures are related to "life-style" factors such as diet, tobacco use, etc. This chapter summarizes several aspects of environmental chemical carcinogenesis that have been extensively studied and illustrates the power of mechanistic investigation combined with molecular epidemiologic approaches in establishing causative linkages between environmental exposures and increased cancer risks. A causative relationship between exposure to aflatoxin, a strongly carcinogenic mold-produced contaminant of dietary staples in Asia and Africa, and elevated risk for primary liver cancer has been demonstrated through the application of well-validated biomarkers in molecular epidemiology. These studies have also identified a striking synergistic interaction between aflatoxin and hepatitis B virus infection in elevating liver cancer risk. Use of tobacco products provides a clear example of cancer causation by a life-style factor involving carcinogen exposure. Tobacco carcinogens and their DNA adducts are central to cancer induction by tobacco products, and the contribution of specific tobacco carcinogens (e.g. PAH and NNK) to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach. Factors considered include presence in tobacco products, carcinogenicity in laboratory animals, human uptake, metabolism and adduct formation, possible role in causing molecular changes in oncogenes or suppressor genes, and other relevant data

  19. Radiation carcinogenesis: radioprotectors and photosensitizers

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1982-01-01

    This paper outlines 1) some of the salient features of radiation carcinogenesis that are pertinent to the questions of how the carcinogenic effects might be influenced, 2) the effects of radioprotectors on ionizing radiation-induced cancer, and 3) the effect of photosensitizers on UVR-induced skin cancer.

  20. Dose response problems in carcinogenesis.

    Science.gov (United States)

    Crump, K S

    1979-03-01

    The estimation of risks from exposure to carcinogens is an important problem from the viewpoint of protection of human health. It also poses some very difficult dose-response problems. Two dose-response models may fit experimental data about equally well and yet predict responses that differ by many orders of magnitude at low doses. Mechanisms of carcinogenesis are not sufficiently understood so that the shape of the dose-response curve at low doses can be satisfactorily predicted. Mathematical theories of carcinogenesis and statistical procedures can be of use with dose-reponse problems such as this and, in addition, can lead to a better understanding of the mechanisms of carcinogenesis. In this paper, mathematical dose-response models of carcinogenesis are considered as well as various proposed dose-response procedures for estimating carcinogenic risks at low doses. Areas are suggested in which further work may be useful. These areas include experimental design problems, statistical procedures for use with time-to-occurrence data, and mathematical models that incorporate such biological features as pharmacokinetics of carcinogens, synergistic effects, DNA repair, susceptible subpopulations, and immune reactions.

  1. Radiogenic cell transformation and carcinogenesis

    Science.gov (United States)

    Yang, T. C.; Georgy, K. A.; Mei, M.; Durante, M.; Craise, L. M.

    1995-01-01

    Radiation carcinogenesis is one of the major biological effects considered important in the risk assessment for space travel. Various biological model systems, including both cultured cells and animals, have been found useful for studying the carcinogenic effects of space radiations, which consist of energetic electrons, protons and heavy ions. The development of techniques for studying neoplastic cell transformation in culture has made it possible to examine the cellular and molecular mechanisms of radiation carcinogenesis. Cultured cell systems are thus complementary to animal models. Many investigators have determined the oncogenic effects of ionizing and nonionizing radiation in cultured mammalian cells. One of the cell systems used most often for radiation transformation studies is mouse embryonic cells (C3H10T1/2), which are easy to culture and give good quantitative dose-response curves. Relative biological effectiveness (RBE) for heavy ions with various energies and linear energy transfer (LET) have been obtained with this cell system. Similar RBE and LET relationship was observed by investigators for other cell systems. In addition to RBE measurements, fundamental questions on repair of sub- and potential oncogenic lesions, direct and indirect effect, primary target and lesion, the importance of cell-cell interaction and the role of oncogenes and tumor suppressor genes in radiogenic carcinogenesis have been studied, and interesting results have been found. Recently several human epithelial cell systems have been developed, and ionizing radiation have been shown to transform these cells. Oncogenic transformation of these cells, however, requires a long expression time and/or multiple radiation exposures. Limited experimental data indicate high-LET heavy ions can be more effective than low-LET radiation in inducing cell transformation. Cytogenetic and molecular analyses can be performed with cloned transformants to provide insights into basic genetic

  2. Liver Development, Regeneration, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Janet W. C. Kung

    2010-01-01

    Full Text Available The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

  3. Cadmium carcinogenesis – some key points

    OpenAIRE

    2011-01-01

    The article presents briefly the main mechanisms of cadmium carcinogenesis and the most important sites of cancer (lung, breast, prostate, testes, kidney) induced by cadmium. In spite of some evidence showing carcinogenic potential of cadmium, further research is still required to elucidate the relative contributions of various molecular mechanisms involved in cadmium carcinogenesis

  4. Cadmium carcinogenesis – some key points

    Directory of Open Access Journals (Sweden)

    Loreta Strumylaite

    2011-09-01

    Full Text Available The article presents briefly the main mechanisms of cadmium carcinogenesis and the most important sites of cancer (lung, breast, prostate, testes, kidney induced by cadmium. In spite of some evidence showing carcinogenic potential of cadmium, further research is still required to elucidate the relative contributions of various molecular mechanisms involved in cadmium carcinogenesis

  5. Selenium in human mammary carcinogenesis

    DEFF Research Database (Denmark)

    Overvad, Kim; Grøn, P.; Langhoff, Otto;

    1991-01-01

    /l and TNM stage II 76 +/- 13 micrograms selenium/l), indicating disease-mediated changes. The evaluation of selenium as a risk indicator in human breast cancer was therefore restricted to TNM stage I patients (n = 36). Multiple logistic regression analyses including variables associated with selenium levels...... revealed no association between selenium levels and breast cancer risk.......In a case-referent study on the possible role of selenium in human mammary carcinogenesis, serum selenium was found to be 79 +/- 12 micrograms/l in 66 cases and 81 +/- 12 micrograms/l in 93 referents. An internal trend in serum selenium was observed among cases (TNM stage I 81 +/- 11 micrograms...

  6. Cyclooxygenase-2 and prostate carcinogenesis.

    Science.gov (United States)

    Hussain, Tajamul; Gupta, Sanjay; Mukhtar, Hasan

    2003-03-10

    In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti-inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our recently published study (Prostate, 42 2000 73-78), we provided the first evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects against prostate carcinogenesis in humans.

  7. Oxidative Stress and HPV Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Federico De Marco

    2013-02-01

    Full Text Available Extensive experimental work has conclusively demonstrated that infection with certain types of human papillomaviruses, the so-called high-risk human papillomavirus (HR-HPV, represent a most powerful human carcinogen. However, neoplastic growth is a rare and inappropriate outcome in the natural history of HPV, and a number of other events have to concur in order to induce the viral infection into the (very rare neoplastic transformation. From this perspective, a number of putative viral, host, and environmental co-factors have been proposed as potential candidates. Among them oxidative stress (OS is an interesting candidate, yet comparatively underexplored. OS is a constant threat to aerobic organisms being generated during mitochondrial oxidative phosphorylation, as well as during inflammation, infections, ionizing irradiation, UV exposure, mechanical and chemical stresses. Epithelial tissues, the elective target for HPV infection, are heavily exposed to all named sources of OS. Two different types of cooperative mechanisms are presumed to occur between OS and HPV: I The OS genotoxic activity and the HPV-induced genomic instability concur independently to the generation of the molecular damage necessary for the emergence of neoplastic clones. This first mode is merely a particular form of co-carcinogenesis; and II OS specifically interacts with one or more molecular stages of neoplastic initiation and/or progression induced by the HPV infection. This manuscript was designed to summarize available data on this latter hypothesis. Experimental data and indirect evidences on promoting the activity of OS in viral infection and viral integration will be reviewed. The anti-apoptotic and pro-angiogenetic role of NO (nitric oxide and iNOS (inducible nitric oxide synthase will be discussed together with the OS/HPV cooperation in inducing cancer metabolism adaptation. Unexplored/underexplored aspects of the OS interplay with the HPV-driven carcinogenesis

  8. Autophagy analysis in oral carcinogenesis.

    Science.gov (United States)

    de Lima, T B; Paz, A H R; Rados, P V; Leonardi, R; Bufo, P; Pedicillo, M C; Santoro, A; Cagiano, S; Aquino, G; Botti, G; Pannone, G; Visioli, F

    2017-09-01

    The aim of this study was to evaluate the levels of autophagy in oral leukoplakia and squamous cell carcinoma and to correlate with clinical pathological features, as well as, the evolution of these lesions. 7 Normal oral mucosa, 51 oral leukoplakias, and 120 oral squamous cell carcinomas (OSCC) were included in the study. Histological sections of the mucosa and leukoplakias were evaluated throughout their length, while the carcinomas were evaluated using Tissue Microarray. After the immunohistochemical technique, LC3-II positive cells were quantified in the different epithelial layers of the mucosa and leukoplakias and in the microarrays of the squamous cell carcinomas. The correlation between positive cells with the different clinical-pathological variables and with the evolution of the lesions was tested using the t test, ANOVA, and Kaplan-Meier survival analysis. We observed increased levels of autophagy in the oral squamous cell carcinomas (p<0.001) in relation to the other groups, but without any association with poorer evolution or survival of these patients. Among the leukoplakias, we observed a higher percentage of positive cells in the intermediate layer of the dysplastic leukoplakias (p=0.0319) and in the basal layer of lesions with poorer evolution (p=0.0133). The levels of autophagy increased during the process of oral carcinogenesis and are correlated with poorer behavior of the leukoplakias. Copyright © 2017 Elsevier GmbH. All rights reserved.

  9. Inhibition of carcinogenesis by tea.

    Science.gov (United States)

    Yang, Chung S; Maliakal, Pius; Meng, Xiaofeng

    2002-01-01

    Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.

  10. [Monoamines stimulations in experimental carcinogenesis].

    Science.gov (United States)

    Popov, I; Spuzić, I; Rakić, Lj

    1994-01-01

    Facts about the role of CNS monoamines in cancerogenesis have been accumulated for many years. The aim of the present study was to investigate the effect of interaction of psychoactive drug (Piracetam) and other treatments on survival time of tumour-bearing rats. 138 Wistar rats were used in the experiment. The animals were injected 1% 3--Methilcholantren suspension in 10% Tylose, s.c. under the dorsal skin of the neck in a dose of 3 mg/animal. Within 4-9 months after a single injection, the rats developed tumours at the site of injection. The surgical removal was performed when tumours reached the size of 1-3 cm. After surgical extirpation of tumours different groups of animals were treated by cyclophosphamide (s.c. one-time dose of 50 mg/kg for female and 100 mg/kg for male) or by psychoactive drug (Piracetam) administrated by GE tube 5 time/week, 100 mg/kg. Autopsy and histological examinations were carried out in all animals. Survival time (> 120 days) was the greatest in group B (Piracetam, after surgical removal of tumours) 81.2%, and group C (Cyclophosphamid, after surgical removal of tumours) 68.8% and in group A (only surgical removal of tumours) 50%. In group B the incidence of metastases was the smallest (87.1% of animals were without metastases), compared with group C (45.4% of animals were without metastases) and group A (27.3% of animals were without metastases). The diference is statistically significant. The mechanism of antineoplastic effect of Piracetam consisted of the interaction of influences both on metabolism of the Central nervous system and the tumour. Probably, it is the neurotransmitter modulation that had its effect on carcinogenesis not only by regulation/disregulation of brain homeostasis, but also via direct effect on intracellular processes during cell development and differentation.

  11. Role of bacteria in oral carcinogenesis

    Directory of Open Access Journals (Sweden)

    R Rajeev

    2012-01-01

    Full Text Available Oral cancer is the most common cancer diagnosed in Indian men and is the leading cause of cancer deaths. It is considered as a multistep and multifactorial disease. Besides accumulation of genetic mutations, numerous other carcinogens are involved. In this category, viral and chemical carcinogens are well studied and documented. However, in the oral cavity, the role of microbiota in carcinogenesis is not known. Microbial populations on mouth mucosa differ between healthy and malignant sites, and certain oral bacterial species have been linked with malignancies, but the evidence is still weak in this respect. Nevertheless, oral microorganisms inevitably up-regulate cytokines and other inflammatory mediators that affect the complex metabolic pathways, and may thus be involved in carcinogenesis. Poor oral health associates statistically with prevalence of many types of cancer such as pancreatic and gastrointestinal cancer. This review presents possible carcinogenesis pathway involved in bacterial carcinogenesis, commonly implicated bacteria in oral carcinogenesis, and their role in cancer therapeutics as well.

  12. Bacterionomics and vironomics in carcinogenesis

    Directory of Open Access Journals (Sweden)

    Pratiwi Sudarmono

    2017-02-01

    Full Text Available Virus and bacteria are microbes which are very common cause human infection. Most of the bacterial infection can be eradicated by antibiotics and infection symptoms disappear. But for virus infection, once infected, the virus will persistently stay in the host, even undergo not only a lytic cycle but also integrated into host genome. Nowadays, at least 6 virus type are consistently related to human cancer, such as EBV,HPV,HTLV,HBV,HCV,HKSV, and the new one Merkel Virus (MCV. Although not every infected people will get cancer, but around 20% of the whole cancer in human are caused by viral oncogene. Class one oncogenic bacterial is Helicobacter pylori. Infection with this bacteria can cause persistent gastro duodenal inflammation which cause some alteration in gastric cell growth into transformation. Expression of Cag gene and Vac gene and some expression of OMP protein usually link to gastric cancer. Molecular mechanisms of carcinogenesis for every virus which cause infection  is a very complex , which include several processes caused by cell transformation. Besides, other host and environmental factors are also play a significant role in cancer development. Some scientist put a Hallmark analysis as a model to quickly summarize what pathobiology process will happen and what gene or protein caused the process. The Hallmark analysis comprise of several process which may happen simultaneously because some of the Hallmark is caused by the same protein. The Hallmark consists of various virus strategies in oncogenesis such as promoting angiogenesis, avoiding immune destruction, genome instability and mutation, deregulating cellular energetic, resisting cell death, sustaining proliferative signaling, evading growth suppressors, enabling cellular immortality, promoting inflammation and activation metastasis. For example, infection by HPV, will cause low grade dysplasia which can continue to invasive cervical cancer. After host cell transformation, in

  13. Modeling Multiple Causes of Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Jones, T D

    1999-01-24

    multiple causes of carcinogenesis and shifts the risk-assessment logic to considerations of "what dose does?" in contrast to the current process of the substance-specific question of "what dose is?" Whether reactive oxygen is the proximate or contributing cause of disease or simply a better estimate of biologically effective dose, it has enormous advantages for improved risk- and policy-based decisions. Various estimates of immune system modulation will be given based on radiobiology.

  14. Diet, lifestyle, and molecular alterations that drive colorectal carcinogenesis

    NARCIS (Netherlands)

    Diergaarde, B.

    2004-01-01

    Environmental factors have been repeatedly implicated in the etiology of colorectal cancer, and much is known about the molecular events involved in colorectal carcinogenesis. The relationships between environmental risk factors and the molecular alterations that drive colorectal carcinogenesis are

  15. A Systems Approach to Radiation Carcinogenesis

    Science.gov (United States)

    Hlatky, Lynn

    Understanding carcinogenesis risk is complicated by a number of factors, among these the lack of a common platform to integrate and analyze the available data, and the inherently systemsbiologic nature of the problem. We have investigated mechanistic approaches to radiogenic risk estimation that draw on unifying biological principles and incorporate data from multiscale sources. The resultant modeling takes into account that carcinogenesis is a multi-scale phenomenon, critically influenced by determinants not only at the molecular level, but at the cell and tissue-levels as well. To account for cell-level carcinogenesis progression as influenced by inter-tissue signaling, we have developed a dynamic carrying capacity construct that couples the growth of a tumor with the degree of induced vascularization. We have also characterized the molecular responses to radiation incorporating tissue-level angiogenesis implications, and have found striking radiation-quality-dependent responses. The molecular-level events of initiation and promotion are considered in our Two-Stage Logistic model, while incorporating in a rudimentary way the larger-scale growth-limiting role of cell-cell interactions. These and other recent studies undertaken to elaborate radiation-induced carcinogenesis are discussed, in pursuit of a more complete paradigm for understanding radiation induction of cancer and the consequent risk.

  16. Sirt3, Mitochondrial ROS, Ageing, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    David Gius

    2011-09-01

    Full Text Available One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS, are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor and this review will outline potential relationships between mitochondrial ROS/superoxide levels, aging, and cell phenotypes permissive for estrogen and progesterone receptor positive breast carcinogenesis.

  17. Experimental radiation carcinogenesis: what have we learned

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1980-01-01

    The author reviews the need for animal experiments in development of a biological model for radioinduced carcinogenesis. He concludes they are vital for: (1) study of mechanisms; (2) establishment of generalizations; (3) elucidation of dose-response and time-dose relationships; and (4) determination of dose-distributions and their results, particularly for radionuclides. (PSB)

  18. Study of chemical and radiation induced carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Chmura, A.

    1995-11-01

    The study of chemical and radiation induced carcinogenesis has up to now based many of its results on the detection of genetic aberrations using the fluorescent in situ hybridization (FISH) technique. FISH is time consuming and this tends to hinder its use for looking at large numbers of samples. We are currently developing new technological advances which will increase the speed, clarity and functionality of the FISH technique. These advances include multi-labeled probes, amplification techniques, and separation techniques.

  19. Genetic and epigenetic alterations in pancreatic carcinogenesis.

    Science.gov (United States)

    Delpu, Yannick; Hanoun, Naïma; Lulka, Hubert; Sicard, Flavie; Selves, Janick; Buscail, Louis; Torrisani, Jérôme; Cordelier, Pierre

    2011-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer. These precursor lesions include: Pancreatic intraepithelial neoplasia (PanIN) that are microscopic lesions of the pancreas, Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) that are both macroscopic lesions. However, the cellular origin of these lesions is still a matter of debate. Classically, neoplasm initiation or progression is driven by several genetic and epigenetic alterations. The aim of this review is to assemble the current information on genetic mutations and epigenetic disorders that affect genes during pancreatic carcinogenesis. We will further discuss the interest of the genetic and epigenetic alterations for the diagnosis and prognosis of PDAC. Large genetic alterations (chromosomal deletion/amplification) and single point mutations are well described for carcinogenesis inducers. Mutations classically occur within key regions of the genome. Consequences are various and include activation of mitogenic pathways or silencing of apoptotic processes. Alterations of K-RAS, P16 and DPC4 genes are frequently observed in PDAC samples and have been described to arise gradually during carcinogenesis. DNA methylation is an epigenetic process involved in imprinting and X chromosome inactivation. Alteration of DNA methylation patterns leads to deregulation of gene expression, in the absence of mutation. Both genetic and epigenetic events influence genes and non-coding RNA expression, with dramatic effects on proliferation, survival and invasion. Besides improvement in our fundamental understanding of PDAC development, highlighting the molecular alterations that occur in pancreatic carcinogenesis could

  20. Lymphotoxin prevention of diethylnitrosamine carcinogenesis in vivo.

    Science.gov (United States)

    Ransom, J H; Evans, C H; DiPaolo, J A

    1982-09-01

    Development of intervention measures to control cancer would be facilitated by being able to monitor in vivo carcinogenesis by in vitro quantitation of early indices of neoplastic transformation to assess the in vivo effectiveness of preventive-therapeutic measures. Pregnant Syrian golden hamsters were used in an in vivo-in vitro transplacental model of carcinogenesis to determine the extent that in vivo administration of immunologic hormone preparations along with chemical carcinogen would prevent morphologic transformation assessed in vitro. Pregnant hamsters at 10-11 days of gestation were given injections ip of 3 mg diethylnitrosamine (DENA)/100 g body weight and were killed 2 days later when fetal cells were seeded for colony formation. The frequency of morphologically transformed colonies was assessed after 7 days of growth. Cloning efficiency and mean transformation frequency after DENA exposure were 3.6% and 1 X 10(-4) per cell seeded, respectively. The ip injection of an immunologic hormone preparation reduced the transformation frequency by 46%. The hormone preparation, containing 10,000 U of lymphotoxin but no detectable interferon, was the ultrafiltered lymphokines (greater than 10,000 mol wt) from phytohemagglutinin-stimulated hamster peritoneal leukocytes. The effect of lymphotoxin on cocarcinogenic exposure of fetal cells to DENA in vivo followed by X-irradiation in vitro was also determined. Cells exposed to 250 rad in vitro had a cloning efficiency of 0.5% and a transformation frequency of 0.4 X 10(-4) per cell seeded. After DENA injection and X-irradiation, the transformation frequency increased to 1 X 10(-4) and was inhibited 64% by lymphotoxin in vivo. Thus immunologic hormones (e.g., lymphotoxin) can prevent carcinogenesis in vivo. Furthermore, in vitro quantitation of transformation is a rapid means for evaluating therapeutic and autochthonous effector mechanisms for their ability to prevent or otherwise modulate carcinogenesis in vivo.

  1. Inhibition of carcinogenesis by retinoids. [Review

    Energy Technology Data Exchange (ETDEWEB)

    Nettesheim, P.

    1979-01-01

    Progress made in recent years in the search for retinoids with anticarcinogenic activity is reviewed. There are many studies to be found in the literature which show no substantial effect of retinoids on carcinogenesis or tumor growth. Some of these negative findings may be related to the carcinogen dose used, the type of retinoid used, the dose, dose schedule or mode of administration of the retinoid. Others may indicate that the particular type of tumor or tumor system is, indeed, refractory to retinoids in general or to those retinoids that were tested. A great gap still exists in our knowledge concerning the pharmake-kinetics of most retinoids their availability to various normal and cancerous tissues, and the role and existence of transport and binding proteins. There are studies which indicate that under certain conditions, particularly conditions of topical application, some retinoids may even enhance carcinogenesis. It seems, however, indisputable by now that some retinoids are effective inhibitors of carcinogenesis in some organ systems and can even inhibit the growth of some established tumors. While the mechanisms of these inhibitory effects are presently not understood, it does seem clear that they are not mediated via the cytotoxic mechanisms typical of chemotherapeutic agents. The hope that retinoids might become an effective tool to halt the progression of some neoplastic diseases, seems to be justified.

  2. Poly(ADP-ribosyl)ation in carcinogenesis.

    Science.gov (United States)

    Masutani, Mitsuko; Fujimori, Hiroaki

    2013-12-01

    Cancer develops through diverse genetic, epigenetic and other changes, so-called 'multi-step carcinogenesis', and each cancer harbors different alterations and properties. Here in this article we review how poly(ADP-ribosyl)ation is involved in multi-step and diverse pathways of carcinogenesis. Involvement of poly- and mono-ADP-ribosylation in carcinogenesis has been studied at molecular and cellular levels, and further by animal models and human genetic approaches. PolyADP-ribosylation acts in DNA damage repair response and maintenance mechanisms of genomic stability. Several DNA repair pathways, including base-excision repair and double strand break repair pathways, involve PARP and PARG functions. These care-taker functions of poly(ADP-ribosyl)ation suggest that polyADP-ribosyation may mainly act in a tumor suppressive manner because genomic instability caused by defective DNA repair response could serve as a driving force for tumor progression, leading to invasion, metastasis and relapse of cancer. On the other hand, the new concept of 'synthetic lethality by PARP inhibition' suggests the significance of PARP activities for survival of cancer cells that harbor defects in DNA repair. Accumulating evidence has revealed that some PARP family molecules are involved in various signaling cascades other than DNA repair, including epigenetic and transcriptional regulations, inflammation/immune response and epithelial-mesenchymal transition, suggesting that poly(ADP-ribosyl)ation both promotes and suppresses carcinogenic processes depending on the conditions. Expanding understanding of poly(ADP-ribosyl)ation suggests that strategies to achieve cancer prevention targeting poly(ADP-ribosyl)ation for genome protection against life-long exposure to environmental carcinogens and endogenous carcinogenic stimuli.

  3. Mechanisms of carcinogenesis prevention by flavonoids

    Directory of Open Access Journals (Sweden)

    G. A. Belitsky

    2014-01-01

    Full Text Available The mechanisms of anticancerogenic effects of flavanoids and isocyanates from the plants widely consumed in the midland belt of Russia were reviewed. Data of studies both in vitro and in vivo were analyzed. Special attention was paid to inhibition of targets responsible for carcinogen metabolic activation, carcinogenesis promotion and tumor progression as well as neoangiogenesis. Besides that the antioxidant properties of flavonoids and their effects on cell cycle regulation, apoptosis initiation and cell mobility were considered.

  4. Visceral adiposity in gastrointestinal and hepatic carcinogenesis.

    Science.gov (United States)

    Vongsuvanh, Roslyn; George, Jacob; Qiao, Liang; van der Poorten, David

    2013-03-01

    There is emerging evidence that the association between obesity and cancer is mediated by visceral rather than generalised body fat. Visceral fat has been directly implicated in the risk and progression of several gastrointestinal cancers including colorectal, oesophageal, pancreatic and hepatocellular carcinomas. Excess visceral adipose tissue induces a state of chronic systemic inflammation and altered metabolic activity that promotes a pro-oncogenic environment. This review examines the evidence linking visceral fat in gastrointestinal and hepatic carcinogenesis and explores our current understanding of the mechanisms underlying this relationship. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  5. Liver is a target of arsenic carcinogenesis.

    Science.gov (United States)

    Liu, Jie; Waalkes, Michael P

    2008-09-01

    Inorganic arsenic is clearly a human carcinogen causing tumors of the skin, lung, urinary bladder, and possibly liver (IARC, 2004). At the time of construction of this monograph, the evidence for arsenic as a hepatocarcinogen in humans was considered controversial and in rodents considered insufficient. However, recent data has accumulated indicating hepatocarcinogenicity of arsenic. This forum reevaluates epidemiology studies, rodent studies together with in vitro models, and focuses on the liver as a target organ of arsenic toxicity and carcinogenesis. Hepatocellular carcinoma and hepatic angiosarcoma, have been frequently associated with environmental or medicinal exposure to arsenicals. Preneoplastic lesions, including hepatomegaly, hepatoportal sclerosis, fibrosis, and cirrhosis often occur after chronic arsenic exposure. Recent work in mice clearly shows that exposure to inorganic arsenic during gestation induces tumors, including hepatocellular adenoma and carcinoma, in offspring when they reach adulthood. In rats, the methylated arsenicals, dimethylarsinic acid promotes diethylnitrosamine-initiated liver tumors, whereas trimethylarsine oxide induces liver adenomas. Chronic exposure of rat liver epithelial cells to low concentrations of inorganic arsenic induces malignant transformation, producing aggressive, undifferentiated epithelial tumors when inoculated into the Nude mice. There are a variety of potential mechanisms for arsenical-induced hepatocarcinogenesis, such as oxidative DNA damage, impaired DNA damage repair, acquired apoptotic tolerance, hyperproliferation, altered DNA methylation, and aberrant estrogen signaling. Some of these mechanisms may be liver specific/selective. Overall, accumulating evidence clearly indicates that the liver could be an important target of arsenic carcinogenesis.

  6. Aberrant DNA methylation in cervical carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Hui-Juan Yang

    2013-01-01

    Persistent infection with high-risk types of human papillomavirus(HPV) is known to cause cervical cancer; however,additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer.DNA methylation is an early and frequent molecular alteration in cervical carcinogenesis.In this review,we summarize DNA methylation within the HPV genome and human genome and identify its clinical implications.Methylation of the HPV long control region (LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm.The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression.Moreover,promoters of tumor suppressor genes (TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers.Some are associated with squamous cell carcinomas,and others are associated with adenocarcinomas.Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV,atypical squamous cells of undetermined significance,or low grade squamous intraepithelial lesion (LSIL).However,consistent panels must be validated for this approach to be translated to the clinic.Furthermore,reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment,but demethylating drugs without toxic carcinogenic and mutagenic properties must be identified and validated.

  7. Carcinogenesis--a new point of view.

    Science.gov (United States)

    Gevorkyan, L; Gambashidze, K

    2014-04-01

    Presented article suggests the novel hypothesis of carcinogenesis, where the key moment for all types (biological, physical, chemical) of carcinogenesis has been discussed. For confirmation of the hypothesis thorough theoretical analysis of the mechanisms of malignant transformation of cells after influence of any type of carcinogens and results of experiments have been presented. Hypothesis highlights are formulated as follows: 1) Covalent bond disorders between S+-methionine and Fe3+ atoms in cytochrome; 2) Electron transport chain blockade with certain ligand after its penetration in cytochrome pocket with further formation of 6th coordination bond between ligand and Fe atom (in one case increase in mitochondrial pH precede-, and in other, it follows electron transport chain blockade in cytochromes); 3) Fe3+ reduction up to Fe2+ leading to blockade of aerobic glycolysis; 4) Decrease in enzyme (Е1-TDP, oxidases etc.) activity due to mitochondrial pH alterations; 5) Production of S-adenosylmethionine owing to lipoic acid amide leading to accumulation of homocysteine in cytoplasm with further penetration in cell nucleus producing DNA mutations; 6) Fe2+ wash-out from cytochrome and its deposition in ferritin.

  8. Role of retinoic receptors in lung carcinogenesis

    Directory of Open Access Journals (Sweden)

    Renyi-Vamos Ferenc

    2008-07-01

    Full Text Available Abstract Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies. In this review we have compiled basic and recent knowledge regarding the role of retinoid receptors in lung carcinogenesis. Sensitive and appropriate biological tools are necessary for screening the risk population and monitoring the efficacy of chemoprevention. Investigation of retinoid receptors is important and may contribute to the establishment of new strategies in chemoprevention for high-risk patients and in the treatment of lung cancer.

  9. (Radiation carcinogenesis in the whole body system)

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1990-12-14

    The objectives of the trip were: to take part in and to give the summary of a Symposium on Radiation Carcinogenesis at Tokyo, and to give a talk at the National Institute of Radiological Sciences at Chiba. The breadth of the aspects considered at the conference was about as broad as is possible, from effects at the molecular level to human epidemiology, from the effects of tritium to cancer induction by heavy ions. The events induced by cancer that lead to cancer and the events that are secondary are beginning to come into better focus but much is still not known. Interest in suppressor genes is increasing rapidly in the studies of human tumors and many would predict that the three or four suppressor genes associated with cancer are only the first sighting of a much larger number.

  10. Parasite Infection, Carcinogenesis and Human Malignancy

    Directory of Open Access Journals (Sweden)

    Hoang van Tong

    2017-02-01

    Full Text Available Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity.

  11. Epstein-Barr virus in hepatocellular carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Wei Li; Bao-An Wu; Yong-Ming Zeng; Guang-Can Chen; Xin-Xin Li; Jun-Tian Chen; Yu-Wen Guo; Man-Hong Li; Yi Zeng

    2004-01-01

    AIM: In recent years, studies have suggested that EpsteinBart virus (EBV) is associated with HCC. The present study was to determine the prevalence of EBV in HCC patients,and whether EBV acted synergistically with hepatitis viruses in HCC carcinogenesis.METHODS: Liver tissue 115 HCC patients and 26 noncarcinoma patients were studied. Polymerase chain reaction (PCR) was performed to detect EBV BamHI W DNA, EBV LMP1 DNA, HBV X DNA, and HBV S DNA. Reverse transcription PCR (RT-PCR) was performed to detect HCV RNA and HDV RNA. Immunohistochemistry was performed to detect LMP1,HBsAg, HBcAg and HCV. The positive ratios were compared between HCC group and control group by χ2 test.RESULTS: Totally, 78 HCC samples whose β-globulin DNA was positively detected by amplified PCR were selected.PCR was performed in all cases for EBV DNA and HBV DNA.RT-PCR was performed in 18 cases for HCV RNA and HDV RNA. EBV BanHI W and EBV LMP1 were positive in 18 and 6 cases, respectively. HBV X gene and HBV S gene were positive in 42 and 27 cases respectively. HCV was positive in one of the 18 cases, and none was positive for HDV. The positive rates were 28.2% (22 of 78) for EBV DNA (BamHI W and/or LMP1) and 56.4% (44 of 78) for HBV DNA (X gene and/or S gene) respectively. In addition, 12 cases were positive for both EBV DNA and HBV DNA. Among the 26 cases in the control group, 2 cases were positive for EBV BamHI W, 4positive for HBV X gene and 3 positive for HBV S gene. The positive rates were 8.0% (2 of 26) and 23.1% (6 of 26),respectively, for EBV DNA and HBV DNA. The result of DNA sequencing of BamHI W was 100% homologous with the corresponding sequence of B95-8. There was significant difference in EBV infection rate between HCC patients and controls (χ2 = 4.622, P<0.05). The difference in HBV infection rate was also significant (χ2 = 8.681, P<0.05). However, there was no obvious correlation between HBV and EBV in HCC patients (χ2 = 0.835,P>0.05). LMP1, HBV (HBsAg, HBc

  12. Diet-related DNA adduct formation in relation to carcinogenesis.

    Science.gov (United States)

    Hemeryck, Lieselot Y; Vanhaecke, Lynn

    2016-08-01

    The human diet contributes significantly to the initiation and promotion of carcinogenesis. It has become clear that the human diet contains several groups of natural foodborne chemicals that are at least in part responsible for the genotoxic, mutagenic, and carcinogenic potential of certain foodstuffs. Electrophilic chemicals are prone to attack nucleophilic sites in DNA, resulting in the formation of altered nucleobases, also known as DNA adducts. Since DNA adduct formation is believed to signal the onset of chemically induced carcinogenesis, the DNA adduct-inducing potential of certain foodstuffs has been investigated to gain more insight into diet-related pathways of carcinogenesis. Many studies have investigated diet-related DNA adduct formation. This review summarizes work on known or suspected dietary carcinogens and the role of DNA adduct formation in hypothesized carcinogenesis pathways.

  13. Effect of Dendrobium officinale Extraction on Gastric Carcinogenesis in Rats.

    Science.gov (United States)

    Zhao, Yi; Liu, Yan; Lan, Xi-Ming; Xu, Guo-Liang; Sun, You-Zhi; Li, Fei; Liu, Hong-Ning

    2016-01-01

    Dendrobium officinale (Tie Pi Shi Hu in Chinese) has been widely used to treat different diseases in China. Anticancer effect is one of the important effects of Dendrobium officinale. However, the molecular mechanism of its anticancer effect remains unclear. In the present study, gastric carcinogenesis in rats was used to evaluate the effect of Dendrobium officinale on cancer, and its pharmacological mechanism was explored. Dendrobium officinale extracts (4.8 and 2.4 g/kg) were orally administered to the rats of the gastric carcinogenesis model. Compared with the cancer model group, the high dose of Dendrobium officinale extracts significantly inhibited the rate of carcinogenesis. Further analysis revealed that Dendrobium officinale extracts could regulate the DNA damage, oxidative stress, and cytokines related with carcinogenesis and induce cell apoptosis in order to prevent gastric cancer.

  14. Effect of Dendrobium officinale Extraction on Gastric Carcinogenesis in Rats

    Directory of Open Access Journals (Sweden)

    Yi Zhao

    2016-01-01

    Full Text Available Dendrobium officinale (Tie Pi Shi Hu in Chinese has been widely used to treat different diseases in China. Anticancer effect is one of the important effects of Dendrobium officinale. However, the molecular mechanism of its anticancer effect remains unclear. In the present study, gastric carcinogenesis in rats was used to evaluate the effect of Dendrobium officinale on cancer, and its pharmacological mechanism was explored. Dendrobium officinale extracts (4.8 and 2.4 g/kg were orally administered to the rats of the gastric carcinogenesis model. Compared with the cancer model group, the high dose of Dendrobium officinale extracts significantly inhibited the rate of carcinogenesis. Further analysis revealed that Dendrobium officinale extracts could regulate the DNA damage, oxidative stress, and cytokines related with carcinogenesis and induce cell apoptosis in order to prevent gastric cancer.

  15. Genomic Instability and Colon Carcinogenesis: From the Perspective of Genes

    OpenAIRE

    RAO, CHINTHALAPALLY V.; Yamada, Hiroshi Y.

    2013-01-01

    Colon cancer is the second most lethal cancer; approximately 600,000 people die of it annually in the world. Colon carcinogenesis generally follows a slow and stepwise process of accumulation of mutations under the influence of environmental and epigenetic factors. To adopt a personalized (tailored) cancer therapy approach and to improve current strategies for prevention, diagnosis, prognosis, and therapy overall, advanced understanding of molecular events associated with colon carcinogenesis...

  16. Cell Selection as Driving Force in Lung and Colon Carcinogenesis

    OpenAIRE

    Schöllnberger, Helmut; Beerenwinkel, Niko; Hoogenveen, Rudolf; Vineis, Paolo

    2010-01-01

    Carcinogenesis is the result of mutations and subsequent clonal expansions of mutated, selectively advantageous cells. To investigate the relative contributions of mutation versus cell selection in tumorigenesis, we compared two mathematical models of carcinogenesis in two different cancer types: lung and colon. One approach is based on a population genetics model, the Wright-Fisher process, whereas the other approach is the two-stage clonal expansion model. We compared the dynamics of tumori...

  17. Comfrey (Symphytum officinale. L. and Experimental Hepatic Carcinogenesis: A Short-Term Carcinogenesis Model Study

    Directory of Open Access Journals (Sweden)

    Maria Fernanda Pereira Lavieri Gomes

    2010-01-01

    Full Text Available Comfrey or Symphytum officinale (L. (Boraginaceae is a very popular plant used for therapeutic purposes. Since the 1980s, its effects have been studied in long-term carcinogenesis studies, in which Comfrey extract is administered at high doses during several months and the neoplastic hepatic lesions are evaluated. However, the literature on this topic is very poor considering the studies performed under short-term carcinogenesis protocols, such as the ‘resistant hepatocyte model’ (RHM. In these studies, it is possible to observe easily the phenomena related to the early phases of tumor development, since pre-neoplastic lesions (PNLs rise in about 1–2 months of chemical induction. Herein, the effects of chronic oral treatment of rats with 10% Comfrey ethanolic extract were evaluated in a RHM. Wistar rats were sequentially treated with N-nitrosodiethylamine (ip and 2-acetilaminofluorene (po, and submitted to hepatectomy to induce carcinogenesis promotion. Macroscopic/microscopic quantitative analysis of PNL was performed. Non-parametric statistical tests (Mann–Whitney and χ2 were used, and the level of significance was set at P ≤ 0.05. Comfrey treatment reduced the number of pre-neoplastic macroscopic lesions up to 1 mm (P ≤ 0.05, the percentage of oval cells (P = 0.0001 and mitotic figures (P = 0.007, as well as the number of Proliferating Cell Nuclear Antigen (PCNA positive cells (P = 0.0001 and acidophilic pre-neoplastic nodules (P = 0.05. On the other hand, the percentage of cells presenting megalocytosis (P = 0.0001 and vacuolar degeneration (P = 0.0001 was increased. Scores of fibrosis, glycogen stores and the number of nucleolus organizing regions were not altered. The study indicated that oral treatment of rats with 10% Comfrey alcoholic extract reduced cell proliferation in this model.

  18. Parasite Infection, Carcinogenesis and Human Malignancy.

    Science.gov (United States)

    van Tong, Hoang; Brindley, Paul J; Meyer, Christian G; Velavan, Thirumalaisamy P

    2017-02-01

    Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Wnt signaling and colon carcinogenesis: Beyond APC

    Directory of Open Access Journals (Sweden)

    Rani Najdi

    2011-01-01

    Full Text Available Activation of the Wnt signaling pathway via mutation of the adenomatous polyposis coli gene (APC is a critical event in the development of colon cancer. For colon carcinogenesis, however, constitutive signaling through the canonical Wnt pathway is not a singular event. Here we review how canonical Wnt signaling is modulated by intracellular LEF/TCF composition and location, the action of different Wnt ligands, and the secretion of Wnt inhibitory molecules. We also review the contributions of non-canonical Wnt signaling and other distinct pathways in the tumor micro environment that cross-talk to the canonical Wnt pathway and thereby influence colon cancer progression. These ′non-APC′ aspects of Wnt signaling are considered in relation to the development of potential agents for the treatment of patients with colon cancer. Regulatory pathways that influence Wnt signaling highlight how it might be possible to design therapies that target a network of signals beyond that of APC and β-catenin.

  20. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  1. Stress and radiation carcinogenesis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Kalisnik, M.; Vraspir-Porenta, O.; Kham-Lindtner, T.; Logonder-Mlinsek, M.; Skrk, J.; Pajntar, M. (Ljubljana Univ. (Yugoslavia). Medicinski Fakultet)

    1981-01-01

    In the present experiment irritation consisting of the combination of an optic signal followed by a mild electric shock administered at regular intervals was started in 2 groups of animals at the age of 3 months. At 4 months of age, one of the irritated and one of the non-irritated groups were exposed to whole-body gamma irradiation with 20 daily doses of 0.5 Gy (50 rad), 1.4 Gy/min (140 rad/min), while the other 2 groups were sham-irradiated. The animals were autopsied and the specimens were microscopically studied for the presence of malignant tumors. Malignant tumors particularly involving the testes and lungs, and leukosis were found in 29% of males, whereas in females the tumor incidence with mammary, pulmonary and ovarian involvement and leukosis was 39%. The irradiation decreased the minimum latency time in the irritated males and both female groups. In males, the irritation lowered the cumulative prevalence of malignant tumors, a significant decrease being noted at the age of 15 months. In females, it was increased, with a significant rise observed to occur at the end of the experiment. The opposite effects of irritation on the radiation carcinogenesis in males and females can be attributed to the radiation-induced specific alterations of the gonads in females and, in part, to a longer survival time observed in the irradiated females.

  2. Multistage chemical carcinogenesis in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Slaga, T.J.; Fischer, S.M.; Weeks, C.E.; Klein-Szanto, A.J.P.

    1979-01-01

    Skin tumors in mice can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct acting carcinogen or a procarcinogen which has to be metabolized before being active and is essentially an irreversible step which probably involves a somatic cell mutation. There is a good correlation between the skin tumor initiating activites of several polycyclic aromatic hydrocarbons (PAH) and their ability to bind covalently to epidermal DNA. Laboratory results suggest that bay region diol-epoxides are the ultimate carcinogenic form of PAH carcinogens. Potent inhibitors and stimulators of PAH tumor initiation appear to affect the level of the PAH diol-epoxide reacting with specific DNA bases. Reecent data suggests that the tumor promotion stage involves at least three important steps: (1) the induction of embryonic looking cells (dark cells) in adult epidermis; (2) an increased production of epidermal prostaglandins and polyamines; (3) sustained proliferation of dark cells. Retinoic acid specifically inhibits step two whereas the anti-inflammatory steriod fluocinolone acetonide is a potent inhibitor of steps one and three. The mechanism and the importance of a specific sequence for each step in chemical carcinogenesis in mouse skin are detailed.

  3. From Reliability to Resilience: Modern Challenges of Safety and Reliability Theory and Applications / Od Nieuszkadzalności Do Odporności: Współczesne Wyzwania Teorii i Inżynierii Niezawodności i Bezpieczeństwa

    Directory of Open Access Journals (Sweden)

    Nowakowski Tomasz

    2015-09-01

    Full Text Available Można wyróżnić główne kierunki rozwoju współczesnej teorii niezawodności; niektóre z nich są przedmiotem codziennych działań inżynierskich, jak np.: kontrola jakości w produkcji masowej czy „czysta” analiza niezawodności. Ale większość tych wyzwań, takich jak: efektywność, odporność czy bezpieczeństwo są obecnie przedmiotem wielu prac koncepcyjnych, modelowania i badań. Celem artykułu jest pokazanie jak wymagania w stosunku do osiągów obiektu technicznego były poszerzane o: oczekiwania klienta (jakość, zdolność do zapobiegania utracie właściwości przez obiekt podczas eksploatacji (nieuszkadzalność i obsługiwalność, skutki niepożądanych zdarzeń i ochrona przed nimi (bezpieczeństwo oraz zdolność do odtworzenia osiągów (odporność na zagrożenia.

  4. Magnesium: its role in nutrition and carcinogenesis.

    Science.gov (United States)

    Blaszczyk, Urszula; Duda-Chodak, Aleksandra

    2013-01-01

    Magnesium (Mg2+) plays a key role in many essential cellular processes such as intermediary metabolism, DNA replication and repair, transporting potassium and calcium ions, cell proliferation together with signalling transduction. Dietary sources rich in magnesium are whole and unrefined grains, seeds, cocoa, nuts, almonds and green leafy vegetables. Hard water is also considered to be an important source of magnesium beneficial to human health. The daily dietary intake of magnesium is however frequently found to be below that recommended in Western countries. Indeed, it is recognised that magnesium deficiency may lead to many disorders of the human body, where for instance magnesium depletion is believed to play an important role in the aetiology of the following; cardiovascular disease (including thrombosis, atherosclerosis, ishaemic heart disease, myocardial infarction, hypertension, arrhythmias and congestive heart failure in human), as well as diabetes mellitus, gastrointestinal (GI) tract disease, liver cirrhosis and diseases of the thyroid and parathyroid glands. Insufficient dietary intake of magnesium may also significantly affect the development and exacerbation ofADHD (Attention Deficit- Hyperactivity Disorder) symptoms in children. The known links between magnesium and carcinogenesis still remain unclear and complex, with conflicting results being reported from many experimental, epidemiological and clinical studies; further knowledge is thus required. Mg2+ ions are enzyme cofactors involved in DNA repair mechanisms that maintain genomic stability and fidelity. Any magnesium deficiencies could thereby cause a dysfunction of these systems to occur leading to DNA mutations. Magnesium deficiency may also be associated with inflammation and increased levels of free radicals where both inflammatory mediators and free radicals so arising could cause oxidative DNA damage and therefore tumour formation. The presented review article now provides a summary

  5. Molecular aspects of carcinogenesis in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Alexandros Koliopanos; Constantinos Avgerinos; Constantina Paraskeva; Zisis Touloumis; Dionisisa Kelgiorgi; Christos Dervenis

    2008-01-01

    BACKGROUND: Pancreatic cancer (PCa) is one of the most aggressive human solid tumors, with rapid growth and metastatic spread as well as resistance to chemotherapeutic drugs, leading rapidly to virtually incurable disease. Over the last 20 years, however, signiifcant advances have been made in our understanding of the molecular biology of PCa, with a focus on the cytogenetic abnormalities in PCa cell growth and differentiation. DATA SOURCES: A MEDLINE search and manual cross-referencing were utilized to identify published data for PCa molecular biology studies between 1986 and 2008, with emphasis on genetic alterations and developmental oncology. RESULTS: Activation of oncogenes, deregulation of tumor suppressor and genome maintenance genes, upregulation of growth factors/growth factor receptor signaling cascade systems, and alterations in cytokine expression, have been reported to play important roles in the process of pancreatic carcinogenesis. Alterations in the K-ras proto-oncogene and the p16INK4a, p53, FHIT, and DPC4 tumor suppressor genes occur in a high percentage of tumors. Furthermore, a variety of growth factors are expressed at increased levels. In addition, PCa often exhibits alterations in growth inhibitory pathways and evades apoptosis through p53 mutations and aberrant expression of apoptosis-regulating genes, such as members of the Bcl family. Additional pathways in the development of an aggressive phenotype, local inifltration and metastasis are still under ongoing genetic research. The present paper reviews recent studies on the pathogenesis of PCa, and includes a brief reference to alterations reported for other types of pancreatic tumor. CONCLUSIONS: Advances in molecular genetics and biology have improved our perception of the pathogenesis of PCa. However, further studies are needed to better understand the fundamental changes that occur in PCa, thus leading to better diagnostic and therapeutic management.

  6. Oral Carcinogenesis and Oral Cancer Chemoprevention: A Review

    Directory of Open Access Journals (Sweden)

    Takuji Tanaka

    2011-01-01

    Full Text Available Oral cancer is one of the major global threats to public health. The development of oral cancer is a tobacco-related multistep and multifocal process involving field cancerization and carcinogenesis. The rationale for molecular-targeted prevention of oral cancer is promising. Biomarkers of genomic instability, including aneuploidy and allelic imbalance, are possible to measure the cancer risk of oral premalignancies. Understanding of the biology of oral carcinogenesis will yield important advances for detecting high-risk patients, monitoring preventive interventions, and assessing cancer risk and pharmacogenomics. In addition, novel chemopreventive agents based on molecular mechanisms and targets against oral cancers will be derived from studies using appropriate animal carcinogenesis models. New approaches, such as molecular-targeted agents and agent combinations in high-risk oral individuals, are undoubtedly needed to reduce the devastating worldwide consequences of oral malignancy.

  7. Experimental, statistical, and biological models of radon carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Cross, F.T.

    1991-09-01

    Risk models developed for underground miners have not been consistently validated in studies of populations exposed to indoor radon. Imprecision in risk estimates results principally from differences between exposures in mines as compared to domestic environments and from uncertainties about the interaction between cigarette-smoking and exposure to radon decay products. Uncertainties in extrapolating miner data to domestic exposures can be reduced by means of a broad-based health effects research program that addresses the interrelated issues of exposure, respiratory tract dose, carcinogenesis (molecular/cellular and animal studies, plus developing biological and statistical models), and the relationship of radon to smoking and other copollutant exposures. This article reviews experimental animal data on radon carcinogenesis observed primarily in rats at Pacific Northwest Laboratory. Recent experimental and mechanistic carcinogenesis models of exposures to radon, uranium ore dust, and cigarette smoke are presented with statistical analyses of animal data. 20 refs., 1 fig.

  8. Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants.

    Science.gov (United States)

    Carini, Francesco; Mazzola, Margherita; Rappa, Francesca; Jurjus, Abdo; Geagea, Alice Gerges; Al Kattar, Sahar; Bou-Assi, Tarek; Jurjus, Rosalyn; Damiani, Provvidenza; Leone, Angelo; Tomasello, Giovanni

    2017-09-01

    One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanisms. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documented the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yield definitive results and were performed mostly in vitro on cell populations, or in vivo in experimental animal models. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  9. The Dual Role of Inflammation in Colon Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Carmine Stolfi

    2012-09-01

    Full Text Available Chronic inflammation characterizing patients with inflammatory bowel disease (IBD represents a major risk factor for the development of colorectal cancer. Mechanisms underlying this neoplastic transformation are not fully understood though studies in experimental models of colon carcinogenesis suggest that inflammatory cell-derived cytokines either directly or indirectly stimulate the uncontrolled growth of cancer cells. Nevertheless, under specific inflammatory conditions, immune cells can boost an anti-tumor immune response with the down-stream effect of eliminating dysplastic and cancerous cells. This review outlines the beneficial and detrimental role of inflammation in colon carcinogenesis.

  10. Hypoxia and cell cycle deregulation in endometrial carcinogenesis

    NARCIS (Netherlands)

    Horrée, N.

    2007-01-01

    Because uterine endometrial carcinoma is the most common malignancy of the female genital tract and 1 of every 5 patients dies of this disease, understanding the mechanisms of carcinogenesis and progression of endometrial carcinoma is important. In general, this thesis can be summarized as a study o

  11. Role of colonic microbiota in colorectal carcinogenesis: a systematic review

    Directory of Open Access Journals (Sweden)

    Marta Borges-Canha

    2015-11-01

    Full Text Available Background and aim: The human colonic mucosa is populated by a wide range of microorganisms, usually in a symbiotic relation with the host. Sometimes this balance is lost and a state of dysbiosis arises, exposing the colon to different metabolic and inflammatory stimuli (according to the microbiota's changing profile. Recent findings lead to hypothesize that this unbalance may create a subclinical pro-inflammatory state that increases DNA mutations and, therefore, colorectal carcinogenesis. In this article we aim to systematically review the scientific evidence regarding colonic microbiota and its role in colorectal carcinogenesis. Methods: Systematic review of PubMed searching results for original articles studying microbiota and colorectal cancer until November 2014. Results: Thirty-one original articles studied the role of colon microbiota in colorectal carcinoma including both human and animal studies. Different and heterogeneous methods were used and different bacteria were considered. Nevertheless, some bacteria are consistently augmented (such as Fusobacteria, Alistipes, Porphyromonadaceae, Coriobacteridae, Staphylococcaceae, Akkermansia spp. and Methanobacteriales, while other are constantly diminished in colorectal cancer (such as Bifidobacterium, Lactobacillus, Ruminococcus, Faecalibacterium spp., Roseburia, and Treponema. Moreover, bacteria metabolites amino acids are increased and butyrate is decreased throughout colonic carcinogenesis. Conclusion: Conclusive evidence shows that colorectal carcinogenesis is associated with microbial dysbiosis. This information may be used to create new prophylactic, diagnostic and therapeutic strategies for colorectal cancer.

  12. The glutathione biotransformation system and colon carcinogenesis in human

    NARCIS (Netherlands)

    Grubben, M.J.A.L.; Nagengast, F.M.; Katan, M.B.; Peters, W.H.M.

    2001-01-01

    Evidence for a protective role of the glutathione biotransformation system in carcinogenesis is growing. However, most data on this system in relation to colorectal cancer originate from animal studies. Here we review the human data. In humans, a significant association was found between glutathione

  13. Carcinogenesis explained within the context of a theory of organisms.

    Science.gov (United States)

    Sonnenschein, Carlos; Soto, Ana M

    2016-10-01

    For a century, the somatic mutation theory (SMT) has been the prevalent theory to explain carcinogenesis. According to the SMT, cancer is a cellular problem, and thus, the level of organization where it should be studied is the cellular level. Additionally, the SMT proposes that cancer is a problem of the control of cell proliferation and assumes that proliferative quiescence is the default state of cells in metazoa. In 1999, a competing theory, the tissue organization field theory (TOFT), was proposed. In contraposition to the SMT, the TOFT posits that cancer is a tissue-based disease whereby carcinogens (directly) and mutations in the germ-line (indirectly) alter the normal interactions between the diverse components of an organ, such as the stroma and its adjacent epithelium. The TOFT explicitly acknowledges that the default state of all cells is proliferation with variation and motility. When taking into consideration the principle of organization, we posit that carcinogenesis can be explained as a relational problem whereby release of the constraints created by cell interactions and the physical forces generated by cellular agency lead cells within a tissue to regain their default state of proliferation with variation and motility. Within this perspective, what matters both in morphogenesis and carcinogenesis is not only molecules, but also biophysical forces generated by cells and tissues. Herein, we describe how the principles for a theory of organisms apply to the TOFT and thus to the study of carcinogenesis.

  14. Carcinogenesis related to intense pulsed light and UV exposure

    DEFF Research Database (Denmark)

    Hedelund, L; Lerche, C; Wulf, H C;

    2006-01-01

    This study examines whether intense pulsed light (IPL) treatment has a carcinogenic potential itself or may influence ultraviolet (UV)-induced carcinogenesis. Secondly, it evaluates whether UV exposure may influence IPL-induced side effects. Hairless, lightly pigmented mice (n=144) received three...

  15. Biomolecular and epidemiological aspects of human papillomavirus induced cervical carcinogenesis

    NARCIS (Netherlands)

    Vermeulen, Christine Frederike Wilhelmine

    2007-01-01

    Cervical cancer remains one of the leading causes of death from cancer among women worldwide. Organised screening programmes aim to trace precursor lesions in order to reduce cervical cancer incidence. Human papillomavirus (HPV) is a necessary cause for cervical carcinogenesis. Most HPV infections a

  16. Oxidative stress and inflammation in liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Natalia Olaya

    2007-02-01

    series of transcription factors. Moreover, in addition to direct production of ROS by these pathogens, liver infiltration by activated phagocytic cells provides an additional source of ROS production that promotes oxidative stress via interleukin or NO production that can damage proteins, lipids and DNA.

    Nuclear MSI was demonstrated first in familial hereditary colorectal cancer (HNPCC and then in sporadic cancers, primarily digestive tract cancers such as colorectal, gastric and pancreatic cancers.In HCC, although nuclear MSI has been shown in some studies (15,18, there is as yet no direct evidence of alteration of the MMR genes and the biological and the clinicopathological significance of the lowlevel MSI seen in HCC is unclear. MSI has also been shown to occur in inflammatory tissues such as chronic hepatitis and cirrhosis as well as in ulcerative colitis, chronic pancreatitis and in non digestive inflammatory diseases such as rheumatoid arthritis.

    Recently, the role of mitochondria in carcinogenesis has been under numerous investigation, in part because their prominent role in apoptosis, ROS production and other aspects of tumour biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of ROS generation in this organelle, coupled with a relatively low level of DNA repair. Somatic mutations of mitochondrial DNA (mtDNA have been shown in HCC as was also observed MSI. These findings suggest a potential role for mitochondrial genome instability in the early steps of tumorigenesis.

    Ischemia-reperfusion injury can occur in several situations and is a major cause of cell damage during surgery. Cells and tissues subjected to hypoxia by prolonged ischemia become acidic

  17. Cervical Carcinogenesis and Immune Response Gene Polymorphisms: A Review

    Directory of Open Access Journals (Sweden)

    Akash M. Mehta

    2017-01-01

    Full Text Available The local immune response is considered a key determinant in cervical carcinogenesis after persistent infection with oncogenic, high-risk human papillomavirus (HPV infections. Genetic variation in various immune response genes has been shown to influence risk of developing cervical cancer, as well as progression and survival among cervical cancer patients. We reviewed the literature on associations of immunogenetic single nucleotide polymorphism, allele, genotype, and haplotype distributions with risk and progression of cervical cancer. Studies on HLA and KIR gene polymorphisms were excluded due to the abundance on literature on that subject. We show that multiple genes and loci are associated with variation in risk of cervical cancer. Rather than one single gene being responsible for cervical carcinogenesis, we postulate that variations in the different immune response genes lead to subtle differences in the effectiveness of the antiviral and antitumour immune responses, ultimately leading to differences in risk of developing cervical cancer and progressive disease after HPV infection.

  18. Cervical Carcinogenesis and Immune Response Gene Polymorphisms: A Review

    Science.gov (United States)

    Mooij, Merel

    2017-01-01

    The local immune response is considered a key determinant in cervical carcinogenesis after persistent infection with oncogenic, high-risk human papillomavirus (HPV) infections. Genetic variation in various immune response genes has been shown to influence risk of developing cervical cancer, as well as progression and survival among cervical cancer patients. We reviewed the literature on associations of immunogenetic single nucleotide polymorphism, allele, genotype, and haplotype distributions with risk and progression of cervical cancer. Studies on HLA and KIR gene polymorphisms were excluded due to the abundance on literature on that subject. We show that multiple genes and loci are associated with variation in risk of cervical cancer. Rather than one single gene being responsible for cervical carcinogenesis, we postulate that variations in the different immune response genes lead to subtle differences in the effectiveness of the antiviral and antitumour immune responses, ultimately leading to differences in risk of developing cervical cancer and progressive disease after HPV infection. PMID:28280748

  19. Experimental Hepatic Carcinogenesis: Oxidative Stress and Natural Antioxidants

    Directory of Open Access Journals (Sweden)

    Velid Unsal

    2017-08-01

    Full Text Available Hepatocellular carcinoma is one of the most common cancers in the world, and it is influenced by agents such as DEN, 2-AAF, phenobarbital, alcohol, aflatoxin B1 metabolite or hepatitis viruses (B and C. Oxidative stress is becoming recognized as a key factor in the progression of hepatocarcinogenesis. Reactive oxygen species can play a leading role in initiation and promotion of hepatic carcinogenesis. The metabolites of DEN Diethylnitrosamine (DEN mediate the binding of tumour promoters by covalently binding to the DNA with one or two oxidation-providing electrons. 2-AAF is the inducer of DEN, and it is involved in tumour formation in the bladder and liver. Reactive Oxygen species (ROS; carbohydrates, lipids, DNA and enzymes, such as affect all important structures. Additionally, an excessive amount of ROS is highly toxic to cells. Antioxidants are protects against ROS, toxic substances, carcinogens. This review focuses on the literature on studies of Hepatic Carcinogenesis, oxidative stress and antioxidant therapy.

  20. Plastics and carcinogenesis: The example of vinyl chloride

    Directory of Open Access Journals (Sweden)

    Paul Wesley Brandt-Rauf

    2012-01-01

    Full Text Available The manufacture, use and disposal of various plastics can pose numerous health risks, including the risk of cancer. A model example of carcinogenic risk from plastics is provided by polyvinyl chloride, since it is composed of the known human carcinogen vinyl chloride (VC. In recent years, much has been learned about the molecular biological pathways of VC carcinogenesis. This has led to molecular epidemiologic studies of VC carcinogenesis in exposed human populations which have identified useful biomarkers of exposure, effect and susceptibility for VC. These studies have in turn provided the basis for new molecular approaches for the prevention and treatment of VC cancers. This model could have much wider applicability for many other carcinogenic exposures and many other human cancers.

  1. Mathematical Modeling of Carcinogenesis Based on Chromosome Aberration Data

    Institute of Scientific and Technical Information of China (English)

    Xiao-bo Li

    2009-01-01

    Objective: The progression of human cancer is characterized by the accumulation of genetic instability. An increasing number of experimental genetic molecular techniques have been used to detect chromosome aberrations. Previous studies on chromosome abnormalities often focused on identifying the frequent loci of chromosome alterations, but rarely addressed the issue of interrelationship of chromosomal abnormalities. In the last few years, several mathematical models have been employed to construct models of carcinogenesis, in an attempt to identify the time order and cause-and-effect relationship of chromosome aberrations. The principles and applications of these models are reviewed and compared in this paper. Mathematical modeling of carcinogenesis can contribute to our understanding of the molecular genetics of tumor development, and identification of cancer related genes, thus leading to improved clinical practice of cancer.

  2. The Thymus in Experimental Mammary Carcinogenesis and Polychemotherapy.

    Science.gov (United States)

    Kazakov, O V; Kabakov, A V; Ishchenko, I Yu; Poveshchenko, A F; Raiter, T V; Strunkin, D N; Michurina, S V; Konenkov, V I

    2017-02-01

    Histological study of structural transformations in the thymus of Wistar females in induced carcinogenesis (N-methyl-N-nitrosourea injection in the right 2-nd mamma) and polychemotherapy (6 months after tumor growth initiation; cyclophosphamide, methotrexate, and 5-fluorouracyl) was carried out. The area of the cortical matter in the thymus decreased 6 months after carcinogenesis induction, the percentage of connective tissue elements and glandular tissue and the counts of immunoblasts and cells with pyknotic nuclei increased, this indicating the development of accidental involution of the thymus. Animals of the experimental tumor+chemotherapy group exhibited morphological signs of lymphocyte migration from the thymus and suppressed activities of the lymphoid and epithelial components (lesser area of connective tissue elements and glandular tissue, lesser density of parenchymatous cell elements, lesser counts of immunoblasts and small lymphocytes, and larger area of the medulla) in comparison with animals without chemotherapy.

  3. Epigenetic targets of arsenic: emphasis on epigenetic modifications during carcinogenesis.

    Science.gov (United States)

    Roy, Ram Vinod; Son, Young-Ok; Pratheeshkumar, Poyil; Wang, Lei; Hitron, John Andrew; Divya, Sasidharan Padmaja; D, Rakesh; Kim, Donghern; Yin, Yuanqin; Zhang, Zhuo; Shi, Xianglin

    2015-01-01

    DNA methylation and histone modification promote opening and closure of chromatin structure, which affects gene expression without altering the DNA sequence. Epigenetic markers regulate the dynamic nature of chromatin structure at different levels: DNA, histone, noncoding RNAs, as well as the higher-order chromatin structure. Accumulating evidence strongly suggests that arsenic-induced carcinogenesis involves frequent changes in the epigenetic marker. However, progress in identifying arsenic-induced epigenetic changes has already been made using genome-wide approaches; the biological significance of these epigenetic changes remains unknown. Moreover, arsenic-induced changes in the chromatin state alter gene expression through the epigenetic mechanism. The current review provides a summary of recent literature regarding epigenetic changes caused by arsenic in carcinogenesis. We highlight the transgenerational studies needed to explicate the biological significance and toxicity of arsenic over a broad spectrum.

  4. Inhibitory effects of acetylsalicylic acid on exocrine pancreatic carcinogenesis.

    Science.gov (United States)

    Yıldız, H; Oztas, H; Yıldız, D; Koc, A; Kalipci, E

    2013-05-01

    We investigated short (6 months) and long (12 months) term inhibitory effects of low (200 ppm) and high (400 ppm) dosages of acetylsalicylic acid (aspirin) on exocrine pancreatic carcinogenesis. It is known that exocrine pancreatic carcinogenesis can be detected by the presence of atypical acinar cell foci (AACF) in pancreas. We investigated possible inhibitory effects of acetylsalicylic acid in an azaserine-treated rat model. AACF were produced in rats by injection with azaserine according to previous studies. Our findings showed that the number, volume and diameter of pancreatic AACF were reduced after acetylsalicylic acid application. These observations suggest that acetylsalicylic acid may exert a protective effect against neoplastic development of pancreatic acinar cells in azaserine injected rats. Our findings corroborate reports in the literature concerning the effects of aspirin in reducing neoplastic development.

  5. TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis.

    Science.gov (United States)

    Hatakeyama, Shigetsugu

    2017-04-01

    Tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activities, have various functions in cellular processes including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. The ubiquitin system is one of the systems for post-translational modifications, which play crucial roles not only as markers for degradation of target proteins by the proteasome but also as regulators of protein-protein interactions and of the activation of enzymes. Accumulating evidence has shown that TRIM family proteins have unique, important roles and that their dysregulation causes several diseases classified as cancer, immunological disease, or developmental disorders. In this review we focus on recent emerging topics on TRIM proteins in the regulation of autophagy, innate immunity, and carcinogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. The Role of Ubiquitine Proteasome Pathway in Carcinogenesis

    Directory of Open Access Journals (Sweden)

    N.Ceren Sumer Turanligil

    2010-02-01

    Full Text Available Ubiquitin works as a marker protein which targets misfolded or injured proteins to cellular degradation. It brings the abnormal proteins to a subcellular organelle named proteasome and it maintains the degradation of proteins in limited lenghts of peptides by leaving the process withuout being changed. Mistakes in ubiquitin-dependent proteolysis in various steps of carcinogenesis is known. In this review, we dealed with the effects of ubiquitin-proteasome pathway (UPP on carcinogenesis via intercellular signaling molecules like Ras, transcription factors like NF-kB, cytokines like TNF-alfa Tumor necrosis factor, protooncogenes like p53 and MDM2(murine double minute 2, components of cell cycle and DNA repair proteins like BRCA1. We also focused on the relationship of UPP on antigen presentation which is active in immune response and its place in the aetiology of colon cancer to provide a specific example. [Archives Medical Review Journal 2010; 19(1.000: 36-55

  7. Role of oxidative stress in cadmium toxicity and carcinogenesis

    OpenAIRE

    2009-01-01

    Cadmium (Cd) is a toxic metal, targeting the lung, liver, kidney, and testes following acute intoxication, and causing nephrotoxicity, immunotoxicity, osteotoxicity and tumors after prolonged exposures. Reactive oxygen species (ROS) are often implicated in Cd toxicology. This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis. Cd-generated superox...

  8. Transcriptional regulation of cadherins during development and carcinogenesis

    OpenAIRE

    2004-01-01

    The cadherin superfamily of Ca2+-dependent homophilic adhesion molecules plays a critical role in regulating cell-to-cell interactions. During development, the expression of different cadherins is highly dynamic, since they are associated with the morphogenesis, establishment and/or maintenance of different tissues. Alterations in cadherin expression or function occur frequently during carcinogenesis, such as the loss of the epithelial cadherin (E-cadherin) and/or the aberrant expression of o...

  9. Colon epithelial proliferation and carcinogenesis in diet-induced obesity.

    Science.gov (United States)

    Takahashi, Hirokazu; Hosono, Kunihiro; Endo, Hiroki; Nakajima, Atsushi

    2013-12-01

    Colorectal cancer is the third leading cause of cancer death in Japan and the United States and is strongly associated with obesity, especially visceral obesity. Several metabolic mediators, such as adiponectin, have been suspected to play a role in obesity-related carcinogenesis. In a previous human study, the existence of a significant correlation between the number of human dysplastic aberrant crypt foci (ACF) and the visceral fat area was demonstrated, and also that of a significant inverse correlation between the number of dysplastic ACF and the plasma adiponectin level. Other studies have investigated the effect of adiponectin under the normal and high-fat diet conditions in a mouse model of azoxymethane-induced colon cancer. Enhanced formation of both ACF and tumors was observed in the adiponectin-deficient mice, as compared with that in the wild-type, under the high-fat diet condition but not under the normal diet condition. Furthermore, that the 5'-AMP-activated kinase/mammalian target of rapamycin pathway is involved in the promotion of colorectal carcinogenesis in adiponectin-deficient mice under the high-fat diet condition was shown. Therefore, that the 5'-AMP-activated kinase/mammalian target of rapamycin signaling pathway may play an important role in colorectal carcinogenesis was speculated. Metformin, a biguanide derivative widely used in the treatment of diabetes mellitus, has been shown to exert a suppressive effect on ACF formation in both mouse models and humans. Therefore, metformin might be a promising candidate as a safe drug for chemoprevention of colorectal carcinogenesis. Further studies with high evidence levels, such as randomized, controlled studies, are needed to clarify these relationships. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  10. Experimental gastric carcinogenesis in Cebus apella nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Joana de Fátima Ferreira Borges da Costa

    Full Text Available The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU. Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9(th day though on the 14(th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940(th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the

  11. Dose-response relationship in multistage carcinogenesis: promoters.

    OpenAIRE

    Kitchin, K T; Brown, J. L.; Setzer, R.W.

    1994-01-01

    Published dose-response curves of promoters of multistage carcinogenesis were selected that met the combined criteria of long study times, multiple doses, and low doses. In rat liver, 12 dose-response studies of 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta-, and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected. These promoters were studied for 7-86 weeks and either altered hepatic foci...

  12. Modulation of carcinogenesis in the urinary bladder by retinoids.

    Science.gov (United States)

    Hicks, R M; Turton, J A; Chowaniec, J; Tomlinson, C N; Gwynne, J; Nandra, K; Chrysostomou, E; Pedrick, M

    1985-01-01

    Bladder cancer has a 70% recurrence rate within five years and a high associated mortality. It commonly occurs in one or both of two predominant growth/behaviour patterns: either well-differentiated, relatively benign exophytic papillary lesions, or flat, poorly differentiated invasive carcinoma usually arising from carcinoma-in-situ. We have used the F344 rat treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as a model for the papillary disease, and the BBN-treated B6D2F1 mouse for flat, invasive bladder carcinoma. In the rat, carcinogenesis is a multistage process and several retinoids will delay or even halt the development of bladder cancer. Inhibition of carcinogenesis is not complete, but there is a consistent reduction in the time-related incidence of papillomas and carcinomas and a concomitant improvement in the overall differentiation of the urothelium. In the BBN/mouse model, retinoids also have anticarcinogenic activity but interpretation of the results is more complicated. Unlike the F344 rat, the B6D2F1 mouse has a non-uniform response to BBN; not all mice develop bladder cancer even after treatment with very high doses of BBN and in those that do, more than one mechanism of carcinogenesis may be involved. Individual retinoids differ markedly in their ability to modulate bladder carcinogenesis in rodents; the behaviour of one analogue cannot be predicted automatically from data obtained with another. Combined data from rodent trials in this and other laboratories have identified N-(4-hydroxyphenyl)retinamide (HPR) as the most anticarcinogenic retinoid tested so far for the rodent bladder. It is also less toxic in rodents and better tolerated in humans than either 13-cis-retinoic acid or etretinate, two retinoids currently used in dermatological practice. A prophylactic chemopreventive trial of HPR in bladder cancer patients starting in 1985 will be centered on the Middlesex Hospital, London.

  13. Experimental Gastric Carcinogenesis in Cebus apella Nonhuman Primates

    Science.gov (United States)

    Silva, Tanielly Cristina Raiol; Andrade Junior, Edilson Ferreira; Rezende, Alexandre Pingarilho; Carneiro Muniz, José Augusto Pereira; Lacreta Junior, Antonio Carlos Cunha; Assumpção, Paulo Pimentel; Calcagno, Danielle Queiroz; Demachki, Samia; Rabenhorst, Silvia Helena Barem; Smith, Marília de Arruda Cardoso; Burbano, Rommel Rodriguez

    2011-01-01

    The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9th day though on the 14th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and

  14. Midkine translocated to nucleoli and involved in carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Li-Cheng Dai

    2009-01-01

    Midkine (MK) is a heparin-binding growth factor with its gene first identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation.MK is frequently and highly expressed in a variety of human carcinomas. Furthermore, the blood MK level is frequently elevated with advance of human carcinomas, decreased after surgical removal of the tumors. Thus, it is expected to become a promising marker for evaluating the progress of carcinomas.There is mounting evidence that MK plays a significant role in carcinogenesis-related activities, such as proliferation, migration, anti-apoptosis, mitogenesis,transforming, and angiogenesis. In addition, siRNA and anti-sense oligonucleotides for MK have yielded great effects in anti-tumor activities. Therefore, MK appears to be a potential candidate molecular target of therapy for human carcinomas. In this paper, we review MK targeting at nucleoli in different tumor cells and its role in carcinogenesis to deepen our understanding of the mechanism of MK involved in carcinogenesis.

  15. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.

    Science.gov (United States)

    Li, Wenjuan; Zhang, Chunjing; Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

  16. EXPRESSION OF GST-π GENE IN HUMAN ESOPHAGEAL CARCINOGENESIS

    Institute of Scientific and Technical Information of China (English)

    FU Baojin; ZHANG Yunhan; WANG Yaohe; GAO Dongling; FU Shuli; WEN Xiaogang; ZHANG Sanshen; WANG Jiang

    1999-01-01

    Objective: To investigate the possible role of GSTπ in esophageal carcinogenesis. Methods: GST-πexpression at mRNA level was studied by in situ hybridization (ISH) and at protein level by immunohistochemistry (IHC). GST-π expression in normal epithelial cells (NC) of the esophagus,hyperplastic cells (HC), dysplastic cells (DC) from grade Ⅰ to Ⅲ, carcinoma in situ (CIS) and all the cells in squamous cell carcinomas (SCC) were examined in the same esophageal cancer specimens (n=48) which provided a model reflecting the process of esophageal carcinogenesis. Results: The positive rate of IHC staining was 87. 5% for NC, 95.3% for HC, 55.9% for DC (grade Ⅰ: 73.9%, grade Ⅱ: 47.4%, grade Ⅲ: 41.2%),36.4% for CIS and 45.8% for SCC. The positive rate of GST-π mRNA expression was 81.2% for NC, 94.4% for HC, 61.9% for DC (grade Ⅰ: 76.5%, grade Ⅱ: 61.5%,grade Ⅲ: 41.7%), 44.4% for CIS and 83.3% for grade ⅠSCC, 30.0% for grade Ⅱ SCC and 0% for grade ⅢSCC. There was no statistically significant difference in GST-π expression at the mRNA and the protein level.Conclusion: There is a decreasing tendency of GST-πexpression from dysplasia to CIS and SCC. The decrease in GST-π expression is an early event in esophageal carcinogenesis.

  17. Carcinogenesis related to intense pulsed light and UV exposure

    DEFF Research Database (Denmark)

    Hedelund, L; Lerche, C; Wulf, H C;

    2006-01-01

    This study examines whether intense pulsed light (IPL) treatment has a carcinogenic potential itself or may influence ultraviolet (UV)-induced carcinogenesis. Secondly, it evaluates whether UV exposure may influence IPL-induced side effects. Hairless, lightly pigmented mice (n=144) received three...... observation period. Side effects were evaluated clinically. No tumors appeared in untreated control mice or in just IPL-treated mice. Skin tumors developed in UV-exposed mice independently of IPL treatments. The time it took for 50% of the mice to first develop skin tumor ranged from 47 to 49 weeks...

  18. Iron:An emerging factor in colorectal carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Anita; CG; Chua; Borut; Klopcic; Ian; C; Lawrance; John; K; Olynyk; Debbie; Trinder

    2010-01-01

    The carcinogenic potential of iron in colorectal cancer(CRC) is not fully understood.Iron is able to undergo reduction and oxidation,making it important in many physiological processes.This inherent redox property of iron,however,also renders it toxic when it is present in excess.Iron-mediated generation of reactive oxygen species via the Fenton reaction,if uncontrolled,may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage.This may promote carcinogenesis through incr...

  19. Contribution of bone marrow derived cells to pancreatic carcinogenesis

    Directory of Open Access Journals (Sweden)

    Christopher J Scarlett

    2013-03-01

    Full Text Available Pancreatic cancer is a complex, aggressive and heterogeneous malignancy driven by the multifaceted interactions within the tumor microenvironment. While it is known that the tumor microenvironment accommodates many cell types, each playing a key role in tumorigenesis, the major source of these stromal cells is not well understood. This review examines the contribution of bone marrow-derived cells (BMDC to pancreatic carcinogenesis, with respect to their role in constituting the tumor microenvironment. In particular, their role in supporting fibrosis, immunosuppression and neovascularisation will be discussed.

  20. Transcriptional regulation of cadherins during development and carcinogenesis.

    Science.gov (United States)

    Peinado, Héctor; Portillo, Francisco; Cano, Amparo

    2004-01-01

    The cadherin superfamily of Ca(2+)-dependent homophilic adhesion molecules plays a critical role in regulating cell-to-cell interactions. During development, the expression of different cadherins is highly dynamic, since they are associated with the morphogenesis, establishment and/or maintenance of different tissues. Alterations in cadherin expression or function occur frequently during carcinogenesis, such as the loss of the epithelial cadherin (E-cadherin) and/or the aberrant expression of other cadherins. Indeed, the aberrant expression of cadherins has been detected during carcinoma invasion, a process which is reminiscent of the epithelial-mesenchymal transition (EMT) so important in many critical developmental processes. The functional regulation of cadherins can occur at many different levels, from transcriptional regulation to the control of the strength of the cadherin-mediated cell-cell interaction. In this review, we will focus on the transcriptional control of cadherin expression, both in development and carcinogenesis, paying particular attention to the regulation of E-cadherin given its proposed role as a suppressor of invasion. We will discuss the main genetic and epigenetic mechanisms involved in down-regulating E-cadherin expression, and we will analyse the mechanisms involved in regulating EMT, in an attempt to elucidate which elements are common to this process in both physiological and pathological situations.

  1. Chemoprevention of rat liver toxicity and carcinogenesis by Spirulina.

    Science.gov (United States)

    Ismail, Mohamed F; Ali, Doaa A; Fernando, Augusta; Abdraboh, Mohamed E; Gaur, Rajiv L; Ibrahim, Wael M; Raj, Madhwa H G; Ouhtit, Allal

    2009-06-02

    Spirulina platensis (SP) is a filamentous cyanobacterium microalgae with potent dietary phyto-antioxidant, anti-inflammatory and anti-cancerous properties. The present study aimed to investigate the chemopreventive effect of SP against rat liver toxicity and carcinogenesis induced by dibutyl nitrosamine (DBN) precursors, and further characterized its underlying mechanisms of action in HepG2 cell line. Investigation by light and electron microscopy showed that DBN treatment induced severe liver injury and histopathological abnormalities, which were prevented by SP supplementation. The incidence of liver tumors was significantly reduced from 80 to 20% by SP. Immunohistochemical results indicated that both PCNA and p53 were highly expressed in the liver of DBN-treated rats, but were significantly reduced by SP supplementation. Molecular analysis indicated that SP treatment inhibited cell proliferation, which was accompanied by increased p21 and decreased Rb expression levels at 48hrs post-treatment. In addition, SP increased Bax and decreased Bcl-2 expression, indicating induction of apoptosis by 48hrs. This is the first report of the in vivo chemopreventive effect of SP against DBN-induced rat liver cytotoxicity and carcinogenesis, suggesting its potential use in chemoprevention of cancer.

  2. Thrombospondin-1 in a Murine Model of Colorectal Carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Zenaida P Lopez-Dee

    Full Text Available Colorectal Cancer (CRC is one of the late complications observed in patients suffering from inflammatory bowel diseases (IBD. Carcinogenesis is promoted by persistent chronic inflammation occurring in IBD. Understanding the mechanisms involved is essential in order to ameliorate inflammation and prevent CRC. Thrombospondin 1 (TSP-1 is a multidomain glycoprotein with important roles in angiogenesis. The effects of TSP-1 in colonic tumor formation and growth were analyzed in a model of inflammation-induced carcinogenesis. WT and TSP-1 deficient mice (TSP-1-/- of the C57BL/6 strain received a single injection of azoxymethane (AOM and multiple cycles of dextran sodium sulfate (DSS to induce chronic inflammation-related cancers. Proliferation and angiogenesis were histologically analyzed in tumors. The intestinal transcriptome was also analyzed using a gene microarray approach. When the area containing tumors was compared with the entire colonic area of each mouse, the tumor burden was decreased in AOM/DSS-treated TSP-1-/- versus wild type (WT mice. However, these lesions displayed more angiogenesis and proliferation rates when compared with the WT tumors. AOM-DSS treatment of TSP-1-/- mice resulted in significant deregulation of genes involved in transcription, canonical Wnt signaling, transport, defense response, regulation of epithelial cell proliferation and metabolism. Microarray analyses of these tumors showed down-regulation of 18 microRNAs in TSP-1-/- tumors. These results contribute new insights on the controversial role of TSP-1 in cancer and offer a better understanding of the genetics and pathogenesis of CRC.

  3. [THE ROLE OF ESTROGENS IN THE CARCINOGENESIS OF LUNG CANCER].

    Science.gov (United States)

    Uchikova, E; Uchikov, A; Dimitrakova, E; Uchikov, P

    2016-01-01

    Morbidity and mortality from lung cancer has dramatically increased in women as compared to men over the past few years. Historically, smoking has been considered the major risk factor for lung cancer regardless of gender. Several recent lines of evidence implicate gender differences in the observed differences in prevalence and histologic type which cannot be explained based on the carcinogenic action of nicotine. Several recent studies underscore the importance of reproductive and hormonal factors in the carcinogenesis of lung cancer Lung cancer morbidity and mortality in Bulgaria was 16.2/100000 women and 14.6/ 100000 women, resp. Lung cancer morbidity in Europe was 39/100000 women. Lung cancer is extremely sensitive to estrogens. The latter act directly or as effect modifiers for the relationship between smoking and lung cancer. Further research examining the relationship between serum estrogen levels and the estrogen receptor expression in normal and tumor lung tissue samples can help elucidate the importance of reproductive and hormonal (exogenous and endogenous) factors in the carcinogenesis of lung cancer.

  4. Langerhans Cells Facilitate UVB-induced Epidermal Carcinogenesis

    Science.gov (United States)

    Lewis, Julia M.; Bürgler, Christina D.; Freudzon, Marianna; Golubets, Kseniya; Gibson, Juliet F.; Filler, Renata B.; Girardi, Michael

    2015-01-01

    Ultraviolet B (UVB) light is considered the major environmental inducer of human keratinocyte DNA mutations, including within the tumor-suppressor gene p53, and chronic exposure is associated with cutaneous squamous cell carcinoma (SCC) formation. Langerhans cells (LC) comprise a dendritic network within the suprabasilar epidermis, yet the role of LC in UVB-induced carcinogenesis is largely unknown. Herein, we show that LC-intact epidermis develops UVB-induced tumors more readily than LC-deficient epidermis. While levels of epidermal cyclopyrimidine dimers (CPD) following acute UVB exposure are equivalent in the presence or absence of LC, chronic UVB-induced p53 mutant clonal islands expand more readily in association with LC which remain largely intact and are preferentially found in proximity to the expanding mutant keratinocyte populations. The observed LC facilitation of mutant p53 clonal expansion is completely αβ and γδ T-cell independent, and is associated with increased intraepidermal expression of interleukin (IL)-22 and the presence of group 3 innate lymphoid cells (ILC3). These data demonstrate that LC play a key role in UVB-induced cutaneous carcinogenesis, and suggest that LC locally stimulate keratinocyte proliferation and innate immune cells that provoke tumor outgrowth. PMID:26053049

  5. Viral Carcinogenesis: Factors Inducing DNA Damage and Virus Integration

    Directory of Open Access Journals (Sweden)

    Yan Chen

    2014-10-01

    Full Text Available Viruses are the causative agents of 10%–15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of DNA oncogenic viruses encode oncogenes that transform infected cells, frequently by targeting p53 and pRB. In addition, integration of viral DNA into the human genome can also play an important role in promoting tumor development for several viruses, including HBV and HPV. Because viral integration requires the breakage of both the viral and the host DNA, the integration rate is believed to be linked to the levels of DNA damage. DNA damage can be caused by both endogenous and exogenous factors, including inflammation induced by either the virus itself or by co-infections with other agents, environmental agents and other factors. Typically, cancer develops years to decades following the initial infection. A better understanding of virus-mediated carcinogenesis, the networking of pathways involved in transformation and the relevant risk factors, particularly in those cases where tumorigenesis proceeds by way of virus integration, will help to suggest prophylactic and therapeutic strategies to reduce the risk of virus-mediated cancer.

  6. A review of molecular events of cadmium-induced carcinogenesis.

    Science.gov (United States)

    Luevano, Joe; Damodaran, Chendil

    2014-01-01

    Cadmium (Cd) is a toxic, heavy industrial metal that poses serious environmental health hazards to both humans and wildlife. Recently, Cd and Cd-containing compounds have been classified as known human carcinogens, and epidemiological data show causal associations with prostate, breast, and lung cancer. The molecular mechanisms involved in Cd-induced carcinogenesis are poorly understood and are only now beginning to be elucidated. The effects of chronic exposure to Cd have recently attracted great interest due to the development of malignancies in Cd-induced tumorigenesis in animals models. Briefly, various in vitro studies demonstrate that Cd can act as a mitogen, can stimulate cell proliferation and inhibit apoptosis and DNA repair, and can induce carcinogenesis in several mammalian tissues and organs. Thus, the various mechanisms involved in chronic Cd exposure and malignant transformations warrant further investigation. In this review, we focus on recent evidence of various leading general and tissue-specific molecular mechanisms that follow chronic exposure to Cd in prostate-, breast-, and lung-transformed malignancies. In addition, in this review, we consider less defined mechanisms such as epigenetic modification and autophagy, which are thought to play a role in the development of Cd-induced malignant transformation.

  7. What gastric cancer proteomic studies show about gastric carcinogenesis?

    Science.gov (United States)

    Leal, Mariana Ferreira; Wisnieski, Fernanda; de Oliveira Gigek, Carolina; do Santos, Leonardo Caires; Calcagno, Danielle Queiroz; Burbano, Rommel Rodriguez; Smith, Marilia Cardoso

    2016-08-01

    Gastric cancer is a complex, heterogeneous, and multistep disease. Over the past decades, several studies have aimed to determine the molecular factors that lead to gastric cancer development and progression. After completing the human genome sequencing, proteomic technologies have presented rapid progress. Differently from the relative static state of genome, the cell proteome is dynamic and changes in pathologic conditions. Proteomic approaches have been used to determine proteome profiles and identify differentially expressed proteins between groups of samples, such as neoplastic and nonneoplastic samples or between samples of different cancer subtypes or stages. Therefore, proteomic technologies are a useful tool toward improving the knowledge of gastric cancer molecular pathogenesis and the understanding of tumor heterogeneity. This review aimed to summarize the proteins or protein families that are frequently identified by using high-throughput screening methods and which thus may have a key role in gastric carcinogenesis. The increased knowledge of gastric carcinogenesis will clearly help in the development of new anticancer treatments. Although the studies are still in their infancy, the reviewed proteins may be useful for gastric cancer diagnosis, prognosis, and patient management.

  8. Sewage sludge does not induce genotoxicity and carcinogenesis

    Science.gov (United States)

    Silva, Paula Regina Pereira; Barbisan, Luis Fernando; Dagli, Maria Lúcia Zaidan; Saldiva, Paulo Hilário Nascimento

    2012-01-01

    Through a series of experiments, the genotoxic/mutagenic and carcinogenic potential of sewage sludge was assessed. Male Wistar rats were randomly assigned to four groups: Group 1 - negative control; Group 2 - liver carcinogenesis initiated by diethylnitrosamine (DEN; 200 mg/kg i.p.); Group 3 and G4-liver carcinogenesis initiated by DEN and fed 10,000 ppm or 50,000 ppm of sewage sludge. The animals were submitted to a 70% partial hepatectomy at the 3rd week. Livers were processed for routine histological analysis and immunohistochemistry, in order to detect glutathione S-transferase positive altered hepatocyte foci (GST-P+ AHF). Peripheral blood samples for the comet assay were obtained from the periorbital plexus immediately prior to sacrificing. Polychromatic erythrocytes (PCEs) were analyzed in femoral bone-marrow smears, and the frequencies of those micronucleated (MNPCEs) registered. There was no sewage-sludge-induced increase in frequency of either DNA damage in peripheral blood leucocytes, or MNPCEs in the femoral bone marrow. Also, there was no increase in the levels of DNA damage, in the frequency of MNPCEs, and in the development of GST-P AHF when compared with the respective control group. PMID:23055806

  9. Effect of luteolin on glycoproteins metabolism in 1, 2-dimethylhydrazine induced experimental colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Manju Vaiyapuri

    2008-12-01

    carcinogenesis. Thus, the present study indicates that luteolin has protected the cell surface and maintained the structural integrity of the cell membranes during DMH induced colon carcinogenesis. Keywords: Colon cancer, 1, 2-dimethylhydrazine, luteolin, glycoproteins Received: 23 January 2009 / Received in revised form: 17 February 2009, Accepted: 28 February 2009, Published online: 3 March 2009

  10. [The role of sonic hedgehog pathway in skin carcinogenesis].

    Science.gov (United States)

    Lesiak, Aleksandra; Sysa-Jedrzejowska, Anna; Narbutt, Joanna

    2010-08-01

    Non melanoma skin cancers (NMSC) involving basal (BCC)--and squamosus cell carcinomas (SCC) and are the most frequent skin cancers in Caucasians. Ultraviolet radiation is the main environmental risk factor for NMSC development. The aim of this paper is to review the latest opinions concerning the role of sonic hedgehog pathway in non-melanoma skin cancers development. Experimental data indicate that sonic hedgehog pathway might be involved in skin carcinogenesis. Under physiological conditions sonic hedgehog pathway is responsible for normal embryogenesis, regeneration of damaged tissues and for regulation of cell proliferation. It was revealed that UVR caused inactivated mutation in PATCHED gene encoding Ptch1 protein. These events lead to deregulation of sonic hedgehog pathway trough activation of Smo protein and Gli transcriptional factors what stimulates cell proliferation and in consequence NMSC development. Literature data indicate that understanding of molecular background of skin cancers might be a reason for introduction of new therapeutic approaches including sonic hedgehog pathway inhibitors.

  11. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis

    DEFF Research Database (Denmark)

    Thorsteinsdottir, Sigrun; Gudjonsson, Thorkell; Nielsen, Ole Haagen;

    2011-01-01

    One of the most serious complications of ulcerative colitis is the development of colorectal cancer. Screening patients with ulcerative colitis by standard histological examination of random intestinal biopsy samples might be inefficient as a method of cancer surveillance. This Review focuses......-driven mechanisms of DNA damage, including the generation and effects of reactive oxygen species, microsatellite instability, telomere shortening and chromosomal instability, are reviewed, as are the molecular responses to genomic stress. We also discuss how these mechanisms can be translated into usable biomarkers....... Although progress has been made in the understanding of inflammation-driven carcinogenesis, markers based on these findings possess insufficient sensitivity or specificity to be usable as reliable biomarkers for risk of colorectal cancer development in patients with ulcerative colitis. However, screening...

  12. Recent advances in the study of HPV-associated carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Liyan; Jin; Zhi-Xiang; Xu

    2015-01-01

    Human papillomaviruses(HPVs) cause virtually all cervical cancers, the second leading cause of death by cancer among women, as well as other anogenital cancers and a subset of head and neck cancers. Approximately half of women, who develop cervical cancer die from it. Despite the optimism that has accompanied the introduction of prophylactic vaccines to prevent some HPV infections, the relatively modest uptake of the vaccine, especially in the developing world, and the very high fraction of men and women who are already infected, means that HPV-associated disease will remain as a significant public health problem for decades. In this review, we summarize some recent findings on HPV-associated carcinogenesis, such as mi RNAs in HPV-associated cancers, implication of stem cells in the biology and therapy of HPV-positive cancers, HPV vaccines, targeted therapy of cervical cancer, and drug treatment for HPV-induced intraepithelial neoplasias.

  13. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis

    DEFF Research Database (Denmark)

    Thorsteinsdottir, Sigrun; Gudjonsson, Thorkell; Nielsen, Ole Haagen

    2011-01-01

    One of the most serious complications of ulcerative colitis is the development of colorectal cancer. Screening patients with ulcerative colitis by standard histological examination of random intestinal biopsy samples might be inefficient as a method of cancer surveillance. This Review focuses...... on the current understanding of the pathogenesis of ulcerative colitis-associated colorectal cancer and how this knowledge can be transferred into patient management to assist clinicians and pathologists in identifying patients with ulcerative colitis who have an increased risk of colorectal cancer. Inflammation....... Although progress has been made in the understanding of inflammation-driven carcinogenesis, markers based on these findings possess insufficient sensitivity or specificity to be usable as reliable biomarkers for risk of colorectal cancer development in patients with ulcerative colitis. However, screening...

  14. ALDH2 polymorphism for the risk of cervical carcinogenesis.

    Science.gov (United States)

    Nunobiki, Osamu; Sano, Daisuke; Akashi, Kyoko; Higashida, Taro; Ogasawara, Toshitada; Akise, Hikari; Izuma, Shinji; Torii, Kiyo; Okamoto, Yoshiaki; Tanaka, Ichiro; Ueda, Masatsugu

    2016-04-01

    To investigate the clinical significance of ALDH2 genetic polymorphisms in cervical carcinogenesis. ALDH2 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 195 cervical smear in exfoliated cervical cell samples using Real-Time polymerase chain reaction (PCR) System. The frequency for the AG+AA genotype was seven in the normal group (70.0 %), 16 in the LSIL group (57.1 %), and 27 in the HSIL group (90.0 %). A significant difference was found between the LSIL and HSIL groups (P = 0.0064). Patients with HSIL lesions frequently had high-risk HPV infections and concurrently belonged to the AG+AA group. ALDH2 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population.

  15. Multi-step pancreatic carcinogenesis and its clinical implications.

    Science.gov (United States)

    Sakorafas, G H; Tsiotou, A G

    1999-12-01

    The poor prognosis of pancreatic cancer relates mainly to its delayed diagnosis. It has been repeatedly shown that earlier diagnosis of pancreatic cancer is associated with a better outcome. Molecular diagnostic methods (mainly detection of K-ras mutations in pure pancreatic or duodenal juice, on specimens obtained by percutaneous fine-needle aspirations or in stool specimens) can achieve earlier diagnosis in selected subgroups of patients, such as patients with chronic pancreatitis (especially hereditary), adults with recent onset of non-insulin-dependent diabetes mellitus and patients with some inherited disorders that predispose to the development of pancreatic cancer. There is increasing evidence that pancreatic carcinogenesis is a multi-step phenomenon. Screening procedures for precursor lesions in these selected subgroups of patients may reduce the incidence and mortality from pancreatic cancer.

  16. Growth-related alterations during liver carcinogenesis: Effect of promoters

    Energy Technology Data Exchange (ETDEWEB)

    Seglen, P.O.; Gerlyng, P. (Norwegian Radium Hospital, Oslo (Norway))

    1990-08-01

    Bromodeoxyuridine labeling of DNA, binuclearity counting, and flow cytometric analysis of isolated hepatocytes and hepatocyte nuclei has been used to assess heptocellular growth patterns related to liver carcinogenesis. Three growth patterns can be distinguished. Mononucleating growth is observed during liver regeneration and after treatment with the tumor promoter 2-acetylaminofluorene (2-AAF) and its analogue 4-AAF. In this growth mode binucleation does not occur, resulting in a decrease in the fraction of binucleated cells. Binucleating growth is observed during normal liver development and after treatment with compounds such as phenobarbital, characterized by progressive polyploidization and maintenance of a binucleated cell fraction. Diploid growth is the growth pattern of neoplastic liver hepatocytes. Most of the cells in neoplastic lesions (foci, nodules, and carcinomas) are diploid, in contrast to the normal liver. Diploid tumor cells have a much higher proliferative activity than tetraploid tumor cells, suggesting that the latter may posses a limited growth potential that makes abrogation of binucleation proliferatively advantageous.

  17. Thymus in experimental carcinogenesis of the prostate gland.

    Science.gov (United States)

    Borodin, Yu I; Lomshakov, A A; Astashov, V V; Kazakov, O V; Mayorov, A P; Larionov, P M

    2014-10-01

    We studied structural changes in the prostate gland, thymus, and lymph nodes in CBA mice after transplantation of Ehrlich ascites tumor cells into the prostate gland. On experimental day 5, the number of blood and lymph vessels decreased in the gland; the percentage of connective tissue elements and glandular tissue and the number of immunoblasts in the thymus increased. On day 18, the number of blood vessels in the tumor decreased; the width of the cortex and glandular tissue increased in the thymus, while the number of immunoblasts was reduced. On day 28, tumor infiltration and increased number of lymphatic vessels in its stroma were observed; parenchyma was reduced, and the area of the connective tissue increased in the thymus. These structural changes indicated the development of accidental involution of the thymus during carcinogenesis of the prostate.

  18. Translesion Synthesis Polymerases in the Prevention and Promotion of Carcinogenesis

    Directory of Open Access Journals (Sweden)

    L. Jay Stallons

    2010-01-01

    Full Text Available A critical step in the transformation of cells to the malignant state of cancer is the induction of mutations in the DNA of cells damaged by genotoxic agents. Translesion DNA synthesis (TLS is the process by which cells copy DNA containing unrepaired damage that blocks progression of the replication fork. The DNA polymerases that catalyze TLS in mammals have been the topic of intense investigation over the last decade. DNA polymerase η (Pol η is best understood and is active in error-free bypass of UV-induced DNA damage. The other TLS polymerases (Pol ι, Pol κ, REV1, and Pol ζ have been studied extensively in vitro, but their in vivo role is only now being investigated using knockout mouse models of carcinogenesis. This paper will focus on the studies of mice and humans with altered expression of TLS polymerases and the effects on cancer induced by environmental agents.

  19. The molecular mechanisms of hazardous metals for carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    ChenJK; LeiYX

    2002-01-01

    The available experimental and epidemiological data have shown that nickel (Ni) and cadmium (Dd) and their compounds are carcinogenic to experimental animals and human.These two metals have been classified as human carcinogens bythe International Agency for Research on Cancer (IARC).However,Their underlying molecular mechanisms remain unknown.The objective of this research was to investigate the molecular mechanisms responsible for Ni and Cd carcinogenesis through epidemiological study in human exposure,transformation expreiments in human epithelial cells (16HBE) and BALB/c-3T3 cell lines in vitro,DNA damage detections (comet,DNA-protein crosslinks) as well as telomerase activity and apoptosis assay,and analysis of oncogens,tumor suppressor genes and their mutation (including genomic instability,k-ras,p15,p16,p53,FHIT) in transformed cell lines or tumor cells/tissue.Furthermore,we also detected and analyses the methylation,related novel genes and encoded protein in Cd transformed cells.The results and conclusion are as follows:(1)There is significant relationship between some hazardous metals and lung cancer (OR=8.76),especially for nickel(OR=11.25).(2)Ni and Cd and their compounds could induce malignant transformation in mammalian cell lines and human epithelial cells,and induce tumorigenesis in nude mice.(3)There is obvious DNA damage during cell transformation and tumorigenesis induced by Ni.(4) Significant genomic instability has been shown during cell transformation and tumorigenesis induced by Ni.(5)Detection of k-ras,p15,p16 genes in point mutation have demonstrated no changes during cell transformation and tumorigenesis induced by hazardous medals,suggesting that gene mutation is not the main way to metal carcinogenesis.(6)There are some aberrant DNA methylation in Cdtransformed cell lines.(7)We found two novel Cd-responsive proto-oncogenes and their encoded proteins in Cd-transformed cell lines.

  20. Effect of Thyroid Function on MNU-Induced Mammary Carcinogenesis.

    Science.gov (United States)

    Vermey, Mackenzie L; Marks, Gregory T; Baldridge, Monika G

    2015-06-01

    Mammary cancer is a disease that affects many women. Extensive research has been conducted to elucidate which variables are involved in the development of this cancer. Studies have highlighted thyroid function as a modulator of tumor growth and development. Thyroxine and 3,3',5-triiodothyronine are responsible for regulating the development, differentiation, homeostasis, and metabolism of cells in the body including mammary tissue. Thyroid hormones also have estrogen-like effects on mammary cancer cell growth by regulating the estrogen receptor. The present study was designed to determine whether medically induced hyperthyroidism increases the multiplicity, prevalence, and mammary tumor burden in rats; and to elucidate whether surgically induced hypothyroidism conversely attenuates the rate of mammary cancer cell growth. Female Sprague-Dawley rats were randomly divided into three groups (euthyroid-control, hyperthyroid, and hypothyroid). Hyperthyroidism was induced via oral administration of levothyroxine; whereas, hypothyroidism was induced by thyroidectomy. Mammary carcinogenesis was induced with a single intraperitoneal injection of N-methyl-N-nitrosurea (MNU). Rats were sacrificed at 38 weeks, and the mammary tumors were excised, fixed for histology and analyzed. Analysis included evaluation of malignancy and immunohistochemistry for ER. MNU-induced mammary carcinogenesis among the groups resulted in a significant difference in tumor burden. The hyperthyroid group had a statistically higher tumor burden than did the euthyroid group, and the hypothyroid group had no tumors of mammary tissue origin at 38 weeks. All excised mammary tumors were ER alpha negative. These data support the hypothesis that thyroid function is one of potentially many factors that contribute to modulation of MNU-induced mammary tumor growth.

  1. Mushroom Ganoderma lucidum prevents colitis-associated carcinogenesis in mice.

    Directory of Open Access Journals (Sweden)

    Daniel Sliva

    Full Text Available BACKGROUND: Epidemiological studies suggest that mushroom intake is inversely correlated with gastric, gastrointestinal and breast cancers. We have recently demonstrated anticancer and anti-inflammatory activity of triterpene extract isolated from mushroom Ganoderma lucidum (GLT. The aim of the present study was to evaluate whether GLT prevents colitis-associated carcinogenesis in mice. METHODS/PRINCIPAL FINDINGS: Colon carcinogenesis was induced by the food-borne carcinogen (2-Amino-1-methyl-6-phenylimidazol[4,5-b]pyridine [PhIP] and inflammation (dextran sodium sulfate [DSS] in mice. Mice were treated with 0, 100, 300 and 500 mg GLT/kg of body weight 3 times per week for 4 months. Cell proliferation, expression of cyclin D1 and COX-2 and macrophage infiltration was assessed by immunohistochemistry. The effect of GLT on XRE/AhR, PXR and rPXR was evaluated by the reporter gene assays. Expression of metabolizing enzymes CYP1A2, CYP3A1 and CYP3A4 in colon tissue was determined by immunohistochemistry. GLT treatment significantly suppressed focal hyperplasia, aberrant crypt foci (ACF formation and tumor formation in mice exposed to PhIP/DSS. The anti-proliferative effects of GLT were further confirmed by the decreased staining with Ki-67 in colon tissues. PhIP/DSS-induced colon inflammation was demonstrated by the significant shortening of the large intestine and macrophage infiltrations, whereas GLT treatment prevented the shortening of colon lengths, and reduced infiltration of macrophages in colon tissue. GLT treatment also significantly down-regulated PhIP/DSS-dependent expression of cyclin D1, COX-2, CYP1A2 and CYP3A4 in colon tissue. CONCLUSIONS: Our data suggest that GLT could be considered as an alternative dietary approach for the prevention of colitis-associated cancer.

  2. Differential network analysis reveals dysfunctional regulatory networks in gastric carcinogenesis.

    Science.gov (United States)

    Cao, Mu-Shui; Liu, Bing-Ya; Dai, Wen-Tao; Zhou, Wei-Xin; Li, Yi-Xue; Li, Yuan-Yuan

    2015-01-01

    Gastric Carcinoma is one of the most common cancers in the world. A large number of differentially expressed genes have been identified as being associated with gastric cancer progression, however, little is known about the underlying regulatory mechanisms. To address this problem, we developed a differential networking approach that is characterized by including a nascent methodology, differential coexpression analysis (DCEA), and two novel quantitative methods for differential regulation analysis. We first applied DCEA to a gene expression dataset of gastric normal mucosa, adenoma and carcinoma samples to identify gene interconnection changes during cancer progression, based on which we inferred normal, adenoma, and carcinoma-specific gene regulation networks by using linear regression model. It was observed that cancer genes and drug targets were enriched in each network. To investigate the dynamic changes of gene regulation during carcinogenesis, we then designed two quantitative methods to prioritize differentially regulated genes (DRGs) and gene pairs or links (DRLs) between adjacent stages. It was found that known cancer genes and drug targets are significantly higher ranked. The top 4% normal vs. adenoma DRGs (36 genes) and top 6% adenoma vs. carcinoma DRGs (56 genes) proved to be worthy of further investigation to explore their association with gastric cancer. Out of the 16 DRGs involved in two top-10 DRG lists of normal vs. adenoma and adenoma vs. carcinoma comparisons, 15 have been reported to be gastric cancer or cancer related. Based on our inferred differential networking information and known signaling pathways, we generated testable hypotheses on the roles of GATA6, ESRRG and their signaling pathways in gastric carcinogenesis. Compared with established approaches which build genome-scale GRNs, or sub-networks around differentially expressed genes, the present one proved to be better at enriching cancer genes and drug targets, and prioritizing

  3. The Anticancer Role of Capsaicin in Experimentallyinduced Lung Carcinogenesis.

    Science.gov (United States)

    Anandakumar, Pandi; Kamaraj, Sattu; Jagan, Sundaram; Ramakrishnan, Gopalakrishnan; Asokkumar, Selvamani; Naveenkumar, Chandrashekar; Raghunandhakumar, Subramanian; Vanitha, Manickam Kalappan; Devaki, Thiruvengadam

    2015-06-01

    Capsaicin (CAP) is the chief pungent principle found in the hot red peppers and the chili peppers that have long been used as spices, food additives and drugs. This study investigated the anticancer potential of CAP through its ability to modify extracellular matrix components and proteases during mice lung carcinogenesis. Swiss albino mice were treated with benzo(a) pyrene (50 mg/kg body weight dissolved in olive oil) orally twice a week for four successive weeks to induce lung cancer at the end of 14(th) week. CAP was administrated (10 mg/kg body weight dissolved in olive oil) intraperitoneally. Extracellular matrix components were assayed; Masson's trichome staining of lung tissues was performed. Western blot analyses of matrix metalloproteases 2 and 9 were also carried out. In comparison with the control animals, animals in which benzo(a)pyrene had induced lung cancer showed significant increases in extracellular matrix components such as collagen (hydroxy proline), elastin, uronic acid and hexosamine and in glycosaminoglycans such as hyaluronate, chondroitin sulfate, keratan sulfate and dermatan sulfate. The above alterations in extracellular matrix components were effectively counteracted in benzo(a)pyrene along with CAP supplemented animals when compared to benzo(a) pyrene alone supplemented animals. The results of Masson's trichome staining for collagen and of, immunoblotting analyses of matrix metalloproteases 2 and 9 further supported the biochemical findings. The apparent potential of CAP in modulating extracellular matrix components and proteases suggests that CAP plays a chemomodulatory and anti- cancer role working against experimentally induced lung carcinogenesis.

  4. The Anticancer Role of Capsaicin in Experimentallyinduced Lung Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Pandi Anandakumar

    2015-06-01

    Full Text Available Objectives: Capsaicin (CAP is the chief pungent principle found in the hot red peppers and the chili peppers that have long been used as spices, food additives and drugs. This study investigated the anticancer potential of CAP through its ability to modify extracellular matrix components and proteases during mice lung carcinogenesis. Methods: Swiss albino mice were treated with benzo(a pyrene (50 mg/kg body weight dissolved in olive oil orally twice a week for four successive weeks to induce lung cancer at the end of 14th week. CAP was administrated (10 mg/kg body weight dissolved in olive oil intraperitoneally. Extracellular matrix components were assayed; Masson’s trichome staining of lung tissues was performed. Western blot analyses of matrix metalloproteases 2 and 9 were also carried out. Results: In comparison with the control animals, animals in which benzo(apyrene had induced lung cancer showed significant increases in extracellular matrix components such as collagen (hydroxy proline, elastin, uronic acid and hexosamine and in glycosaminoglycans such as hyaluronate, chondroitin sulfate, keratan sulfate and dermatan sulfate. The above alterations in extracellular matrix components were effectively counteracted in benzo(apyrene along with CAP supplemented animals when compared to benzo(a pyrene alone supplemented animals. The results of Masson’s trichome staining for collagen and of, immunoblotting analyses of matrix metalloproteases 2 and 9 further supported the biochemical findings. Conclusion: The apparent potential of CAP in modulating extracellular matrix components and proteases suggests that CAP plays a chemomodulatory and anti- cancer role working against experimentally induced lung carcinogenesis.

  5. Protein expression analysis of inflammation-related colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Yasui Yumiko

    2009-01-01

    Full Text Available Background: Chronic inflammation is a risk factor for colorectal cancer (CRC development. The aim of this study was to determine the differences in protein expression between CRC and the surrounding nontumorous colonic tissues in the mice that received azoxymethane (AOM and dextran sodium sulfate (DSS using a proteomic analysis. Materials and Methods: Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight, followed by 2% (w/v DSS in their drinking water for seven days, starting one week after the AOM injection. Colonic adenocarcinoma developed after 20 weeks and a proteomics analysis based on two-dimensional gel electrophoresis and ultraflex TOF/TOF mass spectrometry was conducted in the cancerous and nontumorous tissue specimens. Results: The proteomic analysis revealed 21 differentially expressed proteins in the cancerous tissues in comparison to the nontumorous tissues. There were five markedly increased proteins (beta-tropomyosin, tropomyosin 1 alpha isoform b, S100 calcium binding protein A9, and an unknown protein and 16 markedly decreased proteins (Car1 proteins, selenium-binding protein 1, HMG-CoA synthase, thioredoxin 1, 1 Cys peroxiredoxin protein 2, Fcgbp protein, Cytochrome c oxidase, subunit Va, ETHE1 protein, and 7 unknown proteins. Conclusions: There were 21 differentially expressed proteins in the cancerous tissues of the mice that received AOM and DSS. Their functions include metabolism, the antioxidant system, oxidative stress, mucin production, and inflammation. These findings may provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies to treat carcinogenesis in the inflamed colon.

  6. Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction.

    Science.gov (United States)

    Kanda, Yusuke; Osaki, Mitsuhiko; Okada, Futoshi

    2017-04-19

    A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.

  7. Apoptotic cell death and its relationship to gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Ferda Bir; Nese Calli-Demirkan; A Cevik Tufan; Metin Akbulut; N Lale Satiroglu-Tufan

    2007-01-01

    AIM: To investigate the apoptotic process of cells within the intestinal metaplasia areas co-localizing with chronic gastritis and gastric carcinomas and to analyze the involvement of proteins regulating apoptosis in the process of intestinal metaplasia related gastric carcinogenesis.METHODS: Forty-two gastric carcinoma and seventeen chronic gastritis cases were included in this study. All cases were examined for the existence of intestinal metaplasia. Ten cases randomly selected from each group were processed for TUNEL assay. TUNEL positive cells within the intestinal metaplasia areas, colocalizing either to gastric carcinoma or chronic gastritis,were counted and converted to apoptotic indices.In addition, p53, bcl-2 and bax expression patterns within these tissues were analyzed on the basis of immunohistochemistry.RESULTS: Twenty-eight of the cases were intestinal and 14 of the cases were diffuse type adenocarcinomas.64% (27/42) of the gastric carcinoma cases had intestinal metaplasia. Intestinal metaplasia co-localized more with intestinal type carcinomas compared with diffuse type carcinomas [75% (21/28) vs 42% (6/14),respectively; P≤0.05]. The mean apoptotic index in tumor cells was 0.70±0.08. The mean apoptotic index in intestinal metaplasias co-localizing to tumors was significantly higher than that of intestinal metaplasias co-localizing to chronic gastritis (0.70±0.03 vs 0.09±0.01, respectively; P≤0.05). P53 positivity was not observed in areas of intestinal metaplasia adjacent to tumors or chronic gastritis. Intestinal metaplasia areas adjacent to tumors showed lower cytoplasmic bcl-2 positivity compared to intestinal metaplasia areas adjacent to chronic gastritis [55.5% (15/27) vs 70.5%(12/17), respectively]. On the other hand, intestinal metaplasia areas adjacent to tumors showed significantly higher cytoplasmic bax positivity compared to intestinal metaplasia areas adjacent to chronic gastritis [44.4%(12/27) vs 11.7% (2/17), respectively; P≤0

  8. Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma.

    Science.gov (United States)

    Feng, Wei; Xiao, Jianguo; Zhang, Zhihong; Rosen, Daniel G; Brown, Robert E; Liu, Jinsong; Duan, Xiuzhen

    2007-09-01

    Senescence and apoptosis are two key mechanisms that protect against cancer development. Many cell cycle regulators, such as p14(ARF), p15(INK4b) and p16(INK4a), are important in G1 cell cycle arrest and oncogene-induced senescence. The bcl-2 protein is one of the key components that control apoptosis, while the p53 protein plays key roles in both mechanisms. The genes of these key regulator proteins are often mutated or deleted in various malignancies. It is unknown how senescence and apoptosis are regulated in one of the most common tumors of the female genital tract, cervical squamous cell carcinoma (SCC). In this study the, expression of senescence, apoptosis and proliferation markers in normal cervical epithelium, cervical intraepithelial neoplasia (CIN) and SCC are characterized via immunohistochemical staining for p14(ARF), p15(INK4b), p16(INK4a), bcl-2, p53 and Ki-67 in tissue microarray blocks containing 20 samples each of normal cervix, moderate-to-severe cervical dysplasia (CIN II-III) and invasive SCC. Samples are derived from 60 total cases of cervical biopsies and cervical conizations. Results showed that the proliferation marker, Ki-67, is markedly increased, and the senescence markers, p15(INK4b), p16(INK4a) and p14(ARF) are overexpressed in both dysplasia and carcinoma. P53 immunostain is negative in all normal cervical tissue, and positive in dysplasia and carcinoma. Although the expression of bcl-2 is increased in dysplasia, this marker is negative in approximately half of SCC cases. These results suggest that some senescence pathways are activated and are still maintained in cervical dysplasia and carcinoma. However proliferation is increased and carcinogenesis is not thwarted, leading to eventual development of cervical cancer. Other mechanisms, such as those that account for the apparent overexpression of p53 and paradoxical loss of bcl-2 expression in some SCC cases, as well as additional senescence and apoptotic pathways, may play key roles

  9. The role of B-vitamins - gene interactions in colorectal carcinogenesis: A molecular epidemiological approach

    NARCIS (Netherlands)

    Donk, van den M.

    2005-01-01

    Folate deficiency can affect DNA methylation and DNA synthesis. Both factors may be operative in colorectal carcinogenesis. Many enzymes, like methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MTR), and serine hydroxymethyltransferase (SHMT), are needed for

  10. Effects of environmental stressors on histone modifications and their relevance to carcinogenesis: a systematic review.

    NARCIS (Netherlands)

    Dik, S.; Scheepers, P.T.J.; Godderis, L.

    2012-01-01

    Carcinogenesis is a complex process involving both genetic and epigenetic mechanisms. The cellular molecular epigenetic machinery, including histone modifications, is associated with changes in gene expression induced by exposure to environmental agents. In this paper, we systematically reviewed pub

  11. Relationship between Helicobacter pylori infection and gastric carcinogenesis in elderly patients

    Institute of Scientific and Technical Information of China (English)

    李文新

    2013-01-01

    Objective To explore the relationship between Helicobacter pylori (HP) infection and gastric carcinogenesis,and to investigate its mechanism.Methods Totally 333elderly patients with different degrees of gastric mucosal lesions in our hospital were selected.Patients were

  12. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  13. Modulation of Estrogen Chemical Carcinogenesis by Botanical Supplements used for Postmenopausal Women's Health.

    Science.gov (United States)

    Snelten, Courtney S; Dietz, Birgit; Bolton, Judy L

    2012-06-01

    Breast cancer risk has been associated with long-term estrogen exposure including traditional hormone therapy (HT, formally hormone replacement therapy). To avoid traditional HT and associated risks, women have been turning to botanical supplements such as black cohosh, red clover, licorice, hops, dong gui, and ginger to relieve menopausal symptoms despite a lack of efficacy evidence. The mechanisms of estrogen carcinogenesis involve both hormonal and chemical pathways. Botanical supplements could protect women from estrogen carcinogenesis by modulating key enzymatic steps [aromatase, P4501B1, P4501A1, catechol-O-methyltransferase (COMT), NAD(P)H quinone oxidoreductase 1 (NQO1), and reactive oxygen species (ROS) scavenging] in estradiol metabolism leading to estrogen carcinogenesis as outlined in Figure 1. This review summarizes the influence of popular botanical supplements used for women's health on these key steps in the estrogen chemical carcinogenesis pathway, and suggests that botanical supplements may have added chemopreventive benefits by modulating estrogen metabolism.

  14. Modifying Effects of Fungal and Herb Metabolites on Azoxymethane‐induced Intestinal Carcinogenesis in Rats

    National Research Council Canada - National Science Library

    Yoshimi, Naoki; Wang, Aijin; Morishita, Yukio; Tanaka, Takuji; Sugie, Shigeyuki; Kawai, Kiyoshi; Yamahara, Joji; Mori, Hideki

    1992-01-01

    Modifying effects of a fungal product, flavoglaucin, and four plant‐derived chemicals, shikonin, gingerol, oleanolic acid and paeoniflorin, on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM...

  15. The role of B-vitamins - gene interactions in colorectal carcinogenesis: A molecular epidemiological approach

    NARCIS (Netherlands)

    Donk, van den M.

    2005-01-01

    Folate deficiency can affect DNA methylation and DNA synthesis. Both factors may be operative in colorectal carcinogenesis. Many enzymes, like methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MTR), and serine hydroxymethyltransferase (SHMT), are needed for

  16. Role of MicroRNAs in carcinogenesis that potential for biomarker of endometrial cancer

    OpenAIRE

    Widodo1); Djati, Muhammad Sasmito; Rifa'i, Muhaimin

    2016-01-01

    The non-invasive diagnostic tool for early detection of endometrial cancer still limited. The etiology of this disease is believed to be associated with disharmony hormone production. One predominant factor that regulate hormone production is microRNA (miRNAs). Some studies reported that miRNAs play a significant role in the process carcinogenesis. We have identified 12 of miRNAs that potentially have a role in controlling endometrial carcinogenesis pathways. Further analysis suggested that t...

  17. Modifier-concept of colorectal carcinogenesis: Lipidomics as a technical tool in pathway analysis

    Institute of Scientific and Technical Information of China (English)

    Nikolaus; Gassler; Christina; Klaus; Elke; Kaemmerer; Andrea; Reinartz

    2010-01-01

    In the modifier concept of intestinal carcinogenesis, lipids have been established as important variables and one focus is given to long-chain fatty acids. Increased consumption of long-chain fatty acids is in discussion to modify the development of colorectal carcinoma in humans. Saturated long-chain fatty acids, in particular, are assumed to promote carcinogenesis, whereas poly-unsaturated forms are likely to act in the opposite way. At present, the molecular mechanisms behind these effects are not well u...

  18. BRAFV600E: implications for carcinogenesis and molecular therapy.

    LENUS (Irish Health Repository)

    Cantwell-Dorris, Emma R

    2012-02-01

    The mitogen-activated protein kinase (MAPK)\\/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP\\/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAF(V600E) in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target.

  19. Alert-QSAR. Implications for Electrophilic Theory of Chemical Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Vasile Ostafe

    2011-08-01

    Full Text Available Given the modeling and predictive abilities of quantitative structure activity relationships (QSARs for genotoxic carcinogens or mutagens that directly affect DNA, the present research investigates structural alert (SA intermediate-predicted correlations ASA of electrophilic molecular structures with observed carcinogenic potencies in rats (observed activity, A = Log[1/TD50], i.e., ASA=f(X1SA,X2SA,.... The present method includes calculation of the recently developed residual correlation of the structural alert models, i.e., ARASA=f(A-ASA,X1SA,X2SA,... . We propose a specific electrophilic ligand-receptor mechanism that combines electronegativity with chemical hardness-associated frontier principles, equality of ligand-reagent electronegativities and ligand maximum chemical hardness for highly diverse toxic molecules against specific receptors in rats. The observed carcinogenic activity is influenced by the induced SA-mutagenic intermediate effect, alongside Hansch indices such as hydrophobicity (LogP, polarizability (POL and total energy (Etot, which account for molecular membrane diffusion, ionic deformation, and stericity, respectively. A possible QSAR mechanistic interpretation of mutagenicity as the first step in genotoxic carcinogenesis development is discussed using the structural alert chemoinformation and in full accordance with the Organization for Economic Co-operation and Development QSAR guidance principles.

  20. The diffuse endocrine system: from embryogenesis to carcinogenesis.

    Science.gov (United States)

    Montuenga, Luis M; Guembe, Laura; Burrell, M Angela; Bodegas, M Elena; Calvo, Alfonso; Sola, Jesús J; Sesma, Pilar; Villaro, Ana C

    2003-01-01

    In the present review we will summarise the current knowledge about the cells comprising the Diffuse Endocrine System (DES) in mammalian organs. We will describe the morphological, histochemical and functional traits of these cells in three major systems gastrointestinal, respiratory and prostatic. We will also focus on some aspects of their ontogeny and differentiation, as well as to their relevance in carcinogenesis, especially in neuroendocrine tumors. The first chapter describes the characteristics of DES cells and some of their specific biological and biochemical traits. The second chapter deals with DES in the gastrointestinal organs, with special reference to the new data on the differentiation mechanisms that leads to the appearance of endocrine cells from an undifferentiated stem cell. The third chapter is devoted to DES of the respiratory system and some aspects of its biological role, both, during development and adulthood. Neuroendocrine hyperplasia and neuroendocrine lung tumors are also addressed. Finally, the last chapter deals with the prostatic DES, discussing its probable functional role and its relevance in hormone-resistant prostatic carcinomas.

  1. Influence of caloric intake on experimental carcinogenesis: a review.

    Science.gov (United States)

    Kritchevsky, D; Klurfeld, D M

    1986-01-01

    The effect of caloric intake on tumor growth has been recognized for over 70 years. Inhibition of tumor growth depends primarily on the extent of caloric restriction, but tumor type, animal strain, and dietary composition all exert some influence. Caloric restriction is most effective when maintained during both initiation and promotion, but if limited to one of these phases, restriction during promotion appears to be the more effective modality. The types of tumor that have been studied include spontaneous mammary and lung tumors as well as tumors induced by organ-specific carcinogens or irradiation with ultraviolet light. Numerous investigators have studied the effects of fat, and a diet low in calories but high in fat is generally significantly more effective in inhibiting carcinogenesis than is a diet high in calories but low in fat. Mice fed high fat, low calorie diets exhibited 48% fewer chemically induced skin tumors and 61% fewer tumors induced by ultraviolet irradiation than did mice fed low fat, high calorie diets. Mice fed a diet containing 2% fat exhibited a 66% incidence of skin tumors, whereas mice fed an isocaloric diet containing 61% fat showed a 78% incidence. Rats whose diet was restricted in calories by 40% exhibited no mammary tumors (coconut oil as primary dietary fat) or 75% fewer tumors (corn oil as dietary fat) compared to ad libitum-fed controls; they also exhibited 47% fewer colonic tumors. The mechanism by which caloric restriction exerts its tumor-inhibiting effects remains to be elucidated.

  2. Alert-QSAR. Implications for Electrophilic Theory of Chemical Carcinogenesis

    Science.gov (United States)

    Putz, Mihai V.; Ionaşcu, Cosmin; Putz, Ana-Maria; Ostafe, Vasile

    2011-01-01

    Given the modeling and predictive abilities of quantitative structure activity relationships (QSARs) for genotoxic carcinogens or mutagens that directly affect DNA, the present research investigates structural alert (SA) intermediate-predicted correlations ASA of electrophilic molecular structures with observed carcinogenic potencies in rats (observed activity, A = Log[1/TD50], i.e., ASA=f(X1SA,X2SA,…)). The present method includes calculation of the recently developed residual correlation of the structural alert models, i.e., ARASA=f(A−ASA,X1SA,X2SA,…). We propose a specific electrophilic ligand-receptor mechanism that combines electronegativity with chemical hardness-associated frontier principles, equality of ligand-reagent electronegativities and ligand maximum chemical hardness for highly diverse toxic molecules against specific receptors in rats. The observed carcinogenic activity is influenced by the induced SA-mutagenic intermediate effect, alongside Hansch indices such as hydrophobicity (LogP), polarizability (POL) and total energy (Etot), which account for molecular membrane diffusion, ionic deformation, and stericity, respectively. A possible QSAR mechanistic interpretation of mutagenicity as the first step in genotoxic carcinogenesis development is discussed using the structural alert chemoinformation and in full accordance with the Organization for Economic Co-operation and Development QSAR guidance principles. PMID:21954348

  3. Cocarcinogenic and tumor-promoting agents in tobacco carcinogenesis.

    Science.gov (United States)

    Van Duuren, B L; Goldschmidt, B M

    1976-06-01

    A series of 21 tobacco smoke components and related compounds werere applied to mouse skin (50 female ICR/Ha Swiss mice/group) three times weekly with a low dose (5 mug/application) of benzo[a]pyrene (B[a]P). The test compounds were of five classes: aliphatic hydrocarbons, aromatic hydrocarbons, phenols, and long-chain acids and alcohols. The following compounds enhanced remarkably the carcinogenicity of B[a]P: catechol, pyrogallol, decane, undecane, pyrene, benzo[e]pyrene, and fluoranthene. The following compounds inhibited B[a]P carcinogenicity completely: esculin, quercetin, squalene, and oleic acid. Phenol, eugenol, resorcinol, hydroquinone, hexadecane, and limonene partially inhibited B[a]P carcinogenicity. Six of the 21 compounds were also tested as tumor promoters im two-stage carcinogenesis. No direct correlation existed between tumor-promoting activity and cocarcinogenic activity. The cocarcinogens pyrogallol and catechol did not show tumor-promoting activity. Decane, tetradecane, anthralin, and phorbol myristate acetate showed both types of activity. Structure-activity relationships and possible modes of action were described.

  4. Possible Involvement of Pancreatic Fatty Infiltration in Pancreatic Carcinogenesis

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    Mika Hori

    2016-03-01

    Full Text Available Pancreatic cancer is difficult to diagnose in its early stage and is one of the most lethal human cancers. Thus, it is important to clarify its major risk factors, predictive factors and etiology. Here, we focus on fatty infiltration of the pancreas and suggest that it could be a risk factor for pancreatic cancer. Fatty infiltration of the pancreas is observed as ectopic adipocytes infiltrating the pancreatic tissue and is positively correlated with obesity and the prevalence of diabetes mellitus, which are risk factors for pancreatic cancer. However, whether fatty infiltration is a major risk factor for pancreatic cancer has not been established. Recent clinical studies show there is a positive correlation between fatty infiltration of the pancreas and pancreatic precancerous lesions or ductal adenocarcinomas. Animal experimental studies also show an association between fatty infiltration of the pancreas and pancreatic precancerous lesions or ductal adenocarcinomas development. Syrian golden hamsters, which are sensitive to chemical carcinogens in the pancreas, develop fatty infiltration of the pancreas with age. The combination of a high-fat diet and a chemical carcinogen that induces a K-ras mutation increases the severity of fatty infiltration of the pancreas. Thus, fatty infiltration of the pancreas is suggested to promote pancreatic carcinogenesis via a K-ras activating mutation. It is assumed that increased expression of adipokines and of inflammatory and proliferation-associated factors elicited by fatty infiltration of the pancreas may contribute to pancreatic precancerous lesions or ductal adenocarcinomas development. Accumulating evidence suggests that in addition to suppression of Ras activation, methods to modulate fatty infiltration in the pancreas can be considered as a strategy for preventing pancreatic cancer.

  5. Carcinogenesis ofnasopharyngeal carcinoma:an alternate hypothetical mechanism

    Institute of Scientific and Technical Information of China (English)

    Sharon Shuxian Poh; Melvin Lee Kiang Chua; Joseph TS Wee

    2016-01-01

    Current proposed mechanisms implicate both early and latent Epstein–Barr virus (EBV) infection in the carcinogenic cascade, whereas epidemiological studies have always associated nasopharyngeal carcinoma (NPC) with early child-hood EBV infection and with chronic ear, nose, and sinus conditions. Moreover, most patients with NPC present with IgA antibody titers to EBV capsid antigen (VCA-IgA), which can precede actual tumor presentation by several years. If early childhood EBV infection indeed constitutes a key event in NPC carcinogenesis, one would have to explain the inability to detect the virus in normal nasopharyngeal epithelium of patients at a high risk for EBV infection. It is perhaps possible that EBV resides within the salivary glands, instead of the epithelium, during latency. This claim is indirectly supported by observations that the East Asian phenotype shares the characteristics of an increased sus-ceptibility to NPC and immature salivary gland morphogenesis, the latter of which is inlfuenced by the association of salivary gland morphogenesis with an evolutionary variant of the human ectodysplasin receptor gene (EDAR), EDARV370A. Whether the immature salivary gland represents a more favorable nidus for EBV is uncertain, but in patients with infectious mononucleosis, EBV has been isolated in this anatomical organ. The presence of EBV-induced lymphoepitheliomas in the salivary glands and lungs further addresses the possibility of submucosal spread of the virus. Adding to the fact that the fossa of Rosen Müller contains a transformative zone active only in the ifrst decade of life, one might be tempted to speculate the possibility of an alternative carcinogenic cascade for NPC that is perhaps not dissimilar to the model of human papillomavirus and cervical cancer.

  6. Role of gastrin-peptides in Barrett's and colorectal carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Eduardo Chueca; Angel Lanas; Elena Piazuelo

    2012-01-01

    Gastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition,gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types.Gastrin synthesis and secretion are increased in certain situations,for example,when proton pump inhibitors are used.The impact of sustained hypergastrinemia is currently being investigated.In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although,this relationship is less clear in human beings.Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet,the risk for developing cancer seems to be the same in normo-and hypergastrinemic patients.Some tumors also produce their own gastrin,which can act in an autocrine manner promoting tumor growth.Certain cancers are extremely dependent on gastrin to proliferate.Initial research focused only on the effects of amidated gastrins,but there has been an interest in intermediates of gastrin in the last few decades.These intermediates aren't biologically inactive;in fact,they may exert greater effects on proliferation and apoptosis than the completely processed forms.In certain gastrin overproduction states,they are the most abundant gastrin peptides secreted.The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production,levels,and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett's and colorectal carcinogenesis.

  7. Colorectal carcinogenesis: Review of human and experimental animal studies

    Directory of Open Access Journals (Sweden)

    Tanaka Takuji

    2009-01-01

    Full Text Available This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma. These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.

  8. Thymoquinone Attenuates Diethylnitrosamine Induction of Hepatic Carcinogenesis Through Antioxidant Signaling

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    Mohamed M. Sayed-Ahmed

    2010-01-01

    Full Text Available Hepatocellular carcinoma accounts for about 80–90% of all liver cancer and is the fourth most common cause of cancer mortality. Although there are many strategies for the treatment of liver cancer, chemoprevention seems to be the best strategy for lowering the incidence of this disease. Therefore, this study has been initiated to investigate whether thymoquinone (TQ, Nigella sativa derived-compound with strong antioxidant properties, supplementation could prevent initiation of hepatocarcinogenesis-induced by diethylnitrosamine (DENA, a potent initiator and hepatocarcinogen, in rats. Male Wistar albino rats were divided into four groups. Rats of Group 1 received a single intraperitoneal (I.P. injection of normal saline. Animals in Group 2 were given TQ (4 mg/kg/day in drinking water for 7 consecutive days. Rats of Group 3 were injected with a single dose of DENA (200 mg/kg, I.P.. Animals in Group 4 were received TQ and DENA. DENA significantly increased alanine transaminase (ALT, alkaline phosphatase (ALP, total bilirubin, thiobarbituric acid reactive substances (TBARS and total nitrate/nitrite (NOx and decreased reduced glutathione (GSH, glutathione peroxidase (GSHPx, glutathione-s-transferase (GST and catalase (CAT activity in liver tissues. Moreover, DENA decreased gene expression of GSHPx, GST and CAT and caused severe histopathological lesions in liver tissue. Interestingly, TQ supplementation completely reversed the biochemical and histopathological changes induced by DENA to the control values. In conclusion, data from this study suggest that: (1 decreased mRNA expression of GSHPx, CAT and GST during DENA-induced initiation of hepatic carcinogenesis, (2 TQ supplementation prevents the development of DENA-induced initiation of liver cancer by decreasing oxidative stress and preserving both the activity and mRNA expression of antioxidant enzymes.

  9. Adiponectin and Intelectin-1: Important Adipokine Players in Obesity-Related Colorectal Carcinogenesis

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    Keisuke Kawashima

    2017-04-01

    Full Text Available Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1, whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer.

  10. Adiponectin and Intelectin-1: Important Adipokine Players in Obesity-Related Colorectal Carcinogenesis.

    Science.gov (United States)

    Kawashima, Keisuke; Maeda, Kenichi; Saigo, Chiemi; Kito, Yusuke; Yoshida, Kazuhiro; Takeuchi, Tamotsu

    2017-04-19

    Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer.

  11. Geranylgeranylacetone suppresses colitis‑related mouse colon carcinogenesis.

    Science.gov (United States)

    Inoue, Takuya; Yorifuji, Naoki; Iguchi, Munetaka; Fujiwara, Kaori; Kakimoto, Kazuki; Nouda, Sadaharu; Okada, Toshihiko; Kawakami, Ken; Abe, Yosuke; Takeuchi, Toshihisa; Higuchi, Kazuhide

    2015-04-01

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. GGA protects a variety of cells and tissues against numerous stresses via induction of heat shock protein (HSP) 70, and it has recently been reported to protect mice from experimental ulcerative colitis (UC). However, it is unknown whether GGA exhibits a preventive effect on UC-associated neoplasia. In the present study, we evaluated the preventive effects of GGA on colitis-related carcinogenesis in the mouse colon. Mice were administered 1,2-dimethylhydrazine (DMH) subcutaneously three times within a week, followed by 2 cycles of dextran sulfate sodium (DSS) (each cycle, 3% DSS for 7 days and then distilled water for 14 days) and they were sacrificed 28 days after the completion of the 2 cycles. The mice were divided into the following groups according to the diet received during the experiment: group A, which received a standard diet and served as a disease control; group B, which received a diet mixed with 0.25% GGA; group C, which received a diet mixed with 0.5% GGA; group D, which received a diet mixed with 1.0% GGA; group E, which received a diet mixed with 2.0% GGA; and group F, which received a diet containing no agents, including DSS and served as a normal control. The incidence of neoplasia was assessed. The expression of inducible nitric oxide synthase (iNOS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also determined. In addition, the expression of HSP70 in the colon tissues was determined by immunohistochemistry and western blot analysis. The mean number of tumors was 16.6, 11.0, 9.4, 5.8, 5.4 and 0 in groups A-F, respectively. GGA significantly suppressed the occurrence of neoplasia in a dose-dependent manner. GGA treatment enhanced the expression of HSP70 and suppressed the oxidative damage in the background mucosa (i.e. lesion-free colon). These results suggest that GGA could be useful in the prevention of UC-associated neoplasia.

  12. Chronic Inflammation-Related HPV: A Driving Force Speeds Oropharyngeal Carcinogenesis.

    Science.gov (United States)

    Liu, Xin; Ma, Xiangrui; Lei, Zhengge; Feng, Hao; Wang, Shasha; Cen, Xiao; Gao, Shiyu; Jiang, Yaping; Jiang, Jian; Chen, Qianming; Tang, Yajie; Tang, Yaling; Liang, Xinhua

    2015-01-01

    Oropharyngeal squamous cell carcinoma (OPSCC) has been known to be a highly aggressive disease associated with human papilloma virus (HPV) infection. To investigate the relationship between HPV and chronic inflammation in oropharyngeal carcinogenesis, we collected 140 oral mucous fresh specimens including 50 OPSCC patients, 50 cancer in situ, 30 precancerous lesions, and 10 normal oral mucous. Our data demonstrated that there was a significantly higher proportion of severe chronic inflammation in dysplastic epithelia in comparison with that in normal tissues (Pchronic inflammation degrees from mild to severe inflammation (Pinflammation response and immune suppression in HPV-positive OPSCC. These indicated that persistent chronic inflammation-related HPV infection might drive oropharyngeal carcinogenesis and MDSCs might pay an important role during this process. Thus, a combination of HPV infection and inflammation expression might become a helpful biomedical marker to predict oropharyngeal carcinogenesis.

  13. A review of dietary factors and its influence on DNA methylation in colorectal carcinogenesis.

    Science.gov (United States)

    Arasaradnam, R P; Commane, D M; Bradburn, D; Mathers, J C

    2008-01-01

    Colorectal cancer (CRC) is the most common cancer in non-smokers posing a significant health burden in the UK. Observational studies lend support to the impact of environmental factors especially diet on colorectal carcinogenesis. Significant advances have been made in understanding the biology of CRC carcinogenesis in particular epigenetic modifications such as DNA methylation. DNA methylation is thought to occur at least as commonly as inactivation of tumor suppressor genes. In fact compared with other human cancers, promoter gene methylation occurs most commonly within the gastrointestinal tract. Emerging data suggest the direct influence of certain micronutrients for example folic acid, selenium as well as interaction with toxins such as alcohol on DNA methylation. Such interactions are likely to have a mechanistic impact on CRC carcinogenesis through the methylation pathway but also, may offer possible therapeutic potential as nutraceuticals.

  14. The Combination of Three Natural Compounds Effectively Prevented Lung Carcinogenesis by Optimal Wound Healing.

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    Linxin Liu

    Full Text Available The tumor stroma has been described as "normal wound healing gone awry". We explored whether the restoration of a wound healing-like microenvironment may facilitate tumor healing. Firstly, we screened three natural compounds (shikonin, notoginsenoside R1 and aconitine from wound healing agents and evaluated the efficacies of wound healing microenvironment for limiting single agent-elicited carcinogenesis and two-stage carcinogenesis. The results showed that three compounds used alone could promote wound healing but had unfavorable efficacy to exert wound healing, and that the combination of three compounds made up treatment disadvantage of a single compound in wound healing and led to optimal wound healing. Although individual treatment with these agents may prevent cancer, they were not effective for the treatment of established tumors. However, combination treatment with these three compounds almost completely prevented urethane-induced lung carcinogenesis and reduced tumor burden. Different from previous studies, we found that urethane-induced lung carcinogenesis was associated with lung injury independent of pulmonary inflammation. LPS-induced pulmonary inflammation did not increase lung carcinogenesis, whereas decreased pulmonary inflammation by macrophage depletion promoted lung carcinogenesis. In addition, urethane damaged wound healing in skin excision wound model, reversed lung carcinogenic efficacy by the combination of three compounds was consistent with skin wound healing. Further, the combination of these three agents reduced the number of lung cancer stem cells (CSCs by inducing cell differentiation, restoration of gap junction intercellular communication (GJIC and blockade of the epithelial-to-mesenchymal transition (EMT. Our results suggest that restoration of a wound healing microenvironment represents an effective strategy for cancer prevention.

  15. Green tea catechin extract in intervention of chronic breast cell carcinogenesis induced by environmental carcinogens.

    Science.gov (United States)

    Rathore, Kusum; Wang, Hwa-Chain Robert

    2012-03-01

    Sporadic breast cancers are mainly attributable to long-term exposure to environmental factors, via a multi-year, multi-step, and multi-path process of tumorigenesis involving cumulative genetic and epigenetic alterations in the chronic carcinogenesis of breast cells from a non-cancerous stage to precancerous and cancerous stages. Epidemiologic and experimental studies have suggested that green tea components may be used as preventive agents for breast cancer control. In our research, we have developed a cellular model that mimics breast cell carcinogenesis chronically induced by cumulative exposures to low doses of environmental carcinogens. In this study, we used our chronic carcinogenesis model as a target system to investigate the activity of green tea catechin extract (GTC) at non-cytotoxic levels in intervention of cellular carcinogenesis induced by cumulative exposures to pico-molar 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P). We identified that GTC, at a non-cytotoxic, physiologically achievable concentration of 2.5 µg/mL, was effective in suppressing NNK- and B[a]P-induced cellular carcinogenesis, as measured by reduction of the acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, increased cell mobility, and acinar-conformational disruption. We also detected that intervention of carcinogen-induced elevation of reactive oxygen species (ROS), increase of cell proliferation, activation of the ERK pathway, DNA damage, and changes in gene expression may account for the mechanisms of GTC's preventive activity. Thus, GTC may be used in dietary and chemoprevention of breast cell carcinogenesis associated with long-term exposure to low doses of environmental carcinogens.

  16. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers.

    Science.gov (United States)

    Hayami, Shinya; Kelly, John D; Cho, Hyun-Soo; Yoshimatsu, Masanori; Unoki, Motoko; Tsunoda, Tatsuhiko; Field, Helen I; Neal, David E; Yamaue, Hiroki; Ponder, Bruce A J; Nakamura, Yusuke; Hamamoto, Ryuji

    2011-02-01

    A number of histone demethylases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human disease like cancer have not been well understood. Here, we demonstrate important roles of lysine-specific demethylase 1 (LSD1) in human carcinogenesis. Expression levels of LSD1 are significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (p human embryonic kidney fibroblast cells. Expression profile analysis showed that LSD1 could affect the expression of genes involved in various chromatin-modifying pathways such as chromatin remodeling at centromere, centromeric heterochromatin formation and chromatin assembly, indicating its essential roles in carcinogenesis through chromatin modification.

  17. Role of cholecystokinin in dietary fat-promoted azaserine-induced pancreatic carcinogenesis in rats

    NARCIS (Netherlands)

    Appel, M.J.; Meijers, M.; Garderen-Hoetmer, A. van; Lamers, C.B.H.W.; Rovati, L.C.; Sprij-Mooij, D.; Jansen, J.B.M.J.; Woutersen, R.A.

    1992-01-01

    The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturat

  18. In Vivo SILAC-Based Proteomics Reveals Phosphoproteome Changes during Mouse Skin Carcinogenesis

    DEFF Research Database (Denmark)

    Zanivan, Sara; Meves, Alexander; Behrendt, Kristina

    2013-01-01

    SILAC technology in combination with high-resolution mass spectrometry (MS) can be successfully used to measure phosphoproteomes in vivo. Here, Zanivan, Mann, and colleagues have applied SILAC-based MS to investigate phosphoproteomic changes during skin carcinogenesis, using the DMBA/TPA two-stag...

  19. Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Payne CM

    2011-05-01

    Full Text Available Claire M Payne, Cheray Crowley-Skillicorn, Carol Bernstein, Hana Holubec, Harris BernsteinDepartment of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USAAbstract: Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the “hot spots” in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.Keywords: chromosome 1p, colon carcinogenesis, molecular pathways, cellular pathways

  20. Non-steroidal anti-inflammatory drugs and molecular carcinogenesis of colorectal carcinomas

    NARCIS (Netherlands)

    Huls, G; Koornstra, JJ; Kleibeuker, JH

    2003-01-01

    Context Colorectal cancer is the second most common cause of cancer-related mortality in the west. The high incidence and mortality make effective prevention an important public-health and economic issue. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit colorectal-carcinogenesis and are am

  1. Null effect of dietary restriction on prostate carcinogenesis in the Wistar-Unilever rat.

    Science.gov (United States)

    McCormick, David L; Johnson, William D; Haryu, Todd M; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E

    2007-01-01

    Chronic dietary restriction inhibits carcinogenesis in several sites in laboratory animals. To determine the effects of dietary restriction on prostate carcinogenesis, prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate (50 mg/day; 21 days); testosterone propionate (100 mg/kg/day; 3 days); N-methyl-N-nitrosourea [MNU; 30 mg/kg; single dose]; and testosterone (subcutaneous implants of 2 pellets containing 40 mg each). Dietary restriction (0% [ad libitum control], 15%, or 30%) was initiated 2 wk post-MNU, and continued until study termination at 12 mo. Dietary restriction induced a rapid suppression of body weight gain but conferred no protection against prostate carcinogenesis. 74% of carcinogen-treated ad libitum controls developed accessory sex gland cancers, versus cancer incidences of 64% and 72% in groups restricted by 15% and 30%, respectively. Similarly, 44% of dietary controls developed cancers limited to the dorsolateral/prostate, versus incidences of 45% and 53% in groups restricted by 15% and 30%. The results of the present study do not support the hypothesis that prostate carcinogenesis can be prevented by reducing caloric intake. Reducing mean body weight by up to 25% through chronic dietary restriction has no effect on the induction of prostate cancers in the Wistar-Unilever rat model.

  2. Diet, lifestyle, heritable factors and colorectal carcinogenesis: associations with histopathological and molecular endpoints

    NARCIS (Netherlands)

    Wark, P.A.

    2007-01-01

    Background: Diet, lifestyle and heritable factors have been related to colorectal cancer risk; to date, their relevance to the overall scope of colorectal carcinogenesis, has not been clearly established.Aim and Methods: To evaluate whether distinguishing colorectal tissue by its histopathological a

  3. Fetal cell carcinogenesis of the thyroid: a modified theory based on recent evidence.

    Science.gov (United States)

    Takano, Toru

    2014-01-01

    Thyroid cancer cells were believed to be generated by multi-step carcinogenesis, in which cancer cells are derived from thyrocytes, via multiple incidences of damage to their genome, especially in oncogenes or anti-oncogenes that accelerate proliferation or foster malignant phenotypes, such as the ability to invade the surrounding tissue or metastasize to distant organs, until a new hypothesis, fetal cell carcinogenesis, was presented. In fetal cell carcinogenesis, thyroid tumor cells are assumed to be derived from three types of fetal thyroid cell which only exist in fetuses or young children, namely, thyroid stem cells (TSCs), thyroblasts and prothyrocytes, by proliferation without differentiation. Genomic alternations, such as RET/PTC and PAX8-PPARγ1 rearrangements and a mutation in the BRAF gene, play an oncogenic role by preventing thyroid fetal cells from differentiating. Fetal cell carcinogenesis effectively explains recent molecular and clinical evidence regarding thyroid cancer, including thyroid cancer initiating cells (TCICs), and it underscores the importance of identifying a stem cells and clarifying the molecular mechanism of organ development in cancer research. It introduces three important concepts, the reverse approach, stem cell crisis and mature and immature cancers. Further, it implies that analysis of a small population of cells in a cancer tissue will be a key technique in establishing future laboratory tests. In the contrary, mass analysis such as gene expression profiling, whole genomic scan, and proteomics analysis may have definite limitations since they can only provide information based on many cells.

  4. Mechanisms of carcinogenesis in human skin against the background of papillomavirus infection.

    Science.gov (United States)

    Reva, I V; Reva, G V; Yamamoto, T; Tolmachyov, V E

    2014-09-01

    The cells in the skin tumor developing under conditions of persisting papillomavirus infection are morphologically identical to blast cells in a blood smear from a leukemia patient. The cells filling the lesion focus are morphologically and immunohistochemically related to blood stem cells. A mechanism of epithelial layer modification under conditions of papillomavirus infection leading to carcinogenesis is proposed. The dynamics of structural changes in the skin is characterized by disturbed interactions between the epithelium and adjacent connective tissue, destruction of the basal membrane, disorders in the cambial keratinocyte differentiation, and absence of the spinous and granular layers. We conclude that detection of blast leukocytes in the human skin lesion can be explained by disorders in the cell-cell interactions in the epithelium-mesenchymal tissue system. High proliferative activity followed by death of cambial keratinocytes, migration of effector antigen-presenting CD68 cells to the adjacent connective tissue are the factors inducing migration of blast leukocytic forms to the focus. Not only keratinocyte restitution capacity, but also epithelium-dependent differentiation of young leukocytes disappeared. Undifferentiated cells are migrated from the blood to the epithelium alteration zone, but not in the reverse direction. The insufficiency or the absence of blood blast cell differentiation of the in the focus of epidermal injury and adjacent tissue triggers carcinogenesis. The authors suggest their model of carcinogenesis. The conclusions offer a new concept of cancer pathogenesis and suggest a new strategy in the search for methods for early diagnosis of carcinogenesis.

  5. Effects of dietary fat on virus-induced pancreatic carcinogenesis in guinea fowl

    NARCIS (Netherlands)

    Kirev, T.; Woutersen, R.A.; Kril, A.

    2002-01-01

    The present study was performed to assess the effects of diets supplemented with low (5%) and high (20%) corn oil on a Pts 56 retrovirus-induced model of pancreatic carcinogenesis in guinea fowl. The early microscopic lesions appear after 3 mo after virus treatment and progress over time. Eight to 1

  6. Diet, lifestyle, heritable factors and colorectal carcinogenesis: associations with histopathological and molecular endpoints

    NARCIS (Netherlands)

    Wark, P.A.

    2007-01-01

    Background: Diet, lifestyle and heritable factors have been related to colorectal cancer risk; to date, their relevance to the overall scope of colorectal carcinogenesis, has not been clearly established.Aim and Methods: To evaluate whether distinguishing colorectal tissue by its histopathological

  7. Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma. Part 1: Human papillomavirus-mediated carcinogenesis

    Directory of Open Access Journals (Sweden)

    Khammissa Razia AG

    2010-07-01

    Full Text Available Abstract High-risk human papillomavirus (HPV E6 and E7 oncoproteins are essential factors for HPV-induced carcinogenesis, and for the maintenance of the consequent neoplastic growth. Cellular transformation is achieved by complex interaction of these oncogenes with several cellular factors of cell cycle regulation including p53, Rb, cyclin-CDK complexes, p21 and p27. Both persistent infection with high-risk HPV genotypes and immune dysregulation are associated with increased risk of HPV-induced squamous cell carcinoma.

  8. Histone acetyltransferases and deacetylases: molecular and clinical implications to gastrointestinal carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Wei-Jian Sun; Xiang Zhou; Ji-Hang Zheng; Ming-Dong Lu; Jian-Yun Nie; Xiang-Jiao Yang; Zhi-Qiang Zheng

    2012-01-01

    Histone acetyltransferases and deacetylases are two groups of enzymes whose opposing activities govern the dynamic levels of reversible acetylation on specific lysine residues of histones and many other proteins.Gastrointestinal (GI) carcinogenesis is a major cause of morbidity and mortality worldwide.In addition to genetic and environmental factors,the role of epigenetic abnormalities such as aberrant histone acetylation has been recognized to be pivotal in regulating benign tumorigenesis and eventual malignant transformation.Here we provide an overview of histone acetylation,list the major groups of histone acetyltransferases and deacetylases,and cover in relatively more details the recent studies that suggest the links of these enzymes to GI carcinogenesis.As potential novel therapeutics for GI and other cancers,histone deacetylase inhibitors are also discussed.

  9. Defining the role of polyamines in colon carcinogenesis using mouse models

    Directory of Open Access Journals (Sweden)

    Natalia A Ignatenko

    2011-01-01

    Full Text Available Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.

  10. The pleiotropic roles of transforming growth factor beta inhomeostasis and carcinogenesis of endocrine organs.

    Energy Technology Data Exchange (ETDEWEB)

    Fleisch, Markus C.; Maxwell, Christopher A.; Barcellos-Hoff,Mary-Helen

    2006-01-13

    Transforming growth factor beta (TGF-beta) is a ubiquitous cytokine that plays a critical role in numerous pathways regulating cellular and tissue homeostasis. TGF-beta is regulated by hormones and is a primary mediator of hormone response in uterus, prostate and mammary gland. This review will address the role of TGF-beta in regulating hormone dependent proliferation and morphogenesis. The subversion of TGF-beta regulation during the processes of carcinogenesis, with particular emphasis on its effects on genetic stability and epithelial to mesenchymal transition (EMT), will also be examined. An understanding of the multiple and complex mechanisms of TGF-beta regulation of epithelial function, and the ultimate loss of TGF-beta function during carcinogenesis, will be critical in the design of novel therapeutic interventions for endocrine-related cancers.

  11. Chemomodulatory Potential of Flaxseed Oil Against DMBA/Croton Oil-Induced Skin Carcinogenesis in Mice.

    Science.gov (United States)

    Sharma, Jyoti; Singh, Ritu; Goyal, P K

    2016-09-01

    The present study was conducted to evaluate the potential of flaxseed oil to prevent chemically induced skin cancer in mice. Cancer was induced on 2-stage skin carcinogenesis model by single topical application of 7,12 dimethylbenz [a]anthracene (DMBA), as, initiator, and two weeks later it was promoted by croton oil treatment thrice a week on the dorsal surface of mice for 16 weeks. Flaxseed oil (FSO; 100µL/animal/d) was orally administered 1 week before and 1 week after DMBA application (Peri-initiation stage). The animals of the FSO-administered group showed a significant reduction in tumor incidence (76.67%), cumulative number of tumors (37), tumor yield (3.7), and tumor burden (4.81) when compared with the carcinogen-treated control animals. Biochemical parameters in skin and liver tissue such as LPO and phase I enzymes were significantly (P croton oil-induced skin carcinogenesis in mice.

  12. Gastric Carcinogenesis and Underlying Molecular Mechanisms: Helicobacter pylori and Novel Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Toshihiro Nishizawa

    2015-01-01

    Full Text Available The oxygen-derived free radicals that are released from activated neutrophils are one of the cytotoxic factors of Helicobacter pylori-induced gastric mucosal injury. Increased cytidine deaminase activity in H. pylori-infected gastric tissues promotes the accumulation of various mutations and might promote gastric carcinogenesis. Cytotoxin-associated gene A (CagA is delivered into gastric epithelial cells via bacterial type IV secretion system, and it causes inflammation and activation of oncogenic pathways. H. pylori infection induces epigenetic transformations, such as aberrant promoter methylation in tumor-suppressor genes. Aberrant expression of microRNAs is also reportedly linked to gastric tumorogenesis. Moreover, recent advances in molecular targeting therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER-2 therapies. This updated review article highlights possible mechanisms of gastric carcinogenesis including H. pylori-associated factors.

  13. Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Stav Sapoznik

    2016-02-01

    Full Text Available In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.

  14. Modulatory activity of Brazilian red propolis on chemically induced dermal carcinogenesis.

    Science.gov (United States)

    Pinheiro, Kariny Souza; Ribeiro, Danielle Rodrigues; Alves, Angela Valéria Farias; Pereira-Filho, Rose Nely; Oliveira, Clauberto Rodrigues de; Lima, Sônia Oliveira; Reis, Francisco Prado; Cardoso, Juliana Cordeiro; Albuquerque-Júnior, Ricardo Luiz Cavalcanti de

    2014-02-01

    To evaluate modulatory effects of a hydroalcoholic extract of Brazilian red propolis (HERP) on dermal carcinogenesis using a murine model. The HERP was used at concentrations of 10, 50 and 100 mg/kg (PROP10, PROP50 and PROP100, respectively) to modulate dermal carcinogenesis induced by the application of 9,10-dimetil-1,2-benzatraceno (DMBA) on the backs of animals. The chemical compounds identified in HERP included propyl gallate, catechin, epicatechin and formononetin. PROP100 treatment resulted in significantly decreased tumor multiplicity throughout the five weeks of tumor promotion (p0.05). The oral administration of hydroalcoholic extract of Brazilian red propolis at a dose of 100 mg/kg had a significant modulatory effect on the formation, differentiation and progression of chemically induced squamous cell carcinoma in a murine experimental model.

  15. Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis

    OpenAIRE

    Boopalan, Thiyagarajan; Arumugam, Arunkumar; Parada, Jacqueline; Saltzstein, Edward; Lakshmanaswamy, Rajkumar

    2015-01-01

    Breast cancer is a leading cause of cancer-related death in women. Prolonged exposure to the ovarian hormones estrogen and progesterone increases the risk of breast cancer. Although estrogen is known as a primary factor in mammary carcinogenesis, very few studies have investigated the role of progesterone. Receptor activator for nuclear factor-κB (NF-κB) ligand (RANKL) plays an important role in progesterone-induced mammary carcinogenesis. However, the molecular mechanism underlying RANKL-ind...

  16. Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties.

    Directory of Open Access Journals (Sweden)

    Lenora Ann Pluchino

    Full Text Available Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and benzo[a]pyrene (B[a]P, and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.

  17. Epidemiological studies on radiation carcinogenesis in human populations following acute exposure: nuclear explosions and medical radiation

    Energy Technology Data Exchange (ETDEWEB)

    Fabrikant, J.I.

    1981-05-01

    The current knowledge of the carcinogenic effect of radiation in man is considered. The discussion is restricted to dose-incidence data in humans, particularly to certain of those epidemiological studies of human populations that are used most frequently for risk estimation for low-dose radiation carcinogenesis in man. Emphasis is placed solely on those surveys concerned with nuclear explosions and medical exposures. (ACR)

  18. In Vivo Testing of Chemopreventive Agents Using the Dog Model of Spontaneous Prostate Carcinogenesis

    Science.gov (United States)

    2005-03-01

    squamous cell or basal cell carcinoma , ing for smoking exposure, non-tumorous lung tissue melanoma); oropharyngeal; hepatocellular carcinoma ; of women...supplementation on cancer incidence in a randomized clinical squamous cell carcinoma of the skin in relation to plasma trial: a summary report of the...invasive carcinoma . In vivo screening of promising chemopreventive agents using the dog model of spontaneous prostate carcinogenesis represents a novel

  19. Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies

    OpenAIRE

    2012-01-01

    Context Our previous study suggested that porcine pancreatic extract in hamsters with peripheral insulin resistance, normalizes insulin output, islet size and pancreatic DNA synthetic rate. It also inhibited the growth of human pancreatic cancer cells in nude mice. Objective To examine the potential value of the porcine pancreatic extract in controlling pancreatic carcinogenesis in this model, the present experiment was performed. Design Hamsters were fed a high fat diet and four wee...

  20. Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice

    OpenAIRE

    Feith, David J.; Pegg, Anthony E.; Fong, Louise Y. Y.

    2012-01-01

    Upper aerodigestive tract (UADT) cancers of the oral cavity and esophagus are a significant global health burden, and there is an urgent need to develop relevant animal models to identify chemopreventive and therapeutic strategies to combat these diseases. Antizyme (AZ) is a multifunctional negative regulator of cellular polyamine levels, and here, we evaluate the susceptibility of keratin 5 (K5)-AZ transgenic mice to tumor models that combine chemical carcinogenesis with dietary and genetic ...

  1. JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes,cholangiocarcinoma predisposition and development.Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.

  2. Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria: a systematic review

    Directory of Open Access Journals (Sweden)

    Emanuel Dias-Jácome

    Full Text Available Background and aim: Helicobacter pylori is the strongest risk factor for gastric cancer. However, recent advances in DNA sequencing technology have revealed a complex microbial community in the stomach that could also contribute to the development of gastric cancer. The aim of this study was to present recent scientific evidence regarding the role of non-Helicobacter pylori bacteria in gastric carcinogenesis. Methods: A systematic review of original articles published in PubMed in the last ten years related to gastric microbiota and gastric cancer in humans was performed. Results: Thirteen original articles were included. The constitution of gastric microbiota appears to be significantly affected by gastric cancer and premalignant lesions. In fact, differences in gastric microbiota have been documented, depending on Helicobacter pylori status and gastric conditions, such as non-atrophic gastritis, intestinal metaplasia and cancer. Gastric carcinogenesis can be associated with an increase in many bacteria (such as Lactobacillus coleohominis, Klebsiella pneumoniae or Acinetobacter baumannii as well as decrease in others (such as Porphyromonas spp, Neisseria spp, Prevotella pallens or Streptococcus sinensis. However, there is no conclusive data that confirms if these changes in microbiota are a cause or consequence of the process of carcinogenesis. Conclusions: Even though there is limited evidence in humans, microbiota differences between normal individuals, pre-malignant lesions and gastric cancer could suggest a progressive shift in the constitution of gastric microbiota in carcinogenesis, possibly resulting from a complex cross-talk between gastric microbiota and Helicobacter pylori. However, further studies are needed to elucidate the specific role (if any of different microorganisms.

  3. Carcinogenesis associated with parasites other than Schistosoma, Opisthorchis and Clonorchis: A systematic review.

    Science.gov (United States)

    Machicado, Claudia; Marcos, Luis A

    2016-06-15

    Only three helminths (Schistosoma haematobium, Opisthorchis viverrini and Clonorchis sinensis) are directly associated with carcinogenesis in humans whereas the role of other parasites in cancer remains unclear. This study aimed to perform a systematic review to identify recent insights in the role of other parasite infections in carcinogenesis. We conducted systematic searches of MEDLINE and EMBASE on July 2015. Our primary outcome was the association between parasitic infections and carcinogenesis. Out of 1,266 studies, 19 were selected for detailed evaluation (eight for helminths and 11 for protozoa). The mechanisms of helminth-induced cancer included chronic inflammation, sustained proliferation, modulation of the host immune system, reprogramming of glucose metabolism and redox signaling, induction of genomic instability and destabilization of suppressor tumor proteins, stimulation of angiogenesis, resisting cell death, and activation of invasion and metastasis. In addition to the current knowledge, the following parasites were found in cancers or tumors: Echinococcus, Strongyloides, Fasciola, Heterakis, Platynosomum and Trichuris. Additional parasites were found in this systematic review that could potentially be associated with cancers or tumors but further evidence is needed to elaborate a cause-effect relationship. © 2016 UICC.

  4. The level of claudin-7 is reduced as an early event in colorectal carcinogenesis

    Directory of Open Access Journals (Sweden)

    Tveit Kjell M

    2011-02-01

    Full Text Available Abstract Background Compromised epithelial barriers are found in dysplastic tissue of the gastrointestinal tract. Claudins are transmembrane proteins important for tight junctions. Claudins regulate the paracellular transport and are crucial for maintaining a functional epithelial barrier. Down-regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both in vivo and in vitro. We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression. We have previously shown that the matriptase expression level decreases during colorectal carcinogenesis. In the present study we investigated whether claudin-7 expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue. Methods The mRNA level of claudin-7 (CLDN7 was determined in samples from 18 healthy individuals, 100 individuals with dysplasia and 121 colorectal cancer patients using quantitative real time RT-PCR. In addition, immunohistochemical stainings were performed on colorectal adenomas and carcinomas, to confirm the mRNA findings. Results A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p claudin-7 mRNA levels were also detected in mild/moderate dysplasia (p Conclusions Our results show that the claudin-7 mRNA level is decreased already as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas.

  5. Evidence for a role of E-cadherin in suppressing liver carcinogenesis in mice and men.

    Science.gov (United States)

    Schneider, Marlon R; Hiltwein, Felix; Grill, Jessica; Blum, Helmut; Krebs, Stefan; Klanner, Andrea; Bauersachs, Stefan; Bruns, Christiane; Longerich, Thomas; Horst, David; Brandl, Lydia; de Toni, Enrico; Herbst, Andreas; Kolligs, Frank T

    2014-08-01

    The cell adhesion molecule E-cadherin has critical functions in development and carcinogenesis. Impaired expression of E-cadherin has been associated with disrupted tissue homeostasis, progression of cancer and a worse patient prognosis. So far, the role of E-cadherin in homeostasis and carcinogenesis of the liver is not well understood. By use of a mouse model with liver-specific deletion of E-cadherin and administration of the carcinogen diethylnitrosamine, we demonstrate that loss of E-cadherin expression in hepatocytes results in acceleration of the growth of hepatocellular carcinoma (HCC). In contrast, liver regeneration is not disturbed in mice lacking E-cadherin expression in hepatocytes. In human HCC, we observed four different expression patterns of E-cadherin. Notably, atypical cytosolic expression of E-cadherin was positively correlated with a poorer patient prognosis. The median overall survival of patients with HCC expressing E-cadherin on the membrane only was 221 weeks (95% confidence interval: 51-391) compared with 131 weeks in patients with cytosolic expression (95% confidence interval: 71-191 weeks; P < 0.05). In conclusion, we demonstrate that impaired expression of E-cadherin promotes hepatocellular carcinogenesis and is associated with a worse prognosis in humans.

  6. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Ki Baik Hahm

    2011-07-01

    Full Text Available Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.

  7. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun-Hee; Hong, Kyung-Sook; Hong, Hua [Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Hahm, Ki Baik, E-mail: hahmkb@gachon.ac.kr [Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Department of Gastroenterology, Gachon Graduate School of Medicine, Gil Hospital, Incheon 406-840 (Korea, Republic of)

    2011-07-25

    Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.

  8. Tomatoes versus lycopene in oxidative stress and carcinogenesis: conclusions from clinical trials.

    Science.gov (United States)

    Basu, A; Imrhan, V

    2007-03-01

    To review the effects of tomato product supplementation, containing lycopene, on biomarkers of oxidative stress and carcinogenesis in human clinical trials. Supplementation of tomato products, containing lycopene, has been shown to lower biomarkers of oxidative stress and carcinogenesis in healthy and type II diabetic patients, and prostate cancer patients, respectively. Processed tomato products like tomato juice, tomato paste, tomato puree, tomato ketchup and tomato oleoresin have been shown to provide bioavailable sources of lycopene, with consequent increases in plasma lycopene levels versus baseline. Dietary fats enhance this process and should be consumed together with food sources of lycopene. The mechanisms of action involve protection of plasma lipoproteins, lymphocyte DNA and serum proteins against oxidative damage, and anticarcinogenic effects, including reduction of prostate-specific antigen, upregulation of connexin expression and overall decrease in prostate tumor aggressiveness. There is limited in vivo data on the health benefits of lycopene alone. Most of the clinical trials with tomato products suggest a synergistic action of lycopene with other nutrients, in lowering biomarkers of oxidative stress and carcinogenesis. Consumption of processed tomato products, containing lycopene, is of significant health benefit and can be attributed to a combination of naturally occurring nutrients in tomatoes. Lycopene, the main tomato carotenoid, contributes to this effect, but its role per se remains to be investigated.

  9. Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by azoxymethane in mice

    Institute of Scientific and Technical Information of China (English)

    Tamao Nishihara; Shinji Tamura; Norio Hayashi; Hiroyasu Iishi; Iichiro Shimornura; Miyako Baba; Morihiro Matsuda; Masahiro Inoue; Yasuko Nishizawa; Atsunori Fukuhara; Hiroshi Arald; Shinji Kihara; Tohru Funahashi

    2008-01-01

    AIM: To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model, and to determine the con-tribution of adiponectin deficiency to colorectal cancer development and proliferation. METHODS: We examined the influence of adiponectin deficiency on colorectal carcinogenesis induced by the administration of azoxymethane (AOM) (7.5 mg/kg, in-traperitoneal injection once a week for 8 wk), by using adiponectin-knockout (KO) mice. RESULTS: At 53 wk after the first AOM treatment, KOmice developed larger and histologically more progres-sive colorectal tumors with greater frequency com-pared with wild-type (WT) mice, although the tumor incidence was not different between WT and KO mice. KO mice showed increased cell proliferation of colorec-tal tumor cells, which correlated with the expression levels of cyclooxygenase-2 (COX-2) in the colorectal tumors. In addition, KO mice showed higher incidence and frequency of liver tumors after AOI treatment. Thirteen percent of WT mice developed liver tumors, and these WT mice had only a single tumor. In contrast, 50% of K.O mice developed liver tumors, and 58% of these KO mice had multiple tumors. CONCLUSION: Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice. This study strongly suggests that hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.

  10. Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications

    Science.gov (United States)

    O’Connell, Malaney; Shubhashish, Sarkar

    2016-01-01

    Colorectal carcinogenesis is a multi-step process. While ~25% of colorectal cancers (CRCs) arise in patients with a family history (genetic predisposition), ~75% of CRCs are due to age-associated accumulation of epigenetic alterations which can result in the suppression of key tumor suppressor genes leading to mutations and activation of oncogenic pathways. Sporadic colon-carcinogenesis is facilitated by many molecular pathways of genomic instability which include chromosomal instability (CIN), micro-satellite instability (MSI) and CpG island methylator phenotype (CIMP), leading towards loss of homeostasis and onset of neoplastic transformation. The unopposed activation of Wnt/β-catenin pathways, either due to loss of APC function or up-regulation of related stimulatory pathways, results in unopposed hyperproliferation of colonic crypts, considered the single most important risk factor for colon carcinogenesis. Hypermethylation of CpG islands within the promoters of specific genes can potentially inactivate DNA repair genes and/or critical tumor suppressor genes. Recently, CpG methylation of the 5’ promoter of human (h) DCLK1 gene was reported in many human epithelial cancers, including colorectal cancers (CRCs), resulting in the loss of expression of the canonical long isoform of DCLK1 (DCLK1-L) in hCRCs. Instead, a shorter isoform of DCLK1 (DCLK1-S) was discovered to be expressed in hCRCs, from an alternate β promoter of DCLKL1-gene; the clinical and biological implications of these novel findings, in relation to recent publications is discussed. PMID:27777940

  11. DNA Damage in Inflammation-Related Carcinogenesis and Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Shiho Ohnishi

    2013-01-01

    Full Text Available Infection and chronic inflammation have been recognized as important factors for carcinogenesis. Under inflammatory conditions, reactive oxygen species (ROS and reactive nitrogen species (RNS are generated from inflammatory and epithelial cells and result in oxidative and nitrative DNA damage, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG and 8-nitroguanine. The DNA damage can cause mutations and has been implicated in the initiation and/or promotion of inflammation-mediated carcinogenesis. It has been estimated that various infectious agents are carcinogenic to humans (IARC group 1, including parasites (Schistosoma haematobium (SH and Opisthorchis viverrini (OV, viruses (hepatitis C virus (HCV, human papillomavirus (HPV, and Epstein-Barr virus (EBV, and bacterium Helicobacter pylori (HP. SH, OV, HCV, HPV, EBV, and HP are important risk factors for bladder cancer, cholangiocarcinoma, hepatocellular carcinoma, cervical cancer, nasopharyngeal carcinoma, and gastric cancer, respectively. We demonstrated that 8-nitroguanine was strongly formed via inducible nitric oxide synthase (iNOS expression at these cancer sites of patients. Moreover, 8-nitroguanine was formed in Oct3/4-positive stem cells in SH-associated bladder cancer tissues and in Oct3/4- and CD133-positive stem cells in OV-associated cholangiocarcinoma tissues. Therefore, it is considered that oxidative and nitrative DNA damage in stem cells may play a key role in inflammation-related carcinogenesis.

  12. Type 2 Diabetes Mellitus and Its Association with the Risk of Pancreatic Carcinogenesis: A Review.

    Science.gov (United States)

    Biadgo, Belete; Abebe, Molla

    2016-04-25

    The prevalence of diabetes mellitus (DM) and associated diseases such as cancers are substantially increasing worldwide. About 80% of the patients with pancreatic cancer have glucose metabolism alterations. This suggests an association between type 2 DM and pancreatic cancer risk and progression. There are hypotheses that show metabolic links between the diseases, due to insulin resistance, hyperglycemia, hyperinsulinemia, low grade chronic inflammation, and alteration in the insulin-insulin-like growth factor axis. The use of diabetes medications can influence the extent of carcinogenesis of the pancreas. This study briefly reviews recent literature on investigation of metabolic link of type 2 DM, risk of carcinogenesis of the pancreas and their association, as well as the current understanding of metabolic pathways implicated in metabolism and cellular growth. The main finding of this review, although there are discrepancies, is that according to most research long-term DM does not raise the risk of pancreatic cancer. The longest duration of DM may reflect hypoinsulinemia due to treatment for hyperglycemia, but recent onset diabetes was associated with increased risk for pancreatic cancer due to hyperinsulinemia and hyperglycemia. In conclusion, the review demonstrates that type 2 DM and the duration of diabetes pose a risk for pancreatic carcinogenesis, and that there is biological link between the diseases.

  13. Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Tong Guo; Xi-Sheng Leng; Tao Li; Jing-Ming Zhao; Xi-Hou Lin

    2004-01-01

    AIM: Peroxisome proliferator-activated receptor γ (PPARγ)is known to regulate growth arrest and terminal differentiation of adipocytes and is used clinically as a new class of antidiabetic drugs. Recently, several studies have reported that treatment of cancer cells with PPARγ ligands could induce cell differentiation and apoptosis, suggesting a potential application as chemopreventive agents against carcinogenesis. In the present study, 3 different kinds of PPARγ ligands were subjected to the experiments to confirm their suppressive effects on liver carcinogenesis.METHODS: Three PPARγ ligands, pioglitazone (Pio) (200 ppm),rosiglitazone (Rosi) (200 ppm), and troglitazone (Tro)(1 000 ppm) were investigated on the induction of the placental form of rat glutathione S-transferase (rGST P)positive foci, a precancerous lesion of the liver, and liver cancer formation using a diethylnitrosamine-induced liver cancer model in Wistar rats, and dose dependency of a PPARγ ligand was also examined.RESULTS: PPARγ ligands reduced the formation of rGST P-positive foci by diethylnitrosamine and induction of liver cancers was also markedly suppressed by a continuous feeding of Pio at 200 ppm.CONCLUSION: PPARγ ligands are potential chemopreventive agents for liver carcinogenesis.

  14. The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

    Directory of Open Access Journals (Sweden)

    Brock J. Sishc

    2017-07-01

    Full Text Available DNA double-strand breaks (DSBs are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ’s role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics.

  15. Exploration of Multigene, Mulfistep and Multipathway Models of Nasopharyngeal and Colorectal Carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    ZhihuoYin

    2004-01-01

    OBJECTIVE To construct tree models for nasopharyngeal carcinoma (NPC) and colorectal carcinoma (CC) and explore the oncogeneic process of NPC and CC .METHODS Based on the software that Desper et al. developed, tree models were constructed for CC from the comparative genomic hybridization (CGH) data of 118 CC patients and for NPC from the CGH data of 140 southern Chinese patients, respectively. RESULTS Tree models for CC suggested that loss of 18q and gain of 20q were important early events in colorectal carcinogenesis. As changes in -18q occurred prior to those in -17p, a cause-effect relationship might exist between them. Tree models for NPC suggested that loss of 3p was an important early event in nasopharyngeal carcinogenesis, and deletion of 11q, 14q, 16q and 9p were also nonrandom genetic events in carcinogenesis, suggesting that there might be tumor-associated genes existing on these chromosome arms. The tree model also indicated the existence of oncogenes on the short arm of chromosome 12.CONCLUSION Constructing tree models based on the CGH data to demonstrate the initiation and progression of NPC might help elucidate its multigene, multistep and multipathway development. It may provide valuable clues to explore the mechanism of tumorigenesis.

  16. Effect of Cu supplementation on genomic instability in chemically-induced mammary carcinogenesis in the rat

    Directory of Open Access Journals (Sweden)

    Bobrowska Barbara

    2011-12-01

    Full Text Available Abstract Backround The aim of the present study was to assess the effect of dietary supplementation (copper or copper and resveratrol on the intensity of carcinogenesis and the frequency of microsatellite instability in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethylbenz[a]anthracene (DMBA. Methods DNA was extracted from rat mammary cancers and normal tisues, amplified by PCR, using different polymorphic DNA markers and the reaction products were analyzed for microsatellite instability. Results It was found that irrespectively of the applied diet there was no inhibition of mammary carcinogenesis in the rats due to DMBA. Besides, in the groups supplemented with Cu (II or Cu (II and resveratrol the tumor formation was clearly accelerated. Unlike the animals that were fed with standard diet, the supplemented rats were characterized by the loss of heterozygosity of microsatellite D3Mgh9 in cancer tumors (by respectively 50 and 40%. When the animals received Cu (II and resveratrol supplemented diet the occurrence of genomic instability was additionally found in their livers in the case of microsatellite D1Mgh6 (which was stable in the animals without dietary supplementation. Conclusions Identification of the underlying mechanisms by which dietary factors affect genomic stability might prove useful in the treatment of mammary cancer as well as in the incorporation of dietary factors into mammary cancer prevention strategies.

  17. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis.

    Science.gov (United States)

    Jiang, Li; Chew, Shan-Hwu; Nakamura, Kosuke; Ohara, Yuuki; Akatsuka, Shinya; Toyokuni, Shinya

    2016-07-01

    Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations are similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used i.p. administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition, and nuclear 8-hydroxy-2'-deoxyguanosine levels in mesothelial cells, whereas nitrilotriacetate significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells to counteract asbestos-induced cytotoxicity than in murine macrophages (RAW264.7). Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than rat peritoneal mesothelial cells. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelial carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously.

  18. Causal role of Helicobacter pylori infection and eradication therapy in gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Masanori Ito; Shinji Tanaka; Tomoari Kamada; Ken Haruma; Kazuaki Chayama

    2006-01-01

    Many epidemiological reports indicate that Helicobacter pylori(H pylori) infection plays an important role in gastric carcinogenesis. Several genetic and epigenetic alterations contribute to the initiation, promotion, and progression of the cancer cells in a multi-step manner.H pyloriis known to induce chronic inflammation in the gastric mucosa. Its products, including superoxides,participate in the DNA damage followed by initiation, and the inflammation-derived cytokines and growth factors contribute to the promotion of gastric carcinogenesis.By eradicating H pylori, gastric inflammation can be cured; the therapy diminishes the levels not only of inflammatory cell infiltration, but also atrophyl intestinal metaplasia in part. A randomized controlled trial revealed that the eradication therapy diminished the gastric cancer prevalence in cases without precancerous conditions. In addition, recent epidemiological studies from Japanese groups demonstrated that the development of gastric cancer, especially of the intestinal type, was decreased by successful eradication therapy, although these were designed in a nonrandomized manner. However, it should be mentioned that endoscopic detection is the only way to evaluate the degree of gastric carcinogenesis. We have reported that the endoscopic and histological morphologies could be modified by eradication therapy and it might contribute to the prevalence of gastric cancer development.Considering the biological nature of cancer cell proliferation, it is considered that a sufficiently long-term follow-up would be essential to discuss the anticancer effect of eradication therapy.

  19. Explanation of the mechanism of carcinogenesis and syntheses of anticancer agents with high selectivity

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In 1979, the mechanism of chemical carcinogenesis, a challenging and difficult scientific problem pending for a number of years, was explained by Dai Qianhuan. The mechanism named di-region theory predicted that a carcinogen always metabolizes to form a special bi-functional alkylating agent. This agent induces cross-linkages between the complementary base pairs in DNA and switches on initial mutageneses in genomes including point and frameshift mutations. This, in turn, induces further deep mutageneses including the production of various chimeric chromosomes, deletions and other aberrations found in genomes. In the end this initiates carcinogenesis of the whole cell through the reverse transcription mechanism after a lengthy incubation period. Recently, this laboratory has verified that physical carcinogenesis, including the oncogenesis induced by radiation and asbestos as well as the carcinogenesis induced by endogenous factors such as estrogen or diethylstilbestrol switch on carcinogenesis by inducing the formation of cross-linkages between the complementary base pairs in DNA. Di-region theory has now been supported by many experimental observations such as mutational spectra of various carcinogens. The potential for carcinogenesis, teratogenesis, sterility and mutagenesis lumped together as genetic toxicity appears to originate almost uniformly from the cross-linking between complementary bases, i.e. malignant cross-linking, which is in accordance with di-region theory. Other forms of cross-linking between non-complementary bases, benign cross-linkings, show bi-functional alkylation anticancer activity but lack genetic toxicity. The predictable design and synthesis of a high selectivity anticancer agent with high efficacy and low genetic toxicity, a goal long pursued in cancer chemotherapy, have been realized for the first time in this laboratory by inhibiting malignant and heightening benign cross-linking using the principles of di-region theory. A series of

  20. Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via retinoblastoma pathway

    Institute of Scientific and Technical Information of China (English)

    Christian Gulmann; Helen Hegarty; Antoinette Grace; Mary Leader; Stephen Patchett; Elaine Kay

    2004-01-01

    AIM: Disruption of cell cycle regulation is a critical event in carcinogenesis, and alteration of the retinoblastoma (pRb)tumour suppressor pathway is frequent. The aim of this study was to compare alterations in this pathway in proximal and distal gastric carcinogenesis in an effort to explain the observed striking epidemiological differences.METHODS: Immunohistochemistry was performed to investigate expression of p16 and pRb in the following groups of both proximal (cardia) and distal (antral) tissue samples: (a) biopsies showing normal mucosa, (b) biopsies showing intestinal metaplasia and, (c) gastric cancer resection specimens including uninvolved mucosa and tumour.RESULTS: In the antrum there were highly significant trends for increased p16 expression with concomitant (and in the group of carcinomas inversely proportional)decreased pRb expression from normal mucosa to intestinal metaplasia to uninvolved mucosa (from cancer resections)to carcinoma. In the cardia, there were no differences in p16 expression between the various types of tissue samples whereas pRb expression was higher in normal mucosa compared with intestinal metaplasia and tissue from cancer resections.CONCLUSION: Alterations in the pRb pathway appear to play a more significant role in distal gastric carcinogenesis.Tt may be an early event in the former location since the trend towards p16 overexpression with concomitant pRb underexpression was seen as early as between normal mucosa and intestinal metaplasia. Importantly, the marked differences in expression of pRb and p16 between the cardia and antrum strongly support the hypothesis that tumours of the two locations are genetically different which may account for some of the observed epidemiological differences.

  1. Histological and ultrastructural changes induced by selenium in early experimental gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Yan-Ping Su; Jun-Min Tang; Yan Tang; Hui-Ying Gao

    2005-01-01

    AIM: To investigate the effect and significance of selenium in early experimental gastric carcinogenesis.METHODS: Weaning male Wistar rats were divided randomly into normal control group, experiment control group, low selenium (2 mg/L) group and high selenium (4 mg/L) group. Wistar rat gastric carcinogenesis was induced by N-methyl-N-nitro-N-nitroso guanidine (MNNG) (20 mg/kg) gavage daily for 10 d. Na2SeO3 was given by piped drinking 1 wk prior to MNNG gavage. The rats were killed at the 43rd wk. The surface characteristics of gastric mucosa were observed with naked eyes. Histopathologic changes of rat gastric mucosa were observed by HE staining and AB-PAS methods. The changes of cellular ultrastructure were observed under transmission electron microscope. Statistical analysis was carried out by SPSS.RESULTS: The incidence rate of gastric mucosa erosion,hemorrhage and intestinal metaplasia was 0, 45.5%,66.7%, and 92.9%, respectively (92.9% vs45.5%, P<0.05)in the normal control group, experiment control group,low selenium group, and high selenium group. Leiomyoma formed in the process of inducement of rat gastric carcinoma. Dietary Na2SeO3 (2 and 4 mg/L) slightly increased the incidence rate of leiomyoma (0, 23%, 46.6%, and 46.6%). gastric mucosa did not change in the course of rat gastric carcinogenesis. Dietary Na2SeO3 by pipe drinking could expand the intracellular secretory canaliculus of parietal cells and increase the number of endocrine cells and lysosomes.CONCLUSION: Dietary Na2SeO3 by pipe drinking aggravates gastric erosion, hemorrhage and promotes intestinal metaplasia of gastric mucosa. The mechanism may be related with the function of parietal cells.

  2. Long non-coding RNA HOTAIR promotes carcinogenesis and invasion of gastric adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Na Keum; Lee, Jung Hwa; Park, Chan Hyuk; Yu, Dayeon; Lee, Yong Chan [Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cheong, Jae-Ho; Noh, Sung Hoon [Department of Surgery, Yonsei University College of Medicine (Korea, Republic of); Lee, Sang Kil, E-mail: sklee@yuhs.ac [Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2014-08-22

    Highlights: • HOTAIR expression was tested in fifty patients with gastric cancer. • Cell proliferation was measured after HOTAIR silencing in gastric cancer cell line. • siRNA–HOTAIR suppresses cell invasiveness and capacity of migration. • Knock down of HOTAR leads to decreased expression of EMT markers. • Inhibition of HOTAIR induces apoptosis and cell cycle arrest. - Abstract: Gastric cancer is one of the major causes of cancer death worldwide; however, the mechanism of carcinogenesis is complex and poorly understood. Long non-coding RNA HOTAIR (HOX transcript antisense RNA) recently emerged as a promoter of metastasis in various cancers including gastric cancer. Here we investigated the impact of HOTAIR on apoptosis, cell proliferation and cell cycle to dissect the carcinogenesis of gastric cancer. We examined the mechanism of invasion and metastasis and analyzed the clinical significance of HOTAIR. Downregulation of HOTAIR was confirmed by two different siRNAs. The expression of HOTAIR was significantly elevated in various gastric cancer cell lines and tissues compared to normal control. si-HOTAIR significantly reduced viability in MKN 28, MKN 74, and KATO III cells but not in AGS cells. si-HOTAIR induced apoptosis in KATO III cells. Lymphovascular invasion and lymph node metastasis were more common in the high level of HOTAIR group. si-HOTAIR significantly decreased invasiveness and migration. si-HOTAIR led to differential expression of epithelial to mesenchymal transition markers. We found that HOTAIR was involved in inhibition of apoptosis and promoted invasiveness, supporting a role for HOTAIR in carcinogenesis and progression of gastric cancer.

  3. Identification problem for stochastic models with application to carcinogenesis, cancer detection and radiation biology

    Directory of Open Access Journals (Sweden)

    L. G. Hanin

    2002-01-01

    Full Text Available A general framework for solving identification problem for a broad class of deterministic and stochastic models is discussed. This methodology allows for a unified approach to studying identifiability of various stochastic models arising in biology and medicine including models of spontaneous and induced Carcinogenesis, tumor progression and detection, and randomized hit and target models of irradiated cell survival. A variety of known results on parameter identification for stochastic models is reviewed and several new results are presented with an emphasis on rigorous mathematical development.

  4. A mathematical model of radiation carcinogenesis with induction of genomic instability and cell death.

    Science.gov (United States)

    Ohtaki, M; Niwa, O

    2001-11-01

    We developed a mathematical model of carcinogenesis that incorporates genomic instability, a feature characterized by long-term destabilization of the genome in irradiated cells that leads to an increase in cancer risk in the exposed individuals at the cancer-prone age. This model also considers the induction of cell death, another important effect of radiation on cells. It is assumed that cell killing by radiation may occur at all stages of the carcinogenic process. The resulting model can explain not only the paradoxical relationship between low mutation rates and high cancer incidence but also the low-order dose-response relationship of cancer risk.

  5. The Impact of Neural Stem Cell Biology on CNS Carcinogenesis and Tumor Types

    Directory of Open Access Journals (Sweden)

    K. M. Kurian

    2011-01-01

    Full Text Available The incidence of gliomas is on the increase, according to epidemiological data. This increase is a conundrum because the brain is in a privileged protected site behind the blood-brain barrier, and therefore partially buffered from environmental factors. In addition the brain also has a very low proliferative potential compared with other parts of the body. Recent advances in neural stem cell biology have impacted on our understanding of CNS carcinogenesis and tumor types. This article considers the cancer stem cell theory with regard to CNS cancers, whether CNS tumors arise from human neural stem cells and whether glioma stem cells can be reprogrammed.

  6. Myenteric denervation in gastric carcinogenesis: differential modulation of nitric oxide and annexin-A1

    OpenAIRE

    2012-01-01

    This study evaluated the properties of endogenous nitric oxide synthases (NOS) and annexin-A1 (ANXA1) and determined how they can be exploited in the N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and myenteric denervation model. Male Wistar rats were treated with MNNG and/or aminoguanidine (AG) for 20 weeks. In another set of experiments, rats with nondenervated and denervated stomachs were treated with MNNG or water for 28 weeks. Fragments of the pyloric region we...

  7. Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats

    Institute of Scientific and Technical Information of China (English)

    Salim S Al-Rejaie; Abdulaziz M Aleisa; Abdulaziz A Al-Yahya; Saleh A Bakheet; Abdulmalik Alsheikh; Amal G Fatani; Othman A Al-Shabanah; Mohamed M Sayed-Ahmed

    2009-01-01

    AIM: To investigate whether carnitine deficiency is a risk factor during the development of diethylnitrosamine (DENA)-induced hepatic carcinogenesis.METHODS: A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 (control group) received a single intraperitoneal (i.p.) injection of normal saline.Animals in group 2 (carnitine-supplemented group) were given L-carnitine (200 mg/kg per day) in drinking water for 8 wk. Animals in group 3 (carnitine-depleted group) were given D-carnitine (200 mg/kg per day) and mildronate (200 mg/kg per day) in drinking water for 8 wk. Rats in group 4 (DENA group) were injected with a single dose of DENA (200 mg/kg, i.p.) and 2 wk later received a single dose of carbon tetrachloride (2 mL/kg) by gavage as 1:1 dilution in corn oil. Animals in group 5 (DENA-carnitine depleted group) received the same treatment as group 3 and group 4. Rats in group 6 (DENA-carnitine supplemented group) received the same treatment as group 2 and group 4.RESULTS: Administration of DENA resulted in a significant increase in alanine transaminase (ALT),gamma-glutamyl t ransferase (G-GT) , alkal ine phosphatase (ALP), total bilirubin, thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NOx) and a significant decrease in reduced glutathione (GSH), glutathione peroxidase (GSHPx),catalase (CAT) and total carnitine content in liver tissues. In the carnitine-depleted rat model, DENA induced a dramatic increase in serum ALT, G-GT, ALP and total bilirubin, as well as a progressive reduction in total carnitine content in liver tissues. Interestingly,L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes, TBARS and NOx, and a decrease in total carnitine, GSH, GSHPx,and CAT induced by DENA, compared with the control values. Histopathological examination of liver tissues confirmed the biochemical data, where L-carnitine prevented DENA-induced hepatic

  8. High Dietary Salt Intake Exacerbates Helicobacter pylori-Induced Gastric Carcinogenesis

    OpenAIRE

    Gaddy, Jennifer A.; Radin, Jana N.; Loh, John T.; Zhang, Feng; Washington, M. Kay; Peek, Richard M.; Algood, Holly M. Scott; Cover, Timothy L.

    2013-01-01

    Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA+ H. pylori strain or an isogenic cagA mutant strain and main...

  9. Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

    Science.gov (United States)

    Williams, J. R.; Zhang, Y.; Zhou, H.; Osman, M.; Cha, D.; Kavet, R.; Cuccinotta, F.; Dicello, J. F.; Dillehay, L. E.

    1999-01-01

    The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such

  10. Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry.

    Science.gov (United States)

    El-Bayoumy, Karam; Chen, Kun-Ming; Zhang, Shang-Min; Sun, Yuan-Wan; Amin, Shantu; Stoner, Gary; Guttenplan, Joseph B

    2017-01-17

    Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical. Better understanding of the mechanisms of oral carcinogenesis can assist in the development of novel biomarkers for early detection and strategies for disease prevention. Toward this goal, several animal models for carcinogenesis in the oral cavity have been developed. Among these are xenograft, and transgenic animal models, and others employing the synthetic carcinogens such as 7,12-dimethylbenz[a]anthracene in hamster cheek pouch and 4-nitroquinoline-N-oxide in rats and mice. Additional animal models employing environmental carcinogens such as benzo[a]pyrene and N'-nitrosonornicotine have been reported. Each model has certain advantages and disadvantages. Models that (1) utilize environmental carcinogens, (2) reflect tumor heterogeneity, and (3) accurately represent the cellular and molecular changes involved in the initiation and progression of oral cancer in humans could provide a realistic platform. To achieve this goal, we introduced a novel nonsurgical mouse model to study oral carcinogenesis induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and tobacco smoke constituent, and its diol epoxide metabolite (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene [(±)-anti-DB[a,l]PDE]. On the basis of a detailed comparison of oral cancer induced by DB[a,l]P with that induced by the other above-mentioned oral carcinogens with respect to dose, duration, species and

  11. Environmental pollution and DNA methylation: carcinogenesis, clinical significance, and practical applications.

    Science.gov (United States)

    Cao, Yi

    2015-09-01

    Environmental pollution is one of the main causes of human cancer. Exposures to environmental carcinogens result in genetic and epigenetic alterations which induce cell transformation. Epigenetic changes caused by environmental pollution play important roles in the development and progression of environmental pollution-related cancers. Studies on DNA methylation are among the earliest and most conducted epigenetic research linked to cancer. In this review, the roles of DNA methylation in carcinogenesis and their significance in clinical medicine were summarized, and the effects of environmental pollutants, particularly air pollutants, on DNA methylation were introduced. Furthermore, prospective applications of DNA methylation to environmental pollution detection and cancer prevention were discussed.

  12. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors

    Science.gov (United States)

    Lu, Changxue; Cheng, Sheue-Yann

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis. PMID:19741045

  13. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention.

    Science.gov (United States)

    Peters, Jeffrey M; Shah, Yatrik M; Gonzalez, Frank J

    2012-02-09

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

  14. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Lu, Changxue; Cheng, Sheue-Yann

    2010-03-01

    Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis.

  15. Radiation carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1976-01-01

    The risk of iatrogenic tumors with radiation therapy is so outweighed by the benefit of cure that estimates of risk have not been considered necessary. However, with the introduction of chemotherapy, combined therapy, and particle radiation therapy, the comparative risks should be examined. In the case of radiation, total dose, fractionation, dose rate, dose distribution, and radiation quality should be considered in the estimation of risk. The biological factors that must be considered include incidence of tumors, latent period, degree of malignancy, and multiplicity of tumors. The risk of radiation induction of tumors is influenced by the genotype, sex, and age of the patient, the tissues that will be exposed, and previous therapy. With chemotherapy the number of cells at risk is usually markedly higher than with radiation therapy. Clearly the problem of the estimation of comparative risks is complex. This paper presents the current views on the comparative risks and the importance of the various factors that influence the estimation of risk.

  16. Dynamic changes in the gene expression profile during rat oral carcinogenesis induced by 4-nitroquinoline 1-oxide.

    Science.gov (United States)

    Ge, Shuyun; Zhang, Ji; Du, Yanzhi; Hu, Bin; Zhou, Zengtong; Lou, Jianing

    2016-03-01

    The typical progression of oral cancer is from hyperplastic epithelial lesions through dysplasia to invasive carcinoma. It is important to investigate malignant oral cancer progression and development in order to determine useful approaches of prevention of dysplastic lesions. The present study aimed to gain insights into the underlying molecular mechanism of oral carcinogenesis by establishing a rat model of oral carcinogenesis using 4‑nitroquinoline 1‑oxide. Subsequently, transcription profile analysis using an integrating microarray was performed. The dynamic gene expression changes of the six stages of rat oral carcinogenesis (normal, mild epithelial dysplasia, moderate dysplasia, severe dysplasia, carcinoma in situ and oral squamous cell carcinomas) were analyzed using component plane presentations (CPP)‑self‑organizing map (SOM). Six genes were verified by quantitative polymerase chain reaction, immunohistochemistry and succinate dehydrogenase (SDH) activity assay kit. Numerous differentially expressed genes (DEGs) were identified during rat oral carcinogenesis. CPP‑SOM determined that these DEGs were primarily enriched during cell cycle, apoptosis, inflammatory response and tricarboxylic acid cycle, indicating the coordinated regulation of molecular networks. In addition, the expression of specific DEGs, such as janus kinase 3, cyclin‑dependent kinase A‑1, B‑cell chronic lymphocytic leukaemia/lymphoma 2‑like 2, nuclear factor‑κB, tumor necrosis factor receptor superfamily member 1A, cyclin D1 and SDH were identified to have high concordance with the results from microarray data. The current study demonstrated that oral carcinogenesis is a multi‑step and multi‑gene process, with a distinct pattern alteration along a continuum of malignant transformation. In addition, this comprehensive investigation provided a theoretical basis for the understanding of the molecular alterations associated with oral carcinogenesis.

  17. A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Ling Shao

    Full Text Available Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3, a ubiquitin-editing enzyme that restricts NFκB and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min. While A20(FL/FL villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL villin-Cre APC(min/+ mice contain far greater numbers and larger colonic polyps than control APC(min mice. We find that A20 binds to the β-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of β-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the β-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting β-catenin signaling and preventing colon tumorigenesis.

  18. Does Imaging Technology Cause Cancer? Debunking the Linear No-Threshold Model of Radiation Carcinogenesis.

    Science.gov (United States)

    Siegel, Jeffry A; Welsh, James S

    2016-04-01

    In the past several years, there has been a great deal of attention from the popular media focusing on the alleged carcinogenicity of low-dose radiation exposures received by patients undergoing medical imaging studies such as X-rays, computed tomography scans, and nuclear medicine scintigraphy. The media has based its reporting on the plethora of articles published in the scientific literature that claim that there is "no safe dose" of ionizing radiation, while essentially ignoring all the literature demonstrating the opposite point of view. But this reported "scientific" literature in turn bases its estimates of cancer induction on the linear no-threshold hypothesis of radiation carcinogenesis. The use of the linear no-threshold model has yielded hundreds of articles, all of which predict a definite carcinogenic effect of any dose of radiation, regardless of how small. Therefore, hospitals and professional societies have begun campaigns and policies aiming to reduce the use of certain medical imaging studies based on perceived risk:benefit ratio assumptions. However, as they are essentially all based on the linear no-threshold model of radiation carcinogenesis, the risk:benefit ratio models used to calculate the hazards of radiological imaging studies may be grossly inaccurate if the linear no-threshold hypothesis is wrong. Here, we review the myriad inadequacies of the linear no-threshold model and cast doubt on the various studies based on this overly simplistic model. © The Author(s) 2015.

  19. Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

    Directory of Open Access Journals (Sweden)

    Hitoshi Nakagama

    2011-02-01

    Full Text Available Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropylamine (BOP into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5’ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention.

  20. Helicobacter pylori-infected animal models are extremely suitable for the investigation of gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Masaaki Kodama; Kazunari Murakami; Ryugo Sato; Tadayoshi Okimoto; Akira Nishizono; Toshio Fujioka

    2005-01-01

    Although various animal models have been developed to clarify gastric carcinogenesis, apparent mechanism of gastric cancer was not clarified in recent years. Since the recognition of the pathogenicity of Helicobacter pylori (Hpylori), several animal models with Hpylori infection have been developed to confirm the association between Hpylori and gastric cancer. Nonhuman primate and rodent models were suitable for this study. Japanese monkey model revealed atrophic gastritis and p53mutation after long-term infection of Hpylori. Mongolian gerbil model showed the development of gastric carcinoma with H pylori infection alone, as well as with combination of chemical carcinogens, such as N-methylN-nitrosourea and N-methyl-N-nitro-N'-nitrosoguanidine.The histopathological changes of these animal models after Hpylori inoculation are closely similar to those in human beings with Hpylori infection. Eradication therapy attenuated the development of gastric cancer in Hpyloriinfected Mongolian gerbil. Although several features of animal models differ from those seen in human beings,these experimental models provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of Hpylori infection and assist the planning of eradication therapy to prevent gastric carcinoma.

  1. CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs

    Science.gov (United States)

    De Luca, Paola; Dalton, Guillermo N.; Scalise, Georgina D.; Moiola, Cristian P.; Porretti, Juliana; Massillo, Cintia; Kordon, Edith; Gardner, Kevin; Zalazar, Florencia; Flumian, Carolina; Todaro, Laura; Vazquez, Elba S.; Meiss, Roberto; De Siervi, Adriana

    2016-01-01

    Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis. PMID:26933806

  2. Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis

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    Hisataka Moriwaki

    2012-01-01

    Full Text Available Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1/IGF-1 receptor (IGF-1R axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC and hepatocellular carcinoma (HCC. However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA, which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.

  3. [In vitro and in vivo effects of mango pulp (Mangifera indica cv. Azucar) in colon carcinogenesis].

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    Corrales-Bernal, Andrea; Amparo Urango, Luz; Rojano, Benjamín; Maldonado, Maria Elena

    2014-03-01

    Mango pulp contains ascorbic acid, carotenoids, polyphenols, terpenoids and fiber which are healthy and could protect against colon cancer. The aim of this study was to evaluate the antiproliferative and preventive capacity of an aqueous extract of Mangifera indica cv. Azúcar on a human colon adenocarcinoma cell line (SW480) and in a rodent model of colorectal cancer, respectively. The content of total phenolics, flavonoids and carotenoids were also analyzed in the extract. SW480 cell growth was inhibited in a dose and time dependent manner by 22.3% after a 72h exposure to the extract (200 µg/ mL). Colon carcinogenesis was initiated in Balb/c mice by two intra-peritoneal injections of azoxymethane (AOM) at the third and fourth week of giving mango in drinking water (0.3%, 0.6%, 1.25%). After 10 weeks of treatment, in the colon of mice receiving 0.3% mango, aberrant crypt foci formation was inhibited more than 60% (p=0,05) and the inhibition was dose-dependent when compared with controls receiving water. These results show that mango pulp, a natural food, non toxic, part of human being diet, contains bioactive compounds able to reduce growth of tumor cells and to prevent the appearance of precancerous lesions in colon during carcinogenesis initiation.

  4. Can systems toxicology identify common biomarkers of non-genotoxic carcinogenesis?

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    Plant, Nick

    2008-12-30

    For the rapid development of safe, efficacious chemicals it is important that any potential liabilities are identified as early as possible in the discovery/development pipeline. Once identified it is then possible to make rational decisions on whether to progress a chemical and/or series further; one such liability is chemical carcinogenesis, a highly undesirable characteristic in a novel chemical entity. Chemical carcinogens may be roughly divided into two classes, those that elicit their actions through direct damage to DNA (genotoxic carcinogens) and those that cause carcinogenesis through mechanisms that involve direct damage of the DNA by the agent (non-genotoxic carcinogens). Whereas the former group can be identified by in vitro screens to a good degree of accuracy, the latter group are far more problematic due to their diverse modes of action. This review will focus on the latter class of chemical carcinogens, examining how modern '-omic' technologies have begun to identify signatures that may represent sensitive, early markers for these processes. In addition to their use in signature generation the role of -omic level approaches to delineating molecular mechanisms of action will also be discussed.

  5. In Vivo Antineoplastic Effects of the NSAID Sulindac in an Oral Carcinogenesis Model.

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    Katoumas, Konstantinos; Nikitakis, Nikolaos; Perrea, Despina; Dontas, Ismene; Sklavounou, Alexandra

    2015-07-01

    The antineoplastic properties of the NSAID sulindac have long been studied. The purpose of this study was to explore sulindac's in vivo effects on oral squamous cell carcinoma (SCC) oncogenesis using the hamster cheek pouch oral carcinogenesis model (HOCM). Thirty Syrian golden hamsters were divided into three experimental and two control groups (n = 6 each). The animals' right buccal pouches were treated with carcinogen for 9 weeks in one experimental and one control group and for 14 weeks in all other three groups. The animals of two experimental groups received sulindac from the 1st week and those of the third experimental group from the 10th week. After the end of carcinogenesis, treated buccal pouches were removed and examined. In animals treated with carcinogen for 14 weeks, development of oral SCC and tumor volume were significantly lower in animals that received sulindac from the first week of the experiment. Oral SCC developing in animals that received sulindac were more frequently well differentiated compared with the control group. In animals treated with carcinogen for 9 weeks, the animals that received sulindac developed lower grade of epithelial dysplasia. Proliferation index Ki-67 and positivity for the antiapoptotic molecule survivin were lower in the animals that received sulindac. Treatment with sulindac appears to delays the progression of oral premalignant lesions to oral SCC in the HOCM, also resulting in smaller and better differentiated tumors. These in vivo antineoplastic effects may be related to sulindac's ability to decrease cell proliferation and to prevent survivin expression.

  6. Linking DNA adduct formation and human cancer risk in chemical carcinogenesis.

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    Poirier, Miriam C

    2016-08-01

    Over two centuries ago, Sir Percival Pott, a London surgeon, published a pioneering treatise showing that soot exposure was the cause of high incidences of scrotal cancers occurring in young men who worked as chimney sweeps. Practicing at a time when cellular pathology was not yet recognized, Sir Percival nonetheless observed that the high incidence and short latency of the chimney sweep cancers, was fundamentally different from the rare scrotal cancers typically found in elderly men. Furthermore, his diagnosis that the etiology of these cancers was related to chimney soot exposure, was absolutely accurate, conceptually novel, and initiated the field of "occupational cancer epidemiology." After many intervening years of research focused on mechanisms of chemical carcinogenesis, briefly described here, it is clear that DNA damage, or DNA adduct formation, is "necessary but not sufficient" for tumor induction, and that many additional factors contribute to carcinogenesis. This review includes a synopsis of carcinogen-induced DNA adduct formation in experimental models and in the human population, with particular attention paid to molecular dosimetry and molecular cancer epidemiology. Environ. Mol. Mutagen. 57:499-507, 2016. © 2016 Wiley Periodicals, Inc.

  7. Are the somatic mutation and tissue organization field theories of carcinogenesis incompatible?

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    Rosenfeld, Simon

    2013-01-01

    Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research. These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT). The essence of SMT is that cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations, and that those mutations occur on genes which control cell proliferation and cell cycle. Thus, according to SMT, neoplastic lesions are the results of DNA-level events. Conversely, according to TOFT, carcinogenesis is primarily a problem of tissue organization: carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity. Hence, in TOFT the DNA mutations are the effect, and not the cause, of the tissue-level events. Cardinal importance of successful resolution of the TOFT versus SMT controversy dwells in the fact that, according to SMT, cancer is a unidirectional and mostly irreversible disease; whereas, according to TOFT, it is curable and reversible. In this paper, our goal is to outline a plausible scenario in which TOFT and SMT can be reconciled using the framework and concepts of the self-organized criticality (SOC), the principle proven to be extremely fruitful in a wide range of disciplines pertaining to natural phenomena, to biological communities, to large-scale social developments, to technological networks, and to many other subjects of research.

  8. Alterations of global histone H4K20 methylation during prostate carcinogenesis

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    Behbahani Turang E

    2012-03-01

    Full Text Available Abstract Background Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3 at different stages of prostate cancer (PCA carcinogenesis. Methods Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113, non-malignant prostate disease (n = 27, metastatic hormone-naive PCA (mPCA, n = 30 and castration-resistant PCA (CRPC, n = 34. Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

  9. Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

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    Takahashi, Mami, E-mail: mtakahas@ncc.go.jp; Hori, Mika; Mutoh, Michihiro [Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan); Wakabayashi, Keiji [Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526 (Japan); Nakagama, Hitoshi [Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan)

    2011-02-09

    Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5′ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention.

  10. Implication of human telomerase reverse transcriptase in cervical carcinogenesis and cancer recurrence.

    Science.gov (United States)

    Wang, P-H; Ko, J-L

    2006-01-01

    The objective of this study was to evaluate the implication of human telomerase reverse transcriptase (hTERT) in cervical carcinogenesis and cancer recurrence. One hundred three cases of uterine cervix, including 20 normal, 13 low-grade squamous intraepithelial lesion (LSIL), 30 high-grade squamous intraepithelial lesion (HSIL), and 40 squamous cell carcinoma (SCC) tissues, were evaluated for hTERT immunoreactivity. The expressions of hTERT in normal, LSIL, HSIL, and SCC tissues were compared by Fisher exact or Chi-square test. The relationships between hTERT and clinicopathologic variables of SCC were also assessed. Furthermore, SCC patients were subdivided into negative and positive hTERT expression subgroups, and Kaplan-Meier curves were used to plot the cumulative recurrence hazard for 5 years. There was a significant difference for hTERT expression between LSIL and HSIL subgroups (P recurrence hazard for 5 years was about 29% in positive hTERT expression subgroup compared to 0% in negative hTERT subgroup (P = 0.2866). In conclusion, a point stage of HSIL exists in the progression of cervical carcinogenesis when the hTERT expression increases significantly. Moreover, SCC patients with positive hTERT expression may have higher cumulative recurrence hazard.

  11. ICRP Publication 131: Stem cell biology with respect to carcinogenesis aspects of radiological protection.

    Science.gov (United States)

    Hendry, J H; Niwa, O; Barcellos-Hoff, M H; Globus, R K; Harrison, J D; Martin, M T; Seed, T M; Shay, J W; Story, M D; Suzuki, K; Yamashita, S

    2016-06-01

    Current knowledge of stem cell characteristics, maintenance and renewal, evolution with age, location in 'niches', and radiosensitivity to acute and protracted exposures is reviewed regarding haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. The identity of the target cells for carcinogenesis continues to point to the more primitive and mostly quiescent stem cell population (able to accumulate the protracted sequence of mutations necessary to result in malignancy), and, in a few tissues, to daughter progenitor cells. Several biological processes could contribute to the protection of stem cells from mutation accumulation: (1) accurate DNA repair; (2) rapid induced death of injured stem cells; (3) retention of the intact parental strand during divisions in some tissues so that mutations are passed to the daughter differentiating cells; and (4) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the vital niche. DNA repair mainly operates within a few days of irradiation, while stem cell replications and competition require weeks or many months depending on the tissue type. This foundation is used to provide a biological insight to protection issues including the linear-non-threshold and relative risk models, differences in cancer risk between tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age.

  12. Transforming growth factor-β1 in carcinogenesis, progression, and therapy in cervical cancer.

    Science.gov (United States)

    Zhu, Haiyan; Luo, Hui; Shen, Zhaojun; Hu, Xiaoli; Sun, Luzhe; Zhu, Xueqiong

    2016-06-01

    Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-β1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-β signaling pathway, such as mutations or loss of expression of TGF-β receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-β1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-β1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-β1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

  13. Luteolin supplementation adjacent to aspirin treatment reduced dimethylhydrazine-induced experimental colon carcinogenesis in rats.

    Science.gov (United States)

    Osman, Neamt H A; Said, Usama Z; El-Waseef, Ahmed M; Ahmed, Esraa S A

    2015-02-01

    Previous studies have shown that aspirin is used in colon cancer treatment. However, long-term of Aspirin usage is limited to gastric and renal toxicity. Luteolin (LUT) has cancer prevention and anti-inflammatory effects. The present study was designed to investigate the effect of LUT supplementation and Aspirin treatment in dimethylhydrazine (DMH)-induced carcinogenesis in rats. DMH (20 mg/kg BW/week) treated rats received gavages with Aspirin (50 mg/kg BW/week) and LUT (0.2 mg/kg BW/day) for 15 weeks. DMH injections induce colon polyps and renal bleeding, significantly increasing carcinoembryonic antigen (CEA), cyclooxygenase-2 (COX-2), oxidative stress, and kidney function tests and reducing antioxidant markers. Either Aspirin or LUT gavages alone or combined produce a significant decrease in colon polyp number and size, significantly decreasing CEA, COX-2, and oxidative stress and increasing antioxidant markers. In conclusion, the supplementations of LUT adjacent to Aspirin in the treatment of DMH-induced carcinogenesis in rats reflect a better effect than the use of Aspirin alone.

  14. Downregulation of keratin 76 expression during oral carcinogenesis of human, hamster and mouse.

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    Srikant Ambatipudi

    Full Text Available BACKGROUND: Keratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development. METHODS: We evaluated KRT76 expression by qRT-PCR in normal and tumor tissues of the oral cavity. We also analyzed K76 expression by immunohistochemistry in normal, oral precancerous lesion (OPL, oral squamous cell carcinoma (OSCC and in hamster model of oral carcinogenesis. Further, functional implication of KRT76 loss was confirmed using KRT76-knockout (KO mice. RESULTS: We observed a strong association of reduced K76 expression with increased risk of OPL and OSCC development. The buccal epithelium of DMBA treated hamsters showed a similar trend. Oral cavity of KRT76-KO mice showed preneoplastic changes in the gingivobuccal epithelium while no pathological changes were observed in KRT76 negative tissues such as tongue. CONCLUSION: The present study demonstrates loss of KRT76 in oral carcinogenesis. The KRT76-KO mice data underlines the potential of KRT76 being an early event although this loss is not sufficient to drive the development of oral cancers. Thus, future studies to investigate the contributing role of KRT76 in light of other tumor driving events are warranted.

  15. Mouse endogenous retroviral long terminal repeat (LTR) elements and environmental carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Yang, W.K.; Ch' ang, L-Y; Myer, F.E.; Yang, M.D.; Koh, C.K.

    1988-01-01

    For the past several years, the working hypothesis of this laboratory has been that chromosomal retrovirus-related gene elements play important roles in gene-rearrangement and gene-activation events of carcinogenesis and mutagenesis induced by environmental agents. This working hypothesis is based on the concept of transposable genes as well as the recent understanding of retroviruses (RNA tumor viruses) in relation to the carcinogenesis problem. Activation of transposable gene elements has been discussed from the viewpoint of unprogrammed genomic changes in response to unanticipated genomic shocks. This view was used in considering the possibility of transposable gene elements involved in genetic changes of cancer formation in the animal. In this regard, this concept is similar to the perspectives of RNA tumor viruses, the oncogene-virogene hypothesis, and the provirus hypothesis because retroviruses replicate through DNA forms that carry long terminal repeat (LTR) sequences resembling the insertion sequences (or the IS elements) of prokaryotic transposons. The finding of oncogene myc activation in avian leukosis virus-induced leukemogenesis and proviral insertion in the mouse dilute locus mutation have also pointed to the functional similarity between retroviruses and transposable genes.

  16. Role of Helicobacter pylori infection in gastric carcinogenesis: Current knowledge and future directions

    Science.gov (United States)

    Sokic-Milutinovic, Aleksandra; Alempijevic, Tamara; Milosavljevic, Tomica

    2015-01-01

    Helicobacter pylori (H. pylori) plays a role in the pathogenesis of gastric cancer. The outcome of the infection depends on environmental factors and bacterial and host characteristics. Gastric carcinogenesis is a multistep process that is reversible in the early phase of mucosal damage, but the exact point of no return has not been identified. Therefore, two main therapeutic strategies could reduce gastric cancer incidence: (1) eradication of the already present infection; and (2) immunization (prior to or during the course of the infection). The success of a gastric cancer prevention strategy depends on timing because the prevention strategy must be introduced before the point of no return in gastric carcinogenesis. Although the exact point of no return has not been identified, infection should be eradicated before severe atrophy of the gastric mucosa develops. Eradication therapy rates remain suboptimal due to increasing H. pylori resistance to antibiotics and patient noncompliance. Vaccination against H. pylori would reduce the cost of eradication therapies and lower gastric cancer incidence. A vaccine against H. pylori is still a research challenge. An effective vaccine should have an adequate route of delivery, appropriate bacterial antigens and effective and safe adjuvants. Future research should focus on the development of rescue eradication therapy protocols until an efficacious vaccine against the bacterium becomes available. PMID:26556993

  17. PABPC1 exerts carcinogenesis in gastric carcinoma by targeting miR-34c.

    Science.gov (United States)

    Zhu, Jie; Ding, Hao; Wang, Xiaohong; Lu, Qi

    2015-01-01

    As one of the common malignant tumors that threaten human health severely, gastric carcinoma is the second highest cause of cancer death and the fourth most common cancer globally. However, the mechanism underlying gastric cancer is still not fully understood. PABPC1 plays an important role in translation, control the rate of mRNA deadenylation and participates in mRNA decay, which is involved in carcinogenesis. Here in present study, we reported that PABPC1 is an oncogenic protein in gastric carcinoma. The results showed that PABPC1 is upregulated in gastric carcinoma tissues, and high PABPC1 expression predicts poor survival. PABPC1 regulates proliferation and transformation of gastric cancer cells in vitro and in vivo. PABPC1 knockdown induces apoptosis by upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins. In addition, miR-34c is a target of PABPC1, and miR-34c is critically essential for the function of PABPC1. In summary, PABPC1 exerts carcinogenesis and promotes growth and survival of gastric cancer cells by regulating miR-34c.

  18. Helicobacter pylori-induced modulation of the promoter methylation of Wnt antagonist genes in gastric carcinogenesis.

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    Yang, Hyo-Joon; Kim, Sang Gyun; Lim, Joo Hyun; Choi, Ji Min; Kim, Woo Ho; Jung, Hyun Chae

    2017-06-22

    This study aimed to investigate the changes in the promoter methylation and gene expression of multiple Wnt antagonists between the chronic infection and eradication of Helicobacter pylori (H. pylori) in gastric carcinogenesis. The levels of methylation and corresponding mRNA expression of seven Wnt antagonist genes (SFRP1, -2, -5, DKK1, -2, -3, WIF1) were compared among the patients with H. pylori-positive gastric cancers (GCs), and H. pylori-positive and H. pylori-negative controls, by quantitative MethyLight assay and real-time reverse transcription (RT)-polymerase chain reaction (PCR), respectively. The changes of the methylation and expression levels of the genes were also compared between the H. pylori eradication and H. pylori-persistent groups 1 year after endoscopic resection of GCs. The methylation levels of SFRP and DKK family genes were significantly increased in the patients with H. pylori-positive GCs and followed by H. pylori-positive controls compared with H. pylori-negative controls (P pylori-negative controls, H. pylori-positive controls, and to H. pylori-positive GCs (P pylori eradication (P pylori-associated gastric carcinogenesis. The epigenetic field may not be reversed even after H. pylori eradication except by DKK3 methylation.

  19. A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis.

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    Hattis, D; Chu, M; Rahmioglu, N; Goble, R; Verma, P; Hartman, K; Kozlak, M

    2009-01-01

    This article proposes a system of categories for nonmutagenic modes of action for carcinogenesis. The classification is of modes of action rather than individual carcinogens, because the same compound can affect carcinogenesis in more than one way. Basically, we categorize modes of action as: (1) co-initiation (facilitating the original mutagenic changes in stem and progenitor cells that start the cancer process) (e.g. induction of activating enzymes for other carcinogens); (2) promotion (enhancing the relative growth vs differentiation/death of initiated clones (e.g. inhibition of growth-suppressing cell-cell communication); (3) progression (enhancing the growth, malignancy, or spread of already developed tumors) (e.g. suppression of immune surveillance, hormonally mediated growth stimulation for tumors with appropriate receptors by estrogens); and (4) multiphase (e.g., "epigenetic" silencing of tumor suppressor genes). A priori, agents that act at relatively early stages in the process are expected to manifest greater relative susceptibility in early life, whereas agents that act via later stage modes will tend to show greater susceptibility for exposures later in life.

  20. Latest insights into the effects of Helicobacter pylori infection on gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Kazunari Murakami; Masaaki Kodama; Toshio Fujioka

    2006-01-01

    There appears to be the strong association between Helicobacter pylori (H pylori) and gastric cancer. We reviewed the latest evidences about the effects of H pylori infection on gastric carcinogenesis, classified into epidemiology, dynamics of gastric mucosal changes,DNA damages, virulence factors, host factors, and source of gastric malignancy. Through the considerable progress made in research into virulence factors resulting from differences between H pylori strains, such as cagA positivity, as well as into host factors, such as gene polymorphisms, a diverse spectrum of H pyloriassociated diseases, including gastric cancer, is beginning to lend itself to elucidation. The impact of the novel hypothesis advanced by Houghton et al proposing bonemarrow derived stem cells (BMDC) as a potential source of gastric malignancy on evolving research remains to be seen with interest. Further progress in research into H pylori eradication as a viable prophylaxis of gastric cancer, as well as into the mechanisms of gastric carcinogenesis, is to be eagerly awaited for the current year and beyond.

  1. Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis.

    Science.gov (United States)

    Shimizu, Masahito; Kubota, Masaya; Tanaka, Takuji; Moriwaki, Hisataka

    2012-01-01

    Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.

  2. Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.

    Science.gov (United States)

    Manils, Joan; Gómez, Diana; Salla-Martret, Mercè; Fischer, Heinz; Fye, Jason M; Marzo, Elena; Marruecos, Laura; Serrano, Inma; Salgado, Rocío; Rodrigo, Juan P; Garcia-Pedrero, Juana M; Serafin, Anna M; Cañas, Xavier; Benito, Carmen; Toll, Agustí; Forcales, Sònia-Vanina; Perrino, Fred W; Eckhart, Leopold; Soler, Concepció

    2015-09-08

    TREX2 is a 3'-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.

  3. Possible mechanisms by which pro- and prebiotics influence colon carcinogenesis and tumor growth.

    Science.gov (United States)

    Reddy, B S

    1999-07-01

    Oligofructose and inulin, selective fermentable chicory fructans, have been shown to stimulate the growth of bifidobacteria, which are regarded as beneficial strains in the colon. Studies were designed to evaluate inulin (Raftiline) and oligofructose (Raftilose) for their potential inhibitory properties against the development of colonic aberrant crypt foci (ACF) in rats. ACF are putative preneoplastic lesions from which adenomas and carcinomas may develop in the colon. The results of this study indicate that dietary administration of oligofructose and inulin inhibits the development of ACF in the colon, suggesting the potential colon tumor inhibitory properties of chicory fructans. The degree of ACF inhibition was more pronounced in animals given inulin than in those fed oligofructose. Because these prebiotics selectively stimulate the growth of bifidobacteria, ornithine decarboxylase (ODC) activities, ras-p21 ontoprotein expressions and tumor inhibitory activity of lyophilized cultures of Bifidobacterium longum against chemically induced colon and mammary carcinogenesis and against colonic tumor cell proliferation were examined. Dietary administration of lyophilized cultures of B. longum strongly suppressed colon and mammary tumor development and tumor burden. Inhibition of colon carcinogenesis was associated with a decrease in colonic mucosal cell proliferation and activities of colonic mucosal and tumor ornithine decarboxylase and ras-p21. Human clinical trials are likely to broaden our insight into the importance of the pre- and probiotics in health and disease.

  4. Preventive Effects of Fermented Brown Rice and Rice Bran against Prostate Carcinogenesis in TRAP Rats

    Directory of Open Access Journals (Sweden)

    Toshiya Kuno

    2016-07-01

    Full Text Available Fermented brown rice and rice bran with Aspergillus oryzae (FBRA is considered to have the potential to prevent chemically-induced carcinogenesis in multiple organs of rodents. In the present study, we evaluated the possible chemopreventive effects of FBRA against prostate tumorigenesis. Six-week-old male rats of the transgenic rat for adenocarcinoma of prostate (TRAP strain were fed diets containing 5% or 10% FBRA for 15 weeks. Animals were sacrificed at 21 weeks of age, and the ventral and lateral prostate were removed for histopathological evaluation and immunoblot analyses. FBRA decreased the incidence of adenocarcinoma in the lateral prostate and suppressed the progression of prostate carcinogenesis. Treatment with FBRA induced apoptosis and inhibited cell proliferation in histologically high-grade prostatic intraepithelial neoplasias. Phospho-AMP-activated kinase α (Thr172 was up-regulated in the prostate of rats fed the diet supplemented with FBRA. These results indicate that FBRA controls tumor growth by activating pathways responsive to energy deprivation and suggest that FBRA has translational potential for the prevention of human prostate cancer.

  5. Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Hector Alvarez

    2011-03-01

    Full Text Available Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined "CpG islands," but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1 in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery.

  6. Oxygen radicals in lung carcinogenesis accompanying phagocytosis of diesel exhaust particles.

    Science.gov (United States)

    Ichinose, T; Yamanushi, T; Seto, H; Sagai, M

    1997-09-01

    We sought to examine the involvement of oxygen radicals derived from phagocytosis process in lung carcinogenesis induced by diesel exhaust particles (DEP). The carcinogenic response and formation of 8-hydroxydeoxyguanosine (8-OHdG) were examined in the lungs of mice intratracheally injected with washed DEP (WDEP), DEP, or nontoxic control particles of titanium dioxide (TiO2). After 10 weekly treatments with these particles, the formation of 8-OHdG in the lungs of mice treated with WDEP or DEP showed a significant increase, but not in those treated with TiO2. After 12 months, the incidence of lung tumors in mice treated with WDEP or DEP was higher than that of mice treated with vehicle by 2.3- and 3.1-fold, respectively. A significant difference in the incidence of tumors was found between the vehicle group and DEP-treated group. Treatment with TiO2 had no effect on the incidence of lung tumors. The formation of 8-OHdG in mice treated with these particles was significantly correlated with the development of lung tumors. These results suggest that the induction of DNA damage by oxygen radicals may be an important factor in the initiation of WDEP- and DEP-induced lung carcinogenesis, and that oxygen radicals derived from the phagocytic process may play a role in 8-OHdG formation induced by DEP.

  7. Cell Cycle Phase Abnormalities Do Not Account for Disordered Proliferation in Barrett's Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Pierre Lao-Sirieix

    2004-11-01

    Full Text Available Barrett's esophagus (BE epithelium is the precursor lesion for esophageal adenocarcinoma. Cell cycle proteins have been advocated as biomarkers to predict the malignant potential in BE. However, whether disruption of the cell cycle plays a causal role in Barrett's carcinogenesis is not clear. Specimens from the Barrett's dysplasia—carcinoma sequence were immunostained for cell cycle phase markers (cyclin D1 for G1; cyclin A for S, G2, and M; cytoplasmic cyclin B1 for G2; and phosphorylated histone 3 for M phase and expressed as a proportion of proliferating cells. Flow cytometric analysis of the cell cycle phase of prospective biopsies was also performed. The proliferation status of nondysplastic BE was similar to gastric antrum and D2, but the proliferative compartment extended to the luminal surface. In dysplastic samples, the number of proliferating cells correlated with the degree of dysplasia (P < .001. The overall levels of cyclins A and B1 correlated with the degree of dysplasia (P < .001. However, the cell cycle phase distribution measured with both immunostaining and flow cytometry was conserved during all stages of BE, dysplasia, and cancer. Hence, the increased proliferation seen in Barrett's carcinogenesis is due to abnormal cell cycle entry or exit, rather than a primary abnormality within the cell cycle.

  8. St. John's Wort Attenuates Colorectal Carcinogenesis in Mice through Suppression of Inflammatory Signaling.

    Science.gov (United States)

    Manna, Soumen K; Golla, Srujana; Golla, Jaya Prakash; Tanaka, Naoki; Cai, Yan; Takahashi, Shogo; Krausz, Kristopher W; Matsubara, Tsutomu; Korboukh, Ilia; Gonzalez, Frank J

    2015-09-01

    Despite widespread use as well as epidemiologic indications, there have been no investigations into the effect of St. John's wort (SJW) extract on colorectal carcinogenesis in vivo. This study reports a systematic evaluation of the impact of dietary supplementation of SJW extract on azoxymethane-induced colorectal carcinogenesis in mice. Mice were fed with either AIN-93G (control) diet or SJW extract-supplemented diet (SJW diet) prior to azoxymethane treatment. SJW diet was found to significantly improve the overall survival of azoxymethane-treated mice. Pretreatment with the SJW diet significantly reduced body weight loss as well as decrease of serum albumin and cholesterol levels associated with azoxymethane-induced colorectal tumorigenesis. SJW diet-fed mice showed a significant decrease in tumor multiplicity along with a decrease in incidence of large tumors and a trend toward decreased total tumor volume in a dose-dependent manner. A short-term study, which examined the effect of SJW prior to rectal bleeding, also showed decrease in colorectal polyps in SJW diet-fed mice. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK1/2) pathways were attenuated by SJW administration. SJW extract resulted in early and continuous attenuation of these pathways in the colon epithelium of SJW diet-fed mice under both short-term and long-term treatment regimens. In conclusion, this study demonstrated the chemopreventive potential of SJW extract against colorectal cancer through attenuation of proinflammatory processes.

  9. Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis.

    Science.gov (United States)

    Santos, Juliana Carvalho; Ribeiro, Marcelo Lima

    2015-08-14

    Although thousands of DNA damaging events occur in each cell every day, efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoiding the maintenance of mutations. The DNA repair enzymes continuously monitor the chromosomes to correct any damage that is caused by exogenous and endogenous mutagens. If DNA damage in proliferating cells is not repaired because of an inadequate expression of DNA repair genes, it might increase the risk of cancer. In addition to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes has been associated with carcinogenesis. Gastric cancer represents the second highest cause of cancer mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes during the lifetime. Among the risk factors, Helicobacter pylori (H. pylori) infection is considered the main driving factor to gastric cancer development. Thus, in this review, we summarize the current knowledge of the role of H. pylori infection on the epigenetic regulation of DNA repair machinery in gastric carcinogenesis.

  10. Andrographolide inhibits oral squamous cell carcinogenesis through NF-κB inactivation.

    Science.gov (United States)

    Wang, L-J; Zhou, X; Wang, W; Tang, F; Qi, C-L; Yang, X; Wu, S; Lin, Y-Q; Wang, J-T; Geng, J-G

    2011-10-01

    The NF-κB family of transcription factors is essential for promoting cell proliferation and preventing cell apoptosis. We have previously shown that Andrographolide (Andro) isolated from an herbal plant, Andrographis paniculata, covalently modifies reduced cysteine(62) in the oligonucleotide binding pocket of p50 for inhibition of NF-κB activation. Here we report that Andro, but not its inactive structural analog 4H-Andro, potently suppressed squamous cell carcinogenesis induced by 7,12-dimethyl-1,2-benzanthracene (DMBA) in the hamster model of cheek buccal pouch. Compared with 4H-Andro, Andro reduced phosphorylation of p65 (Ser536) and IκBα (Ser32/36) for inhibiting aberrant NF-κB activation, suppressed c-Myc and cyclin D1 expression and attenuated neoplastic cell proliferation, promoted cancerous cell apoptosis, and mitigated tumor-induced angiogenesis. Consistently, Andro retarded growth, decreased proliferation, and promoted apoptosis of Tb cells, a human tongue squamous cell carcinoma cell line, in time- and dose-dependent manners, with concomitant reduction of the expression of NF-κB targeting molecules in vitro. Our results thus demonstrate that NF-κB activation plays important roles in the pathogenesis of chemically induced squamous cell carcinoma. By inhibition of aberrant NF-κB activation, Andro treats chemically induced oral squamous cell carcinogenesis.

  11. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes.

    Science.gov (United States)

    Wattenberg, L W; Sparnins, V L; Barany, G

    1989-05-15

    Naturally occurring compounds belonging to two chemical groups were studied for their capacities to inhibit N-nitrosodiethylamine (NDEA)-induced carcinogenesis in female A/J mice. One group consists of organosulfur compounds found in Allium species, including garlic, onions, leeks, and shallots, and the other, two monoterpenes, i.e., D-limonene and D-carvone. In an initial experiment, in which organosulfur compounds were investigated, diallyl disulfide, allyl mercaptan, and allyl methyl disulfide were found to produce a marked inhibition of NDEA-induced neoplasia of the forestomach when the test compounds were administered p.o. 96 and 48 h prior to NDEA. The most potent was diallyl disulfide which reduced forestomach tumor formation by more than 90%. Pulmonary adenoma formation also was inhibited but to a considerably lesser extent, i.e., about 30%. In three additional experiments, test compounds were given p.o. either 15 min or 1 h prior to NDEA. Under these conditions diallyl disulfide and allyl mercaptan again inhibited forestomach tumor formation substantially, i.e., greater than 75%, and pulmonary adenoma formation marginally, i.e., less than 20%. In these experiments D-limonene and D-carvone were tested and reduced forestomach tumor formation by slightly over 60% and pulmonary adenoma formation by about 35%. The results of these studies provide evidence of an increasing diversity of naturally occurring compounds having the capacity to inhibit nitrosamine carcinogenesis.

  12. Investigating evolutionary perspective of carcinogenesis with single-cell transcriptome analysis

    Institute of Scientific and Technical Information of China (English)

    Xi Zhang; Cheng Zhang; Zhongjun Li; Jiangjian Zhong; Leslie P. Weiner; Jiang F. Zhong

    2013-01-01

    We developed phase-switch microfluidic devices for molecular profiling of a large number of single cells. Whole genome microarrays and RNA-sequencing are commonly used to determine the expression levels of genes in cell lysates (a physical mix of millions of cells) for inferring gene functions. However, cellular heterogeneity becomes an inherent noise in the measurement of gene expression. The unique molecular characteristics of individual cells, as well as the temporal and quantitative information of gene expression in cells, are lost when averaged among all cells in cell lysates. Our single-cell technology overcomes this limitation and enables us to obtain a large number of single-cell transcriptomes from a population of cells. A collection of single-cell molecular profiles allows us to study carcinogenesis from an evolutionary perspective by treating cancer as a diverse population of cells with abnormal molecular characteristics. Because a cancer cellpopulation contains cells at various stages of development toward drug resistance, clustering similar single-cell molecular profiles could reveal how drug-resistant sub-clones evolve during cancer treatment. Here, we discuss how single-celltranscriptome analysis technology could enable the study of carcinogenesis from an evolutionary perspective and the development of drug-resistance in leukemia. The single-cell transcriptome analysis reported here could have a direct and significant impact on current cancer treatments and future personalized cancer therapies.

  13. Modelling carcinogenesis after radiotherapy using Poisson statistics: implications for IMRT, protons and ions.

    Science.gov (United States)

    Jones, Bleddyn

    2009-06-01

    Current technical radiotherapy advances aim to (a) better conform the dose contours to cancers and (b) reduce the integral dose exposure and thereby minimise unnecessary dose exposure to normal tissues unaffected by the cancer. Various types of conformal and intensity modulated radiotherapy (IMRT) using x-rays can achieve (a) while charged particle therapy (CPT)-using proton and ion beams-can achieve both (a) and (b), but at greater financial cost. Not only is the long term risk of radiation related normal tissue complications important, but so is the risk of carcinogenesis. Physical dose distribution plans can be generated to show the differences between the above techniques. IMRT is associated with a dose bath of low to medium dose due to fluence transfer: dose is effectively transferred from designated organs at risk to other areas; thus dose and risk are transferred. Many clinicians are concerned that there may be additional carcinogenesis many years after IMRT. CPT reduces the total energy deposition in the body and offers many potential advantages in terms of the prospects for better quality of life along with cancer cure. With C ions there is a tail of dose beyond the Bragg peaks, due to nuclear fragmentation; this is not found with protons. CPT generally uses higher linear energy transfer (which varies with particle and energy), which carries a higher relative risk of malignant induction, but also of cell death quantified by the relative biological effect concept, so at higher dose levels the frank development of malignancy should be reduced. Standard linear radioprotection models have been used to show a reduction in carcinogenesis risk of between two- and 15-fold depending on the CPT location. But the standard risk models make no allowance for fractionation and some have a dose limit at 4 Gy. Alternatively, tentative application of the linear quadratic model and Poissonian statistics to chromosome breakage and cell kill simultaneously allows estimation of

  14. Study of the mechanism of carcinogenesis by carcinogens which are negative in the Ames test. Progress report, April 1-September 1, 1979

    Energy Technology Data Exchange (ETDEWEB)

    None

    1979-01-01

    Carcinogens ethionine, thioacetamide, and actinomycin D, all of which are negative in the Ames test and all of which raise the progesterone level in the chicken, were tested to determine their physiological role in carcinogenesis. The optimization of the carcinogenesis model also included evaluation of the chicken as the biological indicator of physiological changes relative to the above compounds. (PCS)

  15. Effect of meat (beef, chicken, and bacon) on rat colon carcinogenesis

    Science.gov (United States)

    Parnaud, Géraldine; Peiffer, Ginette; Taché, Sylviane; Corpet, Denis E.

    1998-01-01

    High intake of red meat or processed meat is associated with increased risk of colon cancer. In contrast, consumption of white meat (chicken) is not associated with risk and might even reduce the occurrence of colorectal cancer. We speculated that a diet containing beef or bacon would increase and a diet containing chicken would decrease colon carcinogenesis in rats. One hundred female Fischer 344 rats were given a single injection of azoxymethane (20 mg/kg i.p.), then randomized to 10 different AIN-76-based diets. Five diets were adjusted to 14% fat and 23% protein and five other diets to 28% fat and 40% protein. Fat and protein were supplied by 1) lard and casein, 2) olive oil and casein, 3) beef, 4) chicken with skin, and 5) bacon. Meat diets contained 30% or 60% freeze-dried fried meat. The diets were given ad libitum for 100 days, then colon tumor promotion was assessed by the multiplicity of aberrant crypt foci [number of crypts per aberrant crypt focus (ACF)]. The ACF multiplicity was nearly the same in all groups, except bacon-fed rats, with no effect of fat and protein level or source (p = 0.7 between 8 groups by analysis of variance). In contrast, compared with lard- and casein-fed controls, the ACF multiplicity was reduced by 12% in rats fed a diet with 30% bacon and by 20% in rats fed a diet with 60% bacon (p fecal water and total fatty acids in feces changed with diet, but there was no correlation between these concentrations and the ACF multiplicity. Thus the hypothesis that colonic iron, bile acids, or total fatty acids can promote colon tumors is not supported by this study. The results suggest that, in rats, beef does not promote the growth of ACF and chicken does not protect against colon carcinogenesis. A bacon-based diet appears to protect against carcinogenesis, perhaps because bacon contains 5% NaCl and increased the rats’ water intake. PMID:10050267

  16. Regulation of TH17 Cells and Associated Cytokines in Wound Healing, Tissue Regeneration, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Leonie Brockmann

    2017-05-01

    Full Text Available Wound healing is a crucial process which protects our body against permanent damage and invasive infectious agents. Upon tissue damage, inflammation is an early event which is orchestrated by a multitude of innate and adaptive immune cell subsets including TH17 cells. TH17 cells and TH17 cell associated cytokines can impact wound healing positively by clearing pathogens and modulating mucosal surfaces and epithelial cells. Injury of the gut mucosa can cause fast expansion of TH17 cells and their induction from naïve T cells through Interleukin (IL-6, TGF-β, and IL-1β signaling. TH17 cells produce various cytokines, such as tumor necrosis factor (TNF-α, IL-17, and IL-22, which can promote cell survival and proliferation and thus tissue regeneration in several organs including the skin, the intestine, and the liver. However, TH17 cells are also potentially pathogenic if not tightly controlled. Failure of these control mechanisms can result in chronic inflammatory conditions, such as Inflammatory Bowel Disease (IBD, and can ultimately promote carcinogenesis. Therefore, there are several mechanisms which control TH17 cells. One control mechanism is the regulation of TH17 cells via regulatory T cells and IL-10. This mechanism is especially important in the intestine to terminate immune responses and maintain homeostasis. Furthermore, TH17 cells have the potential to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype by changing their cytokine profile and acquiring IL-10 production, thereby limiting their own pathological potential. Finally, IL-22, a signature cytokine of TH17 cells, can be controlled by an endogenous soluble inhibitory receptor, Interleukin 22 binding protein (IL-22BP. During tissue injury, the production of IL-22 by TH17 cells is upregulated in order to promote tissue regeneration. To limit the regenerative program, which could promote carcinogenesis, IL-22BP is upregulated during the later phase of

  17. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko [National Institute of Radiological Sciences, Anagawa, Chiba (Japan); Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H. [Univ. of Wisconsin, Department of Human Oncology, Madison, WI (United States)

    2003-07-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of {approx}4 days. After puberty, the doubling time lengthened to {approx}30 days. The total number of clonogens in abdominal and inguinal mammary glands was {approx}200 in 2-week-old rats, while it was {approx}5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics

  18. Lupeol, a bioactive triterpene, prevents tumor formation during 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis.

    Science.gov (United States)

    Palanimuthu, D; Baskaran, N; Silvan, S; Rajasekaran, D; Manoharan, S

    2012-10-01

    The oral cancer chemopreventive efficacy of lupeol, a bioactive triterpene, was assessed by monitoring the tumor incidence and using the status of phase I and II xenobiotic metabolizing enzymes, lipid peroxidation and antioxidants as biochemical end points during 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Oral tumors were developed in the buccal pouch of golden Syrian hamsters by painting with 0.5 % DMBA three times a week for 14 weeks. Well differentiated oral squamous cell carcinoma with marked abnormalities in the status of biochemical markers were noticed in hamsters treated with DMBA alone. Oral administration of lupeol at a dose of 50 mg/kg bw completely inhibited the formation of oral tumors and restored the status of biochemical markers during DMBA induced oral carcinogenesis. The present study thus demonstrates the chemopreventive potential of lupeol in DMBA induced oral carcinogenesis. The chemopreventive potential of lupeol is probably due to its antioxidant or free radical scavenging property and modulating effect on phase I and II xenobiotic metabolizing enzymes in favour of the excretion of carcinogenic metabolites during DMBA induced hamster buccal pouch carcinogenesis.

  19. Effects of long term feeding of raw soya bean flour on virus- induced pancreatic carcinogenesis in guinea fowl

    NARCIS (Netherlands)

    Kirev, T.; Woutersen, R.A.; Kiril, A.

    1999-01-01

    The effects of a diet enriched with 25% raw soya bean flour (RSF) on the pancreas and on the avian retrovirus Pts 56-induced pancreatic carcinogenesis in guinea fowl were studied. It has been shown that prolonged RSF feeding of new-hatched virus-infected and uninfected guinea fowl-poults induced enl

  20. Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis.

    NARCIS (Netherlands)

    Hausen, A zur; Rees, van B.P.; Beek, van J.; Craanen, M.E.; Bloemena, E.; Offerhaus, GJ; Meijer, C.J.L.M.; Brule, van den AJ

    2004-01-01

    BACKGROUND: To determine at what stage during gastric carcinogenesis Epstein-Barr virus (EBV) enters the gastric epithelial cells, the presence of EBV was investigated in two pathogenetically related but distinct forms of adenocarcinoma of the stomach-gastric carcinoma of the intact stomach (GCIS)

  1. Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis.

    NARCIS (Netherlands)

    Hausen, A zur; Rees, van B.P.; Beek, van J.; Craanen, M.E.; Bloemena, E.; Offerhaus, GJ; Meijer, C.J.L.M.; Brule, van den AJ

    2004-01-01

    BACKGROUND: To determine at what stage during gastric carcinogenesis Epstein-Barr virus (EBV) enters the gastric epithelial cells, the presence of EBV was investigated in two pathogenetically related but distinct forms of adenocarcinoma of the stomach-gastric carcinoma of the intact stomach (GCIS) a

  2. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies

    Science.gov (United States)

    Robertis, Mariangela De; Massi, Emanuela; Poeta, Maria Luana; Carotti, Simone; Morini, Sergio; Cecchetelli, Loredana; Signori, Emanuela; Fazio, Vito Michele

    2011-01-01

    Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci–adenoma–carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS–treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model. PMID:21483655

  3. Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Borg, D.C.

    1984-01-01

    Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures. (ACR)

  4. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID during Inflammation-Associated Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Tsutomu Chiba

    2011-06-01

    Full Text Available Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID, a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  5. Caryocar brasiliense camb protects against genomic and oxidative damage in urethane-induced lung carcinogenesis

    Science.gov (United States)

    Colombo, N.B.R.; Rangel, M.P.; Martins, V.; Hage, M.; Gelain, D.P.; Barbeiro, D.F.; Grisolia, C.K.; Parra, E.R.; Capelozzi, V.L.

    2015-01-01

    The antioxidant effects of Caryocar brasiliense Camb, commonly known as the pequi fruit, have not been evaluated to determine their protective effects against oxidative damage in lung carcinogenesis. In the present study, we evaluated the role of pequi fruit against urethane-induced DNA damage and oxidative stress in forty 8-12 week old male BALB/C mice. An in vivo comet assay was performed to assess DNA damage in lung tissues and changes in lipid peroxidation and redox cycle antioxidants were monitored for oxidative stress. Prior supplementation with pequi oil or its extract (15 µL, 60 days) significantly reduced urethane-induced oxidative stress. A protective effect against DNA damage was associated with the modulation of lipid peroxidation and low protein and gene expression of nitric oxide synthase. These findings suggest that the intake of pequi fruit might protect against in vivo genotoxicity and oxidative stress. PMID:26200231

  6. Suppressive effects of dietary genistin and daidzin on rat prostate carcinogenesis.

    Science.gov (United States)

    Kato, K; Takahashi, S; Cui, L; Toda, T; Suzuki, S; Futakuchi, M; Sugiura, S; Shirai, T

    2000-08-01

    High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and / or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epidemiological findings.

  7. Caryocar brasiliense camb protects against genomic and oxidative damage in urethane-induced lung carcinogenesis

    Directory of Open Access Journals (Sweden)

    N.B.R. Colombo

    2015-01-01

    Full Text Available The antioxidant effects of Caryocar brasiliense Camb, commonly known as the pequi fruit, have not been evaluated to determine their protective effects against oxidative damage in lung carcinogenesis. In the present study, we evaluated the role of pequi fruit against urethane-induced DNA damage and oxidative stress in forty 8-12 week old male BALB/C mice. An in vivo comet assay was performed to assess DNA damage in lung tissues and changes in lipid peroxidation and redox cycle antioxidants were monitored for oxidative stress. Prior supplementation with pequi oil or its extract (15 µL, 60 days significantly reduced urethane-induced oxidative stress. A protective effect against DNA damage was associated with the modulation of lipid peroxidation and low protein and gene expression of nitric oxide synthase. These findings suggest that the intake of pequi fruit might protect against in vivo genotoxicity and oxidative stress.

  8. Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis — A Literature Review

    Directory of Open Access Journals (Sweden)

    Leena Rivina

    2012-12-01

    Full Text Available As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus remains one of the best animal model systems for cancer research due to its molecular and physiological similarities to man, small size, ease of breeding in captivity and a fully sequenced genome. This work reviews relevant M. musculus inbred and F1 hybrid animal models and methodologies of induction of radiation-induced leukemia, thymic lymphoma, breast, and lung cancer in these models. Where available, the associated molecular pathologies are also included.

  9. Potential role of septins in oral carcinogenesis: An update and avenues for future research

    Directory of Open Access Journals (Sweden)

    Rooban Thavarajah

    2012-01-01

    Full Text Available Septins belong to the GTPase superclass of conserved proteins and have been identified to play a role in diverse aspects of cell biology, from cytokinesis to the maintenance of cellular morphology. At least 14 septins have been identified in humans. With their complex patterns in gene expressions and interaction, it has been reported that alterations in septin expression are observed in human diseases. Although much is not known about the role of human septins in oral carcinogenesis, circumstantial evidence does indicate that it may play a major role. This review intends to summarize the basis of septin biology, with the focus being on the evidence for septin involvement in human oral cancer.

  10. Chronic inflammation-related DNA damage response: a driving force of gastric cardia carcinogenesis.

    Science.gov (United States)

    Lin, Runhua; Xiao, Dejun; Guo, Yi; Tian, Dongping; Yun, Hailong; Chen, Donglin; Su, Min

    2015-02-20

    Gastric cardia cancer (GCC) is a highly aggressive disease associated with chronic inflammation. To investigate the relationship between DNA damage response (DDR) and chronic inflammation, we collected 100 non-tumor gastric cardia specimens of Chaoshan littoral, a high-risk region for esophageal and gastric cardia cancer. A significantly higher proportion of severe chronic inflammation was found in dysplastic epithelia (80.9%) in comparison with that in non-dysplastic tissues (40.7%) (Pchronic inflammation degrees from normal to severe inflammation (Pchronic inflammation-related DNA damage response may be a driving force of gastric cardia carcinogenesis. Based on these findings, DNA damage response in non-malignant tissues may become a promising biomedical marker for predicting malignant transformation in the gastric cardia.

  11. Synergistic effect of radiation on colon carcinogenesis induced by methylazoxymethanol acetate in ACI/N rats

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji; Morishita, Yukio; Kawamori, Toshihiko; Suzui, Masumi; Kojima, Toshihiro; Sugie, Shigeyuki; Mori, Hideki (Gifu Univ. (Japan). Faculty of Medicine)

    1993-10-01

    The effect on colon and liver carcinogenicity in rats of a single X-irradiation exposure given either before or after methylazoxymethanol (MAM) acetate was studied in ACI/N rats of both sexes. A single dose of X-irradiation (3 Gy) was administered either 3 months before or after three weekly s.c. injection of MAM acetate (25 mg/kg body weight). At 365 days after the start, the incidence and multiplicity of MAM acetate-induced intestinal tumors were enhanced by X-irradiation either prior to or after the MAM acetate treatment. In addition, X-irradiation before MAM acetate increased the incidence of hepatocellular foci in either sex. In females, X-irradiation either before or after MAM acetate exposure decreased intestinal tumorigenesis. These findings suggest an apparent synergism of these agents in intestinal carcinogenesis of male rats. (author).

  12. Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: targets for chemopreventive strategies.

    Science.gov (United States)

    Pathak, S K; Sharma, R A; Steward, W P; Mellon, J K; Griffiths, T R L; Gescher, A J

    2005-01-01

    Over the last decade, epidemiological, experimental and clinical studies have implicated oxidative stress in the development and progression of prostate cancer. Oxidative stress may be linked to the effects of androgens, anti-oxidant systems and the pre-malignant condition, high-grade prostatic intraepithelial neoplasia. Cyclooxygenase-2 activity has been linked with prostate carcinogenesis. Evidence suggests that oxidative stress and cyclo-oxygenase-2 activity may be mechanistically linked. Agents such as anti-oxidants and cyclo-oxgenase-2 inhibitors may be of value in the chemoprevention of prostate cancer. The feasibility of intervention with such agents will depend on the development and validation of biomarkers for clinical trials, particularly markers of oxidative damage caused by reactive oxygen species (ROS). A greater understanding of the molecular events associated with oxidative stress will enhance the development of such biomarkers and should result in better strategies for the chemoprevention of prostate cancer.

  13. The Role of Fibroblast Growth Factor Binding Protein 1 in Skin Carcinogenesis and Inflammation

    DEFF Research Database (Denmark)

    Schmidt, Marcel Oliver; Garman, Khalid Ammar; Lee, Yong Gu

    2017-01-01

    of the epidermis associated with a decreased transepidermal water loss and increased pro-inflammatory gene expression in the skin was detected. Also, skin carcinogen challenge by DMBA/TPA resulted in delayed and reduced papillomatosis in KO mice. This was paralleled by delayed healing of skin wounds and reduced...... angiogenic sprouting in subcutaneous matrigel plugs. Heterozygous GFP-knock-in mice revealed rapid induction of gene expression during papilloma induction and during wound healing. Examination of WT skin grafted onto Fgfbp1 GFP knockin reporter hosts and bone marrow transplants from the GFP reporter model...... into WT hosts revealed that circulating Fgfbp1-expressing cells migrate into healing wounds. We conclude that tissue-resident and circulating Fgfbp1-expressing cells modulate skin carcinogenesis and inflammation....

  14. The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis

    DEFF Research Database (Denmark)

    Ingerslev, Kasper; Hogdall, Estrid; Schnack, Tine Henrichsen

    2017-01-01

    BACKGROUND: The etiological cause of ovarian cancer is poorly understood. It has been theorized that bacterial or viral infection as well as pelvic inflammatory disease could play a role in ovarian carcinogenesis. AIM: To review the literature on studies examining the association between ovarian...... cancer and bacterial or viral infection or pelvic inflammatory disease. METHODS: Database search through MEDLINE, applying the medical subject headings: "Ovarian neoplasms", AND "Chlamydia infections", "Neisseria gonorrhoeae", "Mycoplasma genitalium", "Papillomaviridae", or "pelvic inflammatory disease...... than in studies from Western countries. Cytomegalovirus was the only other virus to be detected and was found in 50% of cases in a case-control study. The association between ovarian cancer and pelvic inflammatory disease was examined in seven epidemiological studies, two of which, reported...

  15. Resistance of germfree athymic nude mice to two-stage skin carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Holland, J.M.; Perkins, E.H.

    1979-01-01

    Germfree athymic and normal littermate mice were compared with respect to their relative sensitivity to single skin application of dimethylbenzanthacine followed either by croton oil or TPA applied as a co-carcinogen. In separate experiments the acute response of both phenotypes to TPA was assessed by histologic examination of skin as well as the incorporttion of tritiated thymidine into acid insoluble material obtained from the isolated epidermis. Nude mice were observed to be less, equal, or more sensitive than normal littermate to topical skin carcinogenesis depending upon experimental variables. The tendency of solvent to spread rapidly on the skin of nude mice appeared to have the greatest influence on susceptibility to papilloma induction. Other factors of potential, although unproven importance, include differences in skin structure, possibly associated with accelerated activity of hair follicles as well as resistance to both the inflammatory and hyperplasiogenic effects of TPA.

  16. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Takai, Atsushi; Marusawa, Hiroyuki, E-mail: maru@kuhp.kyoto-u.ac.jp; Chiba, Tsutomu [Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507 (Japan)

    2011-06-22

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  17. The role of adiponectin in obesity-associated female-specific carcinogenesis.

    Science.gov (United States)

    Nagaraju, Ganji Purnachandra; Rajitha, Balney; Aliya, Sheik; Kotipatruni, Rama P; Madanraj, Appiya Santharam; Hammond, Anthea; Park, Dongkyoo; Chigurupati, Srinivasulu; Alam, Afroz; Pattnaik, Subasini

    2016-10-01

    Adipose tissue is a highly vascularized endocrine organ, and its secretion profiles may vary with obesity. Adiponectin is secreted by adipocytes that make up adipose tissue. Worldwide, obesity has been designated a serious health problem among women and is associated with a variety of metabolic disorders and an increased risk of developing cancer of the cervix, ovaries, uterus (uterine/endometrial), and breast. In this review, the potential link between obesity and female-specific malignancies is comprehensively presented by discussing significant features of the intriguing and complex molecule, adiponectin, with a focus on recent findings highlighting its molecular mechanism of action in female-specific carcinogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. γ-glutamyl tranferase in a model of carcinogenesis in rats

    Directory of Open Access Journals (Sweden)

    S. O. Babij

    2010-07-01

    compounds of rhenium (III with organic ligands and cisplatin (rhenium-platinum system was studied. The increased activity of the membrane bound enzyme and decrease of its cytosolic activity in the red blood cells during development of Guerin’s carcinoma T8 was found. Also the positive impact of the rheniumplatinum system on the enzymatic activity in the erythrocytes was shown, namely: the reduction of membrane bound and increase of cytosolic activity. As a result, the ratio between activity of the membrane bound enzyme and cytosolic one verged towards the correct level. The conclusion was made that the use of membrane bound and soluble γ-glutamyl transferase in the erythrocytes as a diagnostic enzyme of carcinogenesis is reasonable.

  19. Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis.

    Science.gov (United States)

    Margan, Madalin Marius; Jitariu, Andreea Adriana; Cimpean, Anca Maria; Nica, Cristian; Raica, Marius

    2016-06-01

    Normal human breast tissue consists of epithelial and nonepithelial cells with different molecular profiles and differentiation grades. This molecular heterogeneity is known to yield abnormal clones that may contribute to the development of breast carcinomas. Stem cells that are found in developing and mature breast tissue are either positive or negative for cytokeratin 19 depending on their subtype. These cells are able to generate carcinogenesis along with mature cells. However, scientific data remains controversial regarding the monoclonal or polyclonal origin of breast carcinomas. The majority of breast carcinomas originate from epithelial cells that normally express BRCA1. The consecutive loss of the BRCA1 gene leads to various abnormalities in epithelial cells. Normal breast epithelial cells also express hypoxia inducible factor (HIF) 1α and HIF-2α that are associated with a high metastatic rate and a poor prognosis for malignant lesions. The nuclear expression of estrogen receptor (ER) and progesterone receptor (PR) in normal human breast tissue is maintained in malignant tissue as well. Several controversies regarding the ability of ER and PR status to predict breast cancer outcome remain. Both ER and PR act as modulators of cell activity in normal human breast tissue. Ki-67 positivity is strongly correlated with tumor grade although its specific role in applied therapy requires further studies. Human epidermal growth factor receptor 2 (HER2) oncoprotein is less expressed in normal human breast specimens but is highly expressed in certain malignant lesions of the breast. Unlike HER2, epidermal growth factor receptor expression is similar in both normal and malignant tissues. Molecular heterogeneity is not only found in breast carcinomas but also in normal breast tissue. Therefore, the molecular mapping of normal human breast tissue might represent a key research area to fully elucidate the mechanisms of breast carcinogenesis.

  20. Does excess iron play a role in breast carcinogenesis? An unresolved hypothesis.

    Science.gov (United States)

    Kabat, Geoffrey C; Rohan, Thomas E

    2007-12-01

    Free iron is a pro-oxidant and can induce oxidative stress and DNA damage. The carcinogenicity of iron has been demonstrated in animal models, and epidemiologic studies have shown associations with several human cancers. However, a possible role of excess body iron stores or of elevated iron intake in breast carcinogenesis has received little attention epidemiologically. We propose that iron overload and the disruption of iron homeostasis with a resulting increase in free iron may contribute to the development of breast cancer, and we summarize the relevant evidence from mechanistic studies, animal experiments, and studies in humans. Over time a high intake of iron can lead to iron overload. Furthermore, body iron stores increase in women following menopause. Reactive oxygen species produced by normal aerobic cellular metabolism can lead to the release of free iron from ferritin. In the presence of superoxide radical and hydrogen peroxide, stored ferric iron (Fe(3+)) is reduced to ferrous iron (Fe(2+)), which catalyzes the formation of the hydroxyl radical (*OH). *OH in turn can promote lipid peroxidation, mutagenesis, DNA strand breaks, oncogene activation, and tumor suppressor inhibition, increasing the risk of breast cancer. In addition to its independent role as a proxidant, high levels of free iron may potentiate the effects of estradiol, ethanol, and ionizing radiation - three established risk factors for breast cancer. In order to identify the role of iron in breast carcinogenesis, improved biomarkers of body iron stores are needed, as are cohort studies which assess heme iron intake. Ultimately, it is important to determine whether iron levels in the breast and iron-induced pathology are higher in women who go on to develop breast cancer compared to women who do not.

  1. Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelial carcinogenesis in rats.

    Science.gov (United States)

    Nagai, Hirotaka; Okazaki, Yasumasa; Chew, Shan Hwu; Misawa, Nobuaki; Yasui, Hiroyuki; Toyokuni, Shinya

    2013-11-01

    Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction.

  2. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Science.gov (United States)

    Yildiz, Gokhan; Arslan-Ergul, Ayca; Bagislar, Sevgi; Konu, Ozlen; Yuzugullu, Haluk; Gursoy-Yuzugullu, Ozge; Ozturk, Nuri; Ozen, Cigdem; Ozdag, Hilal; Erdal, Esra; Karademir, Sedat; Sagol, Ozgul; Mizrak, Dilsa; Bozkaya, Hakan; Ilk, Hakki Gokhan; Ilk, Ozlem; Bilen, Biter; Cetin-Atalay, Rengul; Akar, Nejat; Ozturk, Mehmet

    2013-01-01

    Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene

  3. Epithelial nuclear factor-κB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes.

    Science.gov (United States)

    Zaynagetdinov, R; Stathopoulos, G T; Sherrill, T P; Cheng, D-S; McLoed, A G; Ausborn, J A; Polosukhin, V V; Connelly, L; Zhou, W; Fingleton, B; Peebles, R S; Prince, L S; Yull, F E; Blackwell, T S

    2012-06-28

    The mechanisms by which chronic inflammatory lung diseases, particularly chronic obstructive pulmonary disease, confer enhanced risk for lung cancer are not well-defined. To investigate whether nuclear factor (NF)-κB, a key mediator of immune and inflammatory responses, provides an interface between persistent lung inflammation and carcinogenesis, we utilized tetracycline-inducible transgenic mice expressing constitutively active IκB kinase β in airway epithelium (IKTA (IKKβ trans-activated) mice). Intraperitoneal injection of ethyl carbamate (urethane), or 3-methylcholanthrene (MCA) and butylated hydroxytoluene (BHT) was used to induce lung tumorigenesis. Doxycycline-treated IKTA mice developed chronic airway inflammation and markedly increased numbers of lung tumors in response to urethane, even when transgene expression (and therefore epithelial NF-κB activation) was begun after exposure to carcinogen. Studies using a separate tumor initiator/promoter model (MCA+BHT) indicated that NF-κB functions as an independent tumor promoter. Enhanced tumor formation in IKTA mice was preceded by increased proliferation and reduced apoptosis of alveolar epithelium, resulting in increased formation of premalignant lesions. Investigation of inflammatory cells in lungs of IKTA mice revealed a substantial increase in macrophages and lymphocytes, including functional CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Importantly, Treg depletion using repetitive injections of anti-CD25 antibodies limited excessive tumor formation in IKTA mice. At 6 weeks following urethane injection, antibody-mediated Treg depletion in IKTA mice reduced the number of premalignant lesions in the lungs in association with an increase in CD8 lymphocytes. Thus, persistent NF-κB signaling in airway epithelium facilitates carcinogenesis by sculpting the immune/inflammatory environment in the lungs.

  4. Methylation-mediated transcriptional repression of microRNAs during cervical carcinogenesis

    Science.gov (United States)

    Wilting, Saskia M.; Verlaat, Wina; Jaspers, Annelieke; Makazaji, Nour A.; Agami, Reuven; Meijer, Chris J.L.M.; Snijders, Peter J.F.

    2013-01-01

    Deregulated expression of microRNAs (miRNAs) is common and biologically relevant in cervical carcinogenesis and appears only partly related to chromosomal changes. We recently identified 32 miRNAs showing decreased expression in high-grade cervical intraepithelial neoplasia (CIN) and carcinomas not associated with a chromosomal loss, 6 of which were located within a CpG island. This study aimed to investigate to what extent these miRNAs are subject to DNA methylation-mediated transcriptional repression in cervical carcinogenesis.   Methylation-specific PCR (MSP) analysis on a cell line panel representing different stages of human papillomavirus (HPV) induced transformation revealed an increase in methylation of hsa-miR-149, -203 and -375 with progression to malignancy, whereas expression of these miRNAs was restored upon treatment with a demethylating agent. All three miRNAs showed significantly increased levels of methylation in cervical carcinomas, whereas methylation levels of hsa-miR-203 and -375 were also significantly increased in high-grade CIN. A pilot analysis showed that increased hsa-miR-203 methylation was also detectable in HPV-positive cervical scrapes of women with high-grade CIN compared with controls. Similar to recent findings on hsa-miR-375, ectopic expression of hsa-miR-203 in cervical cancer cells decreased both the proliferation rate and anchorage independent growth. We found evidence for methylation-mediated transcriptional repression of hsa-miR-149, -203 and -375 in cervical cancer. Methylation of the latter two was already apparent in precancerous lesions and represent functionally relevant events in HPV-mediated transformation. Increased hsa-miR-203 methylation was detectable in scrapes of women with high-grade CIN, indicating that methylated miRNAs may provide putative markers to assess the presence of (pre)cancerous lesions. PMID:23324622

  5. The Role of Oxidative Stress in Carcinogenesis Induced by Metals and Xenobiotics

    Directory of Open Access Journals (Sweden)

    Frank Henkler

    2010-04-01

    Full Text Available In addition to a wide range of adverse effects on human health, toxic metals such as cadmium, arsenic and nickel can also promote carcinogenesis. The toxicological properties of these metals are partly related to generation of reactive oxygen species (ROS that can induce DNA damage and trigger redox-dependent transcription factors. The precise mechanisms that induce oxidative stress are not fully understood. Further, it is not yet known whether chronic exposures to low doses of arsenic, cadmium or other metals are sufficient to induce mutations in vivo, leading to DNA repair responses and/or tumorigenesis. Oxidative stress can also be induced by environmental xenobiotics, when certain metabolites are generated that lead to the continuous release of superoxide, as long as the capacity to reduce the resulting dions (quinones into hydroquinones is maintained. However, the specific significance of superoxide-dependent pathways to carcinogenesis is often difficult to address, because formation of DNA adducts by mutagenic metabolites can occur in parallel. Here, we will review both mechanisms and toxicological consequences of oxidative stress triggered by metals and dietary or environmental pollutants in general. Besides causing DNA damage, ROS may further induce multiple intracellular signaling pathways, notably NF-kB, JNK/SAPK/p38, as well as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that could promote proliferation or confer apoptosis resistance to exposed cells. The significance of these additional modes depends on tissue, cell-type and is often masked by alternate oncogenic mechanisms being activated in parallel.

  6. Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Marques, Ricardo; Vaz, Cátia V.; Maia, Cláudio J. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Gomes, Madalena [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Gama, Adelina [Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD) (Portugal); Alves, Gilberto; Santos, Cecília R. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Schmitt, Fernando [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Medical Faculty, University of Porto, Porto (Portugal); Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto (Canada); Department of Pathology, University Health Network, Toronto (Canada); Socorro, Sílvia, E-mail: ssocorro@fcsaude.ubi.pt [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal)

    2015-01-15

    Regucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland. - Highlights: • RGN immunoreactivity was negatively correlated with breast cancer differentiation. • Transgenic overexpression of RGN diminished incidence of carcinogen-induced tumors. • Transgenic overexpression of RGN restricted proliferation and fostered apoptosis. • RGN has a protective role in the carcinogenesis of mammary gland.

  7. Loss of the Association between Telomere Length and Mitochondrial DNA Copy Number Contribute to Colorectal Carcinogenesis.

    Science.gov (United States)

    Lee, Hyunsu; Cho, Ji-Hyoung; Park, Won-Jin; Jung, Soo-Jung; Choi, In-Jang; Lee, Jae-Ho

    2017-05-09

    Positive association between telomere length and mitochondrial DNA (mtDNA) copy number were introduced in healthy and patients with psychiatric disorder. Based on frequent genetic changes of telomere and mitochondria in colorectal carcinomas (CRC), we studied their clinical characteristics and their association in colorectal carcinogenesis. DNA was extracted from 109 CRCs, 64 colorectal tubular adenomas (TAs), and 28 serrated polyps (SPs), and then, telomere length and mtDNA copy number were analyzed in these legions by using a real-time PCR assay. Telomere length and mtDNA copy number (mean ± S.D) in CRCs was 1.87 ± 1.52 and 1.61 ± 1.37, respectively. In TAs and SPs, relative mtDNA copy number was 0.92 ± 0.71 and 1.84 ± 1.06, respectively, shoing statistical difference (p = 0.017). However, telomere length was similar in these precancerous legions. Telomere length and mtDNA copy number did not show clinical and prognostic values in CRCs, however, positive correlation between telomere length and mitochondrial DNA copy number were found in CRC (r = 0.408, p < 0.001). However, this association was not shown in precancerous lesions (r = -0.031, p = 0.765). This result suggests that loss of co-regulation between telomeres and mitochondrial function may induce the initiation or play a role as trigger factor of colorectal carcinogenesis.

  8. Role of microsatellites instability in carcinogenesis of postcricoid carcinoma on top of plummer-vinson syndrome.

    Science.gov (United States)

    Badawy, Badawy Shahat; Ahmad, Mohamed Abdel-Kader; Sayed, Ramadan Hashem; Habib, Tito Naeem

    2010-10-01

    To develop a molecular pattern that might help in understanding carcinogenesis of postcricoid carcinoma (PCC) on top of Plummer-Vinson syndrome (PVS) in a prospective controlled study. Twenty-four patients with PVS were diagnosed and followed up over a 4 year period, during which eight of them showed malignant change to PCC. Twenty volunteers free of neoplastic diseases were included as a control group. In the two groups, DNA extraction from mononuclear peripheral blood cells, and analysis of loss of heterozygosity (LOH) and microsatellite instability (MSI) using six paired simple tandem repeats (STRs) primers were done. The molecular weight of each STRs locus was scored and statistical correlations were performed. LOH occurred in 55.6 and 72.9% of PVS and PCC cases compared to 25% of control group. At loci D17S695, D9S753 and D9S171, LOH occurred in 54.2, 66.7, and 70.8% of PVS cases; and in 62.5% of PCC cases for each locus compared to 15, 25 and 45% of control cases. D3S1286 and CFS1-R displayed the highest frequency of LOH in PCC (100% for each) while recorded in 58.3 and 33.3% in PVS compared to 30 and 0% in control cases. Certain genetic events tend to occur as early and late events in malignant change of PVS to PCC. Detection of these events may help in understanding carcinogenesis and in early detection of malignancy. CFS1-R is the most informative marker of tumor progression.

  9. Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis.

    Science.gov (United States)

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Doi, Kazutaka; Tani, Shusuke; Ishikawa, Ken-ichi; Yamashita, Satoshi; Ushijima, Toshikazu; Imai, Takashi; Shimada, Yoshiya

    2014-04-01

    Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were γ-irradiated (0.2-2 Gy) and/or exposed to 1-methyl-1-nitrosourea (MNU) (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model.

  10. IL-1R–MyD88 signaling in keratinocyte transformation and carcinogenesis

    Science.gov (United States)

    Cataisson, Christophe; Salcedo, Rosalba; Hakim, Shakeeb; Moffitt, B. Andrea; Wright, Lisa; Yi, Ming; Stephens, Robert; Dai, Ren-Ming; Lyakh, Lyudmila; Schenten, Dominik

    2012-01-01

    Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88−/− or IL-1R−/− keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88−/− keratinocytes form only a few small tumors in orthotopic grafts, IL-1R–deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1α, IL-1R, and MyD88 leading to phosphorylation of IκBα and NF-κB activation. Blocking IL-1α–mediated NF-κB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes. PMID:22908325

  11. Promoter hypermethylation of KLF4 inactivates its tumor suppressor function in cervical carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Wen-Ting Yang

    Full Text Available OBJECTIVE: The KLF4 gene has been shown to be inactivated in cervical carcinogenesis as a tumor suppressor. However, the mechanism of KLF4 silencing in cervical carcinomas has not yet been identified. DNA methylation plays a key role in stable suppression of gene expression. METHODS: The methylation status of the KLF4 promoter CpG islands was analyzed by bisulfite sequencing (BSQ in tissues of normal cervix and cervical cancer. KLF4 gene expression was detected by RT-PCR, immunohistochemistry and western blot. KLF4 promoter methylation in cervical cancer cell line was determined by BSQ and methylation-specific polymerase chain reaction (MS-PCR. Cell proliferation ability was detected by cell growth curve and MTT assay. RESULTS: The methylated allele was found in 41.90% of 24 cervical cancer tissues but only in 11.11% of 11 normal cervix tissues (P<0.005. KLF4 mRNA levels were significantly reduced in cervical cancer tissues compared with normal cervix tissues (P<0.01 and KLF4 mRNA expression showed a significant negative correlation with the promoter hypermethylation (r = -0.486, P = 0.003. Cervical cancer cell lines also showed a significant negative correlation between KLF4 expression and hypermethylation. After treatment with the demethylating agent 5-Azacytidine (5-Aza, the expression of KLF4 in the cervical cancer cell lines at both mRNA and protein levels was drastically increased, the cell proliferation ability was inhibited and the chemosensitivity for cisplatin was significantly increased. CONCLUSION: KLF4 gene is inactivated by methylation-induced silencing mechanisms in a large subset of cervical carcinomas and KLF4 promoter hypermethylation inactivates the gene's function as a tumor suppressor in cervical carcinogenesis.

  12. Expression of ATP6V1C1 during oral carcinogenesis.

    Science.gov (United States)

    Oliveira Alves, M G; Carta, C F L; Padín-Iruegas, M-E; Pérez-Sayáns, M; Suarez-Peñaranda, J M; Issa, J S; García-García, A; Almeida, J D

    2016-01-01

    We investigated the gene and protein expressions of V-type ATPase protein subunit C1 (ATP6V1C1) in cases of oral squamous cell carcinoma (OSCC) and contralateral normal mucosa in smokers, nonsmokers and former smokers. Subjects were separated into five groups of 15: group 1, smokers with OSCC; group 2, normal contralateral mucosa of OSCC patients; group 3, chronic smokers; group 4, former smokers who had stopped smoking 1 year earlier; group 5, individuals who had never smoked. Exfoliative cytology specimens from oral mucosa of smokers, former smokers and nonsmokers showed normal gene and protein expression. We found significantly greater gene expression in the OSCC group than in the nonsmoker groups. No difference in gene expression was observed between normal contralateral mucosa and nonsmoker groups, smoker and nonsmoker groups or former smoker and nonsmoker groups. We observed intense immunostaining for ATP6V1C1 protein in all cases of OSCC and weak or no staining in smoker, former smoker and nonsmoker groups. Significantly greater expression of ATP6V1C1 protein was observed in the OSCC group compared to the other groups, which supports the role of ATP6V1C1 in effecting changes associated with oral cancer. Analysis of the mucosae of chronic smokers, former smokers and the normal contralateral mucosa of patients with OSCC showed unaltered ATP6V1C1 gene and protein expression. Early stages of carcinogenesis, represented by altered epithelium of chronic smokers, had neither gene nor protein alterations as seen in OSCC. Therefore, we infer that the changes in ATP6V1C1 occur during later stages of carcinogenesis. Our preliminary study provides a basis for future studies of using ATP6V1C1 levels for detecting early stage OSCC.

  13. Amelioration of renal carcinogenesis by bee propolis: a chemo preventive approach.

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    Rashid, Summya; Ali, Nemat; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2013-09-01

    The present study was designed to investigate the chemo preventive efficacy of bee propolis (BP) against diethylnitrosamine (DEN) initiated and ferric nitrilotriacetate (Fe-NTA) promoted renal carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. BP is a resinous material collected by bees from various plants which has been used from centuries in folk medicine. Renal cancer was initiated by single intraperitoneal injection of N-nitrosodiethylamine (DEN 200 mg/kg body weight) and promoted by twice weekly administration of Fe-NTA 9 mg Fe/kg body weight for 16 weeks. The chemo preventive efficacy of BP was studied in terms of lipid peroxidation (LPO), renal anti-oxidant armory such as catalase, superoxide dismustase, glutathione S-transferase, glutathione peroxidase, glutathione reductase and glutathione (GSH), serum toxicity markers, cell proliferation, tumor suppressor protein and inflammation markers. Administration of Fe-NTA enhances renal LPO, with concomitant reduction in reduced GSH content and antioxidant enzymes. It induces serum toxicity markers, viz., blood urea nitrogen, creatinine and lactate dehydrogenase. Chemo preventive effects of BP were associated with upregulation of antioxidant armory and down regulation of serum toxicity markers. BP was also able to down regulate expression of proliferative cell nuclear antigen, cyclooxygenase-2, tumor necrosis factor-alpha and upregulated p53 along with induction of apoptosis. Histopathological changes further confirmed the biochemical and immunohistochemical results. These results provide a powerful evidence for the chemo preventive efficacy of BP against renal carcinogenesis possibly by modulation of multiple molecular pathways.

  14. A central role for heme iron in colon carcinogenesis associated with red meat intake.

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    Bastide, Nadia M; Chenni, Fatima; Audebert, Marc; Santarelli, Raphaelle L; Taché, Sylviane; Naud, Nathalie; Baradat, Maryse; Jouanin, Isabelle; Surya, Reggie; Hobbs, Ditte A; Kuhnle, Gunter G; Raymond-Letron, Isabelle; Gueraud, Françoise; Corpet, Denis E; Pierre, Fabrice H F

    2015-03-01

    Epidemiology shows that red and processed meat intake is associated with an increased risk of colorectal cancer. Heme iron, heterocyclic amines, and endogenous N-nitroso compounds (NOC) are proposed to explain this effect, but their relative contribution is unknown. Our study aimed at determining, at nutritional doses, which is the main factor involved and proposing a mechanism of cancer promotion by red meat. The relative part of heme iron (1% in diet), heterocyclic amines (PhIP + MeIQx, 50 + 25 μg/kg in diet), and NOC (induced by NaNO₂+ NaNO₂; 0.17 + 0.23 g/L of drinking water) was determined by a factorial design and preneoplastic endpoints in chemically induced rats and validated on tumors in Min mice. The molecular mechanisms (genotoxicity, cytotoxicity) were analyzed in vitro in normal and Apc-deficient cell lines and confirmed on colon mucosa. Heme iron increased the number of preneoplastic lesions, but dietary heterocyclic amines and NOC had no effect on carcinogenesis in rats. Dietary hemoglobin increased tumor load in Min mice (control diet: 67 ± 39 mm²; 2.5% hemoglobin diet: 114 ± 47 mm², P = 0.004). In vitro, fecal water from rats given hemoglobin was rich in aldehydes and was cytotoxic to normal cells, but not to premalignant cells. The aldehydes 4-hydroxynonenal and 4-hydroxyhexenal were more toxic to normal versus mutated cells and were only genotoxic to normal cells. Genotoxicity was also observed in colon mucosa of mice given hemoglobin. These results highlight the role of heme iron in the promotion of colon cancer by red meat and suggest that heme iron could initiate carcinogenesis through lipid peroxidation. .

  15. Anticarcinogenesis effect of Gynura procumbens (Lour Merr on tongue carcinogenesis in 4NQO-induced rat

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    D. Agustina

    2006-09-01

    Full Text Available In Indonesia Gynura procumbens (Lour Merr leaves have been long used as various cancers medication. Many in vitro and in vivo studies have demonstrated anticarcinogenesis of ethanol extract of Gynura procumbens leaves. The aim of this study was to investigate the anticarcinogenesis of the ethanol extract of Gynura procumbens leaves on 4 nitroquinoline 1-oxide (4NQO-induced rat tongue carcinogenesis. Fifty six 4 week old male Sprague Dawley rats were used in this study and divided into 7 groups. Group 1, 2 and 3 were lingually induced by 4NQO for 8 weeks. In groups 2 and 3 the extract was given simultaneously with or after 4NQO induction finished, each for 10 weeks and 26 weeks, respectively. Groups 4, 5 and 6 were induced by 4NQO for 16 weeks. However, in groups 5 and 6 the extract was given as well simultaneously with or after the 4NQO induction, each for 18 weeks, respectively. Group 7 served as the as untreated control group. The results from microscopical assessment showed that tongue squamous cell carcinomas (SCC developed in 100% (3/3 of group 1. However, only 33.3% (2/6 and 25% (2/8 of rats in groups 2 and 3, respectively demonstrated tongue SCC. Among groups 4, 5 and 6, no significant difference of tongue SCC incidence was observed. From these results it is apparent that the ethanol extract of Gynura procumbens leaves could inhibit the progression of 4NQOinduced rat tongue carcinogenesis in the initiation phase.

  16. Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis

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    Dawei W. Dong

    2015-12-01

    Full Text Available Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial electron transport component, the cytochrome c oxidase (CcO, leads to increased glycolysis and carcinogenesis. Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca2+ sensitive Calcineurin (Ppp3ca and the expression of PI3-kinase (Pik3r4 and Pik3cb increased by two folds. This Ca2+/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01 between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10−5. Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.

  17. Nanocytological field carcinogenesis detection to mitigate overdiagnosis of prostate cancer: a proof of concept study.

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    Hemant K Roy

    Full Text Available To determine whether nano-architectural interrogation of prostate field carcinogenesis can be used to predict prognosis in patients with early stage (Gleason 6 prostate cancer (PCa, which is mostly indolent but frequently unnecessarily treated.We previously developed partial wave spectroscopic microscopy (PWS that enables quantification of the nanoscale intracellular architecture (20-200 nm length scale with remarkable accuracy. We adapted this technique to assess prostate needle core biopsies in a case control study from men with Gleason 6 disease who either progressed (n = 20 or remained indolent (n = 18 over a ~3 year follow up. We measured the parameter disorder strength (Ld characterizing the spatial heterogeneity of the nanoscale cellular structure and nuclear morphology from the microscopically normal mucosa ~150 histologically normal epithelial cells.There was a profound increase in nano-architectural disorder between progressors and non-progressors. Indeed, the Ld from future progressors was dramatically increased when compared to future non-progressors (1±0.065 versus 1.30±0.0614, respectively p = 0.002. The area under the receiver operator characteristic curve (AUC was 0.79, yielding a sensitivity of 88% and specificity of 72% for discriminating between progressors and non-progressors. This was not confounded by demographic factors (age, smoking status, race, obesity, thus supporting the robustness of the approach.We demonstrate, for the first time, that nano-architectural alterations occur in prostate cancer field carcinogenesis and can be exploited to predict prognosis of early stage PCa. This approach has promise in addressing the clinically vexing dilemma of management of Gleason 6 PCa and may provide a paradigm for dealing with the larger issue of cancer overdiagnosis.

  18. Age-Related Differences in Susceptibility to Carcinogenesis: A Quantitative Analysis of Empirical Animal Bioassay Data

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    Hattis, Dale; Goble, Robert; Russ, Abel; Chu, Margaret; Ericson, Jen

    2004-01-01

    In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA’s original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power). Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning–60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth–weaning period per dose ÷ (body weight0.75-day) for mutagenic carcinogens and a somewhat smaller increase—centered about 5-fold—for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth–weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the “adult” period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90–105 days of age). PMID:15289159

  19. Expression of some tumor associated factors in human carcinogenesis and development of gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Ming-Dong Zhao; Xue-Mei Hu; Dian-Jing Sun; Qun Zhang; Yu-Hao Zhang; Wei Meng

    2005-01-01

    AIM: To study the effect of IGF-1/IGF-1R and gastrin/ CCK-BR on carcinogenesis and development of human gastric carcinoma and to explore its mechanism and provide a credible theoretical foundation for early diagnosis and molecular therapy of gastric carcinoma. METHODS: mRNA expression levels of IGF-1/IGF-1R and gastrin/CCK-BR were assessed by RT-PCR method in gastric cancer tissues, adjacent mucosa, and tumor-free tissues from 56 patients with gastric carcinoma and normal gastric mucosae from 56 healthy controls. Tissue specimens were obtained by biopsy and confirmed by histological evaluation.RESULTS: The mRNA levels of IGF-1/IGF-1R were increased in gastric cancer tissues compared with normal tissues from healthy controls and successively increased in tumor-free tissues, adjacent mucosa, and gastric cancer tissues. The mRNA levels of gastrin/CCK-BR were increased in gastric cancer tissues compared with normal tissues from healthy controls. There was a significant difference between gastric cancer tissues and adjacent mucosa and tumor-free tissues, but the mRNA levels of gastrin were not significantly increased in adjacent mucosa and gastric cancer tissues compared with tumorfree tissues. The mRNA levels of CCK-BR were increased in gastric cancer tissues and adjacent mucosa compared with tumor-free tissues, but not significantly increased in adjacent mucosa and gastric cancer tissues compared with gastric cancer tissues. CONCLUSION: Overexpression of IGF-1/IGF-1R and gastrin/CCK-BR promotes the disorderly proliferation of gastric mucosa epithelia and it is of great significance in the carcinogenesis and development of gastric carcinoma.

  20. Raman spectroscopy detects biomolecular changes associated with nanoencapsulated hesperetin treatment in experimental oral carcinogenesis

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    Gurushankar, K.; Gohulkumar, M.; Kumar, Piyush; Krishna, C. Murali; Krishnakumar, N.

    2016-03-01

    Recently it has been shown that Raman spectroscopy possesses great potential in the investigation of biomolecular changes of tumor tissues with therapeutic drug response in a non-invasive and label-free manner. The present study is designed to investigate the antitumor effect of hespertin-loaded nanoparticles (HETNPs) relative to the efficacy of native hesperetin (HET) in modifying the biomolecular changes during 7,12-dimethyl benz(a)anthracene (DMBA)-induced oral carcinogenesis using a Raman spectroscopic technique. Significant differences in the intensity and shape of the Raman spectra between the control and the experimental tissues at 1800-500 cm-1 were observed. Tumor tissues are characterized by an increase in the relative amount of proteins, nucleic acids, tryptophan and phenylalanine and a decrease in the percentage of lipids when compared to the control tissues. Further, oral administration of HET and its nanoparticulates restored the status of the lipids and significantly decreased the levels of protein and nucleic acid content. Treatment with HETNPs showed a more potent antitumor effect than treatment with native HET, which resulted in an overall reduction in the intensity of several biochemical Raman bands in DMBA-induced oral carcinogenesis being observed. Principal component and linear discriminant analysis (PC-LDA), together with leave-one-out cross validation (LOOCV) on Raman spectra yielded diagnostic sensitivities of 100%, 80%, 91.6% and 65% and specificities of 100%, 65%, 60% and 55% for classification of control versus DMBA, DMBA versus DMBA  +  HET, DMBA versus DMBA  +  HETNPs and DMBA  +  HET versus DMBA  +  HETNPs treated tissue groups, respectively. These results further demonstrate that Raman spectroscopy associated with multivariate statistical algorithms could be a valuable tool for developing a comprehensive understanding of the process of biomolecular changes, and could reveal the signatures of the

  1. Significance of CpG methylation for solar UV-induced mutagenesis and carcinogenesis in skin.

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    Ikehata, Hironobu; Ono, Tetsuya

    2007-01-01

    Mutations detected in the p53 gene in human nonmelanoma skin cancers show a highly UV-specific mutation pattern, a dominance of C --> T base substitutions at dipyrimidine sites plus frequent CC --> TT tandem substitutions, indicating a major involvement of solar UV in the skin carcinogenesis. These mutations also have another important characteristic of frequent occurrences at CpG dinucleotide sites, some of which actually show prominent hotspots in the p53 gene. Although mammalian solar UV-induced mutation spectra were studied intensively in the aprt gene using rodent cultured cells and the UV-specific mutation pattern was confirmed, the second characteristic of the p53 mutations in human skin cancers had not been reproduced. However, studies with transgenic mouse systems developed thereafter for mutation research, which harbor methyl CpG-abundant transgenes as mutation markers, yielded complete reproductions of the situation of the human skin cancer mutations in terms of both the UV-specific pattern and the frequent occurrence at CpG sites. In this review, we evaluate the significance of the CpG methylation for solar UV mutagenesis in the mammalian genome, which would lead to skin carcinogenesis. We propose that the UV-specific mutations at methylated CpG sites, C --> T transitions at methyl CpG-associated dipyrimidine sites, are a solar UV-specific mutation signature, and have estimated the wavelength range effective for the solar-UV-specific mutation as 310-340 nm. We also recommend the use of methyl CpG-enriched sequences as mutational targets for studies on solar-UV genotoxicity for human, rather than conventional mammalian mutational marker genes such as the aprt and hprt genes.

  2. Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma

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    Mei-Ying Zhang

    2014-08-01

    Full Text Available Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05. According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM than adenoma and carcinoma (p < 0.05. Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05. Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05, but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM staging, differentiation or serum carcinoembryonic antigen (CEA concentration (p > 0.05. Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05. Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05. It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.

  3. Expression Patterns of Cancer Stem Cell Markers During Specific Celecoxib Therapy in Multistep Rat Colon Carcinogenesis Bioassays.

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    Salim, Elsayed I; Hegazi, Mona M; Kang, Jin Seok; Helmy, Hager M

    2016-01-01

    The purpose of this study was to investigate the role of colon cancer stem cells (CSCs) during chemicallyinduced rat multi-step colon carcinogenesis with or without the treatment with a specific cyclooxygenase-2 inhibitor drug (celecoxib). Two experiments were performed, the first, a short term 12 week colon carcinogenesis bioassay in which only surrogate markers for colon cancer, aberrant crypt foci (ACF) lesions, were formed. The other experiment was a medium term colon cancer rat assay in which tumors had developed after 32 weeks. Treatment with celecoxib lowered the numbers of ACF, as well as the tumor volumes and multiplicities after 32 weeks. Immunohistochemical proliferating cell nuclear antigen (PCNA) labeling indexes LI (%) were downregulated after treatment by celecoxib. Also different cell surface antigens known to associate with CSCs such as the epithelial cell adhesion molecule (EpCAM), CD44 and CD133 were compared between the two experiments and showed differential expression patterns depending on the stage of carcinogenesis and treatment with celecoxib. Flow cytometric analysis demonstrated that the numbers of CD133 cells were increased in the colonic epithelium after 12 weeks while those of CD44 but not CD133 cells were increased after 32 weeks. Moreover, aldehyde dehydrogenase-1 activity levels in the colonic epithelium (a known CSC marker) detected by ELISA assay were found down-regulated after 12 weeks, but were up-regulated after 32 weeks. The data have also shown that the protective effect of celecoxib on these specific markers and populations of CSCs and on other molecular processes such as apoptosis targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. Therefore, uncovering these distinction roles of CSCs during different phases of carcinogenesis and during specific treatment could be useful for targeted therapy.

  4. Copper and resveratrol attenuates serum catalase, glutathione peroxidase, and element values in rats with DMBA-induced mammary carcinogenesis.

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    Skrajnowska, Dorota; Bobrowska-Korczak, Barbara; Tokarz, Andrzej; Bialek, Slawomir; Jezierska, Ewelina; Makowska, Justyna

    2013-12-01

    In this paper, a hypothesis was assessed whether or not the intoxication with copper and supplementation with copper plus resveratrol would result in changes in the activities of catalase and glutathione peroxidase and moreover if the characteristic changes would appear in concentrations of copper, iron, calcium, magnesium, and zinc in the serum of rats with chemically induced carcinogenesis. Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet, were treated with copper (42.6 mg Cu/kg food as CuSO4·5H2O) or copper plus resveratrol (0.2 mg/kg body) via gavage for a period from 40 days until 20 weeks of age. In cancer groups, the rats were treated with a dose of 80 mg/body weight of 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) given in rapeseed oil at 50 and 80 days of age to induce mammary carcinogenesis. The control groups included the rats kept in the same conditions and fed with the same diet as the animals from the study groups, but not DMBA-treated. The activity of catalase significantly decreased in groups of rats with mammary carcinogenesis that were supplemented with copper (p copper plus resveratrol (p cancer groups of nonsupplemented rats, the increase of glutathione peroxidase activity was observed. The process of carcinogenesis and the applied supplementation significantly altered the concentrations of trace elements in serum, in particular as concerns iron and copper. The mean serum iron levels in rats with breast cancer were significantly lower than those in the control groups (p copper levels significantly decreased in the groups of rats with mammary carcinogenesis that were supplemented with copper or copper plus resveratrol in comparison with the control groups that received the same diets (p copper and zinc/iron ratios in blood may be used as one of the prognostic factors in breast cancer research.

  5. ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection.

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    Niwa, O; Barcellos-Hoff, M H; Globus, R K; Harrison, J D; Hendry, J H; Jacob, P; Martin, M T; Seed, T M; Shay, J W; Story, M D; Suzuki, K; Yamashita, S

    2015-12-01

    This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells

  6. Low ABCB1 gene expression is an early event in colorectal carcinogenesis.

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    Vibeke Andersen

    Full Text Available The ABCB1/MDR1 gene product ABCB1/P-glycoprotein is implicated in the development of colorectal cancer (CRC. NFKB1 encodes transcription factors regulating expression of a number of genes including ABCB1. We have previously found association between the ABCB1 C-rs3789243-T polymorphism and CRC risk and interactions between the ABCB1 C-rs3789243-T and C3435T polymorphisms and meat intake in relation to CRC risk (Andersen, BMC Cancer, 2009, 9, 407. ABCB1 and NFKB1 mRNA levels were assessed in intestinal tissue from 122 CRC cases, 101 adenoma cases (12 with severe dysplasia, 89 with mild-moderate dysplasia and from 18 healthy individuals, together with gene polymorphisms in ABCB1 and NFKB1. ABCB1 mRNA levels were highest in the healthy individuals and significantly lower in mild/moderate and severe dysplasia tissue (P<0.05 for both, morphologically normal tissues close to the tumour (P<0.05, morphologically normal tissue at a distance from the tumour (P<0.05 and CRC tissue (P<0.001. Furthermore, ABCB1 mRNA levels were lower in adenomas and carcinomas compared to morphologically normal tissue from the same individuals (P<0.01. The ABCB1 C-rs3789243-T and NFKB1 -94ins/del homozygous variant genotypes were associated with low ABCB1 mRNA levels in morphologically normal sigmoid tissue from adenoma cases (P<0.05 for both. NFKB1 mRNA levels were lower in both tumour and normal tissue from cancer patients (P<0.001 as compared to healthy individuals but we were unable to show association between NFKB1 -94ins/del genotype and NFKB1 mRNA levels. This study suggests that low ABCB1 mRNA levels are an early event in CRC development and that the two polymorphisms affect ABCB1 mRNA levels whereas low NFKB1 mRNA levels occur later in carcinogenesis. Low ABCB1 protein levels may promote colorectal carcinogenesis through increasing intracellular exposure to carcinogenic ABCB1 substrates.

  7. Role of EZH2 protein expression in gastric carcinogenesis among Asians: a meta-analysis.

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    Guo, Lin; Yang, Teng-Fei; Liang, Shi-Chao; Guo, Ji-Xiang; Wang, Qiang

    2014-07-01

    The present meta-analysis aggregated the results of relevant studies to identify the role of zeste homolog 2 (EZH2) expression in gastric carcinogenesis among Asians. Related articles were found by searching the following electronic databases without language restrictions: PubMed, SpringerLink, Karger Medical and Scientific Publishers, Chinese Biomedical Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Google Scholar. Meta-analysis was performed using STATA statistical software. Crude odds ratios (ORs) or hazard ratios (HRs) with their corresponding 95 % confidence interval (95 % CI) were calculated. Ten relevant studies, which enrolled a total of 872 gastric cancer patients, were selected for statistical analysis. The most important findings of our meta-analysis was that cancer tissues exhibited higher expression levels of EZH2 protein than normal, adjacent and benign tissues (cancer tissues vs normal tissues: OR = 32.15, 95 % CI 22.58 ~ 45.79, P < 0.001; cancer tissues vs adjacent tissues: OR = 16.10, 95 % CI 11.35 ~ 22.84, P < 0.001; cancer tissues vs benign tissues: OR = 2.66, 95 % CI 1.89 ~ 3.75, P < 0.001; respectively). Furthermore, we observed positive correlations between EZH2 expression and the TNM stage (OR = 2.86, 95 % CI 1.72 ~ 4.75, P < 0.001) as well as lymph node metastasis (OR = 3.02, 95 % CI 2.01 ~ 4.53, P < 0.001) of patients with gastric carcinoma. The correlation between EZH2 expression and gastric cancer prognosis was also evaluated in the meta-analysis. Statistical analysis demonstrated that the overall survival (OS) of EZH2-negative patients was shorter than that of patients with positive expressions of EZH2 (HR = 0.54, 95 % CI = 0.05 ~ 1.03, P = 0.032). Our meta-analysis confirmed the view that EZH2 expression might participate in the development of gastric carcinogenesis. Thus, EZH2 protein may be a valuable biomarker for the diagnosis and prognosis of gastric cancer.

  8. Potential effect of hepatitis C Virus non-structural protein 4B on liver carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Xia Chen; Changping Li; Zhongqiong Wang; Guanghong DU

    2006-01-01

    Objective: To investigate the effect of hepatitis C virus non-structural protein 4B(HCV NS4B) on c-Myc, P53,ras gene expression' and apoptosis in hepatic cells and study the possible role that NS4B played in the carcinogenesis of hepatoma. Methods: The recombinant plasmid(PCXN2-NS4B, PCXN2-P53) and the empty vector were transfected or co-transfected into Chang liver cells with liposome. Screening was performed with G418. Plasmid mRNA was detected by RT-PCR. The pro tein expressions of c-Myc and ras genes were analyzed by immunocytochemistry. The expressions of wild-type P53 (wtp53) gene were detected by in situ hybridization. TUNEL(flow cytometry) was used for assessing the rate of apoptosis. Results :No expression of c-Myc gene was found in PCXN2 group. The expression of c-Myc gene in NS4B group was 21.3% ± 1.2%. The ex pression of ras gene in PCXN2 group was lower than that in NS4B group. Compared with PCXN2 group, the expression of P53mRNA was not promoted or inhibited in NS4B group. But the expression of P53 mRNA in NS4B-P53 group was lower than that in P53 group. In PCXN2, NS4B, P53 and NS4B-P53 group, the rates of apoptosis were 17.02% ± 1.24%, 11.94% ± 2.24%,25.84% ± 3.49% and 18.34% ± 1.55% respectively. Conclusion:HCV NS4B induces the expression of c-Myc and ras gene. HCV NS4B may play a role in the inhibition of cell death through P53-dependent manner. Results from this study suggested that HCV NS4B might conuibute to the viral carcinogenesis.

  9. Role of infectious agents in the carcinogenesis of brain and head and neck cancers

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    Alibek Kenneth

    2013-02-01

    Full Text Available Abstract This review concentrates on tumours that are anatomically localised in head and neck regions. Brain cancers and head and neck cancers together account for more than 873,000 cases annually worldwide, with an increasing incidence each year. With poor survival rates at late stages, brain and head and neck cancers represent serious conditions. Carcinogenesis is a multi-step process and the role of infectious agents in this progression has not been fully identified. A major problem with such research is that the role of many infectious agents may be underestimated due to the lack of or inconsistency in experimental data obtained globally. In the case of brain cancer, no infection has been accepted as directly oncogenic, although a number of viruses and parasites are associated with the malignancy. Our analysis of the literature showed the presence of human cytomegalovirus (HCMV in distinct types of brain tumour, namely glioblastoma multiforme (GBM and medulloblastoma. In particular, there are reports of viral protein in up to 100% of GBM specimens. Several epidemiological studies reported associations of brain cancer and toxoplasmosis seropositivity. In head and neck cancers, there is a distinct correlation between Epstein-Barr virus (EBV and nasopharyngeal carcinoma (NPC. Considering that almost every undifferentiated NPC is EBV-positive, virus titer levels can be measured to screen high-risk populations. In addition there is an apparent association between human papilloma virus (HPV and head and neck squamous cell carcinoma (HNSCC; specifically, 26% of HNSCCs are positive for HPV. HPV type 16 was the most common type detected in HNSCCs (90% and its dominance is even greater than that reported in cervical carcinoma. Although there are many studies showing an association of infectious agents with cancer, with various levels of involvement and either a direct or indirect causative effect, there is a scarcity of articles covering the role of

  10. Multistage Carcinogenesis Modelling of Low and Protracted Radiation Exposure for Risk Assessment

    Science.gov (United States)

    Brugmans, M. J. P.; Bijwaard, H.

    Exposure to cosmic radiation in space poses an increased risk for radiation-induced cancer later in life. Modelling is essential to quantify these excess risks from low and protracted exposures to a mixture of radiation types, since they cannot be determined directly in epidemiological studies. Multistage carcinogenesis models provide a mechanistic basis for the extrapolation of epidemiological data to the regime that is relevant for radiation protection. In recent years, we have exploited the well-known two-mutation carcinogenesis model to bridge the gap between radiobiology and epidemiology. We have fitted this model to a number of animal and epidemiological data sets, using dose-response relationships for the mutational steps that are well established in cellular radiobiology. The methodology and implications for radiation risks are illustrated with analyses of two radiation-induced tumours: bone cancer from internal (high-LET and low-LET) emitters and lung cancer after radon exposure. For the risks of bone-seeking radionuclides (Ra-226, Sr-90, Pu-239), model fits to beagle data show that the dose-effect relationship for bone cancer at low intakes is linear-quadratic. This is due to a combination of equally strong linear dose-effects in the two subsequent mutational steps in the model. This supra-linear dose-effect relationship is also found in a model analysis of bone cancer in radium dial painters. This implies that at low intakes the risks from bone seekers are significantly lower than estimated from a linear extrapolation from high doses. Model analyses of radon-exposed rats and uranium miners show that lung-cancer induction is dominated by a linear radiation effect in the first mutational step. For two miner cohorts with significantly different lung cancer baselines a uniform description of the effect of radon is obtained in a joint analysis. This demonstrates the possibility to model risk transfer across populations. In addition to biologically based risk

  11. Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses

    Directory of Open Access Journals (Sweden)

    Xie Z

    2015-03-01

    Full Text Available Zhaohui Xie,1 Yine Qu,2 Yanli Leng,2 Wenxiu Sun,2 Siqi Ma,2 Jingbo Wei,2 Jiangong Hu,3 Xiaolan Zhang1 1Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Histology and Embryology, Hebei United University School of Basic Medicine, Tangshan, Hebei, People’s Republic of China; 3Department of Pathology, the Second Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China Abstract: Inflammation is known to contribute to carcinogenesis in human colorectal cancer. Proinflammatory cytokine interleukin-17 (IL-17 or IL-17A has been shown to play a critical role in colon carcinogenesis in mouse models. However, few studies have investigated IL-17A in human colon tissues. In the present study, we assessed IL-17-driven inflammatory responses in 17 cases of human colon adenocarcinomas, 16 cases of human normal colon tissues adjacent to the resected colon adenocarcinomas, ten cases of human ulcerative colitis tissues from biopsies, and eight cases of human colon polyps diagnosed as benign adenomas. We found that human colon adenocarcinomas contained the highest levels of IL-17A cytokine, which was significantly higher than the IL-17A levels in the adenomas, ulcerative colitis, and normal colon tissues (P<0.01. The levels of IL-17 receptor A (IL-17RA were also the highest in human colon adenocarcinomas, followed by adenomas and ulcerative colitis. The increased levels of IL-17A and IL-17RA were accompanied with increased IL-17-driven inflammatory responses, including activation of extracellular signal-regulated kinase (ERK1/2 and c-Jun N-terminal kinase (JNK pathways, increase in expression of matrix metalloproteinase (MMP9, MMP7, MMP2, B-cell lymphoma (Bcl-2, and cyclin D1, decrease in Bcl-2-associated X protein (BAX expression, and increase in vascular endothelial growth factor (VEGF and VEGF receptor (VEGFR expression that

  12. [Alcohol dehydrogenase and aldehyde dehydrogenase as tumour markers and factors intensifying carcinogenesis in colorectal cancer].

    Science.gov (United States)

    Jelski, Wojciech; Orywal, Karolina; Kedra, Bogusław; Szmitkowski, Maciej

    2008-06-01

    Numerous experiments have shown that alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are present in cells of various cancers and play role in carcinogenesis. The aim of this study was to compare the capacity for ethanol metabolism measured by ADH isoenzymes and ALDH activity, between colorectal cancer and normal colonic mucosa. We have also investigated the serum activity of these enzymes in colorectal cancer patients as potential tumour markers. The activities of ADH isoenzymes and ALDH were measured in the: cancer tissue, healthy colonic mucosa and serum of 42 patients with colorectal cancer. For the measurement of the activity of class I ADH isoenzyme and ALDH activity the fluorometric methods was employed. The total ADH activity and activity of class III and IV isoenzymes was measured by the photometric method. The activity of total alcohol dehydrogenase and class I of ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH had higher activities in cancer tissue but the differences were not statistically significant. The activity of ALDH was significantly lower in the cancer cells. The activities of all tested enzymes and isoenzymes in colorectal cancer tissue were not significantly higher in drinkers than in non-drinkers. Additionally we observed statistically significant increasing activity of class I ADH isoenzymes in the sera of patients with colorectal cancer. For this reason the total ADH activity was also significantly increased. The activities of ADH III and ADH IV isoenzymes and ALDH were unchanged in the sera of patients. There were no marked differences in activities of all tested enzymes and isoenzymes between drinkers and non-drinkers (with colorectal cancer). The differences in activities of total ADH and class I ADH isoenzymes between colorectal cancer tissues and healthy mucosa might be a factor of ethanol metabolism disorders, which can intensify carcinogenesis. The increased total

  13. Inhibitory effects of Zengshengping fractions on DMBA-induced buccal pouch carcinogenesis in hamsters

    Institute of Scientific and Technical Information of China (English)

    GUAN Xiao-bing; SUN Zheng; CHEN Xiao-xin; WU Hong-ru; ZHANG Xin-yan

    2012-01-01

    Background Zengshengping (ZSP) tablets had inhibitory effects on oral precancerous lesions by reducing the incidence of oral cancer.However,the severe liver toxicity caused by systemic administration of ZSP limits the long-term use of this anti-cancer drug.The purpose of this study was to evaluate the tumor inhibitory effects due to the topical application of extracts from ZSP,a Chinese herbal drug,on 7,12-dimethlbenz(a)anthracene (DMBA) induced oral tumors in hamsters.The study also investigated the anti-cancer mechanisms of the ZSP extracts on oral carcinogenesis.Methods DMBA (0.5%) was applied topically to the buccal pouches of Syrian golden hamsters (6-8 weeks old) three times per week for six weeks in order to induce the development of oral tumors.Different fractions of ZSP were either applied topically to the oral tumor lesions or fed orally at varying dosages to animals with oral tumors for 18 weeks.Tumor volume was measured by histopathological examination.Tumor cell proliferation was evaluated by counting BrdU labeled cells and by Western blotting for mitogen-activated protein kinase (MAPK) protein levels.The protein levels of apoptosis marker Caspase-3 and regulator Bcl-2 protein were also measured by Western blotting.Results Topical application of DMBA to the left pouch of hamsters induced oral tumor formation.Animals treated with DMBA showed a loss in body weight while animals treated with ZSP maintained normal body weights.Both the ZSP n-butanol fraction and water fraction significantly reduced tumor volume by 32.6% (P <0.01) and 22.9% (P <0.01)respectively.Topical application of ZSP also markedly decreased the BrdU-positive cell numbers in oral tumor lesions and reduced the expression level of MAPK.In addition,ZSP promoted tumor cell apoptosis by increasing Caspase-3 expression but decreasing Bcl-2 protein production.Conclusion The n-butanol and water fractions of ZSP are effective at inhibiting tumor cell proliferation and stimulating

  14. Adenovirus-expressed preS2 antibody inhibits hepatitis B virus infection and hepatic carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Qian Zhang; Zhi-Qing Li; Hu Liu; Jia-He Yang

    2012-01-01

    AIM: To investigate the inhibitory effect of hepatitis B virus (HBV) preS2 antibody (preS2Ab) against HBV infection and HBV-associated hepatic carcinogenesis. METHODS: An adenoviral vector carrying the fulllength light and heavy chains of the HBV preS2Ab gene, Ad315-preS2Ab, was constructed. Enzyme linked immunosorbent assay (ELISA) and Western blotting analyses were used to determine the preS2Ab expression levels in vitro . Immunofluorescent techniques were used to examine the binding affinity between the expressed HBV preS2Ab and HBV-positive liver cells. ELISAs were also used to determine hepatitis B surface antigen (HBsAg) levels to assess the inhibitory effect of the preS2Ab against HBV infection in L02 cells. The inhibitory effect of preS2Ab against hepatic carcinogenesiswas studied with diethylnitrosamine (DEN)-induced hepatocellular carcinomas (HCCs) in HBV transgenic mice. RESULTS: The expression of HBV preS2Ab increased with increases in the multiplicity of infection (MOI) of Ad315-preS2Ab in L02 cells, with 350.87 ± 17.37 μg/L of preS2Ab when the MOI was 100 plaque forming units (pfu)/cell. The expressed preS2Abs could recognize liver cells from HBV transgenic mice. ELISA results showed that L02 cells expressing preS2Ab produced less HBsAg after treatment with the serum of HBV patients than parental L02 cells expressing no preS2Ab. HBV transgenic mice treated with Ad315-preS2Ab had fewer and smaller cancerous nodes after induction with DEN than mice treated with a blank Ad315 vector or untreated mice. Additionally, the administration of Ad315-preS2Ab could alleviate hepatic cirrhosis and decrease the serum levels of alanine transaminase and aspartate transaminase. CONCLUSION: Adenovirus-mediated HBV preS2Ab expression could inhibit HBV infection in L02 cells, and then inhibit DEN-induced hepatocellular carcinogenesis and protect hepatic function in HBV transgenic mice.

  15. Development of a potential probiotic yoghurt using selected anti-inflammatory lactic acid bacteria for prevention of colitis and carcinogenesis in mice.

    Science.gov (United States)

    Del Carmen, S; de Moreno de LeBlanc, A; LeBlanc, J G

    2016-09-01

    To evaluate the beneficial properties of a potentially probiotic yoghurt obtained by the fermentation of two selected anti-inflammatory bacterial strains using in vivo mouse models of intestinal inflammation and colon carcinogenesis. Yoghurt was administered to mice suffering chemically induced intestinal inflammation or colon carcinogenesis. It was shown that this novel yoghurt was able to prevent local inflammation in the intestines of mice through a regulation of the immune response, prevent macroscopic and histological damages, and prevent colon carcinogenesis through an anti-inflammatory response. The developed yoghurt showed in vivo anti-inflammatory properties by modulation of the host immune response for the prevention of colon inflammation and carcinogenesis. This new yoghurt could thus be considered a probiotic food and be useful as a complement to current treatment protocols for inflammatory bowel diseases and colon cancer, a first since there are no current functional foods specifically oriented for these patients. © 2016 The Society for Applied Microbiology.

  16. Radiation carcinogenesis and acute radiation mortality in the rat as produced by 2.2 GeV protons

    Science.gov (United States)

    Shellabarger, C. J.; Straub, R. F.; Jesseph, J. E.; Montour, J. L.

    1972-01-01

    Biological studies, proton carcinogenesis, the interaction of protons and gamma-rays on carcinogenesis, proton-induced acute mortality, and chemical protection against proton-induced acute mortality were studied in the rat and these proton-produced responses were compared to similar responses produced by gamma-rays or X-rays. Litter-mate mice were assigned to each experimental and control group so that approximately equal numbers of litter mates were placed in each group. Animals to be studied for mammary neoplasia were handled for 365 days post-exposure when all animals alive were killed. All animals were examined frequently for mammary tumors and as these were found, they were removed, sectioned and given a pathologic classification.

  17. In Situ Nuclear Morphology Measurements Using Light Scattering as Biomarkers of Neoplastic Change in Animal Models of Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Adam Wax

    2008-01-01

    Full Text Available Light scattering spectroscopy measurements can be used to determine the structure of tissue samples. Through refined data acquisition and signal processing techniques, quantitative nuclear morphology measurements may be obtained from light scattering data. These data have been used primarily as a biomarker of neoplastic change in a wide range of settings. Here, we review the application of light scattering to assessing the health status of tissues drawn from animal models of carcinogenesis, in particular, the rat esophagus and the golden Syrian hamster trachea carcinogenesis models. In addition, we present results from ex vivo human tissues to demonstrate the relevance of the use of animal models which are excellent surrogates for several human cancers. These models provide the opportunity to develop biomarkers and test chemopreventive and therapy strategies before application in humans.

  18. Downstream carcinogenesis signaling pathways by green tea polyphenols: a translational perspective of chemoprevention and treatment for cancers.

    Science.gov (United States)

    Hu, Guohua; Zhang, Lei; Rong, Yefei; Ni, Xiaoling; Sun, Yihong

    2014-01-01

    Green tea is one of the most popular beverages around the world. For several decades, numerous epidemiological, preclinical and clinical studies have demonstrated that green tea polyphenols (GTPs), especially epigallocatechin-3-gallate (EGCG) have cancer-preventing effects on various cancers. In this review, we present inhibition of carcinogenesis in different animal models by GTPs or EGCG, including prostate cancer, bladder cancer, breast cancer, intestinal cancer, colon cancer, gastric cancer, lung cancer, oral cancer and skin cancer. In vitro studies showed that GTPs/EGCG potently induces apoptosis, cell cycle arrest and suppresses metastasis in tumor cells but not in their normal cell counterparts. The molecular mechanisms of these activities are discussed in detail to elucidate GTPs/EGCG downstream carcinogenesis signaling pathways and their values of perspective of chemoprevention and treatment for cancers.

  19. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji, E-mail: tmntt08@gmail.com [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Mori, Takayuki [Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502 (Japan); Watanabe, Naoki [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Naiki, Takafumi [Department of Clinical Laboratory, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513 (Japan); Moriwaki, Hisataka [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi [The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501 (Japan)

    2014-07-21

    Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation.

  20. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response

    OpenAIRE

    Ericksen, Russell E; Rose, Shannon; Westphalen, Christoph Benedikt; Shibata, Wataru; Muthupalani, Sureshkumar; Tailor, Yagnesh; Friedman, Richard A.; Han, Weiping; Fox, James G.; Ferrante, Anthony W.; Wang, Timothy C.

    2013-01-01

    Objective: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. Results: H felis...

  1. 52. INHIBITORY EFFECTS OF VITAMIN E SUCCINATE ON BENZO(A) PYRENE-INDUCED FORESTOMACH CARCINOGENESIS IN FEMALE MICE

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@This study is a part of an effort to develop effective chemoprevention for carcinogenesis of the forestomach. Vitamin E succinate(VES) administered by oral gavage and by intraperitioneal (IP) injections was used for the studies. Experimental design involved treating mice with Benzo(a) pyrene and VES(1.25 g/kg and 2.5 g/kg for gavage; 20 mg/kg for IP injections) for 4 weeks in order to study the

  2. Apc-Mutant Kyoto Apc Delta (KAD Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Takuji Tanaka

    2014-07-01

    Full Text Available Despite widening interest in the possible association between infection/ inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females and F344/NS1c (22 males and 23 females rats received drinking water with or without 4-NQO (20 ppm for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01 and female F344/NS1c rats (p < 0.05. The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue carcinogenesis associated with inflammation.

  3. Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats

    OpenAIRE

    Anna Kakehashi; Midori Yoshida; Yoshiyuki Tago; Naomi Ishii; Takahiro Okuno; Min Gi; Hideki Wanibuchi

    2016-01-01

    Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in u...

  4. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Xiaojun [The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Park, Eunmi [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 (United States); Fischer, Susan M. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78967 (United States); Hu, Yinling, E-mail: huy2@mail.nih.gov [Cancer and Inflammation Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701 (United States)

    2013-02-15

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.

  5. Curcumin and resveratrol in combination modulate drug-metabolizing enzymes as well as antioxidant indices during lung carcinogenesis in mice.

    Science.gov (United States)

    Liu, Y; Wu, Y-M; Yu, Y; Cao, C-S; Zhang, J-H; Li, K; Zhang, P-Y

    2015-06-01

    This study investigated combined chemopreventive potential of curcumin and resveratrol during benzo(a)pyrene (BP)-induced lung carcinogenesis in mice. The mice were segregated into five groups that included normal control, BP-treated, BP + curcumin-treated, BP + resveratrol-treated, and BP + curcumin + resveratrol-treated groups. A statistically significant increase in the levels of lipid peroxidation (LPO) was observed in the lungs of mice after 22 weeks of single dose of benzo(a)pyrene. Further, BP treatment also resulted in a significant increase in the enzyme activities of aryl hydrocarbon hydroxylase as well as drug-metabolizing enzymes, namely cytocrome P450 and cytochrome b5. On the other hand, reduced glutathione (GSH) levels, the activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione-S-transferase (GST) were found to be significantly decreased following BP treatment. Supplementation with curcumin and resveratrol to BP-treated mice significantly decreased the LPO levels, GSH levels, and enzyme activities of drug-metabolizing enzymes. Further, treatment of curcumin and resveratrol to BP-treated mice significantly elevated the activities of SOD, GR, and GST. Histoarchitectural studies showed well-differentiated signs of lung carcinogenesis following BP administration to mice. However, combined treatment with curcumin and resveratrol resulted in a noticeable improvement in the lung histoarchitecture. This study, therefore, concludes that curcumin and resveratrol when supplemented in combination regulate drug-metabolizing enzymes as well as antioxidant enzymes during lung carcinogenesis in mice. © The Author(s) 2014.

  6. Use of grape polyphenols against carcinogenesis: putative molecular mechanisms of action using in vitro and in vivo test systems.

    Science.gov (United States)

    Gollucke, Andrea P B; Aguiar, Odair; Barbisan, Luis Fernando; Ribeiro, Daniel Araki

    2013-03-01

    Polyphenols are present in foods and beverages and are related to sensorial qualities such as color, bitterness, and astringency, which are relevant in wine, tea, grape juice, and other products. These compounds occur naturally in forms varying from simple phenolic acids to complex polymerized tannins. Thus, it is reasonable to expect that grape-derived products elaborated in the presence of skins and seeds, such as wine and grape juice, are natural sources of flavonoids in the diet. Carcinogenesis is a multistep process that is characterized by genetic, epigenetic, and phenotypic changes. With increasing knowledge of these mechanisms, and the conclusion that most cases of cancer are preventable, efforts have focused on identifying the agents with potential anticancer properties. The use of grape polyphenols against the carcinogenesis process seems to be a suitable alternative for either prevention and/or therapeutic purposes. The aim of this article is to show the molecular data generated from the use of grape polyphenols against carcinogenesis using in vivo and in vitro test systems.

  7. Inhibitory effects of polysaccharides isolated from Phellinus gilvus on benzo(a)pyrene-induced forestomach carcinogenesis in mice

    Institute of Scientific and Technical Information of China (English)

    Jae-Sung Bae; Kwang-Ho Jang; Hyunee Yim; Seung-Chun Park; Hee-Kyung Jin

    2005-01-01

    AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study.METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4,PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis.RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk.CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.

  8. Strawberry phytochemicals inhibit azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis in Crj: CD-1 mice.

    Science.gov (United States)

    Shi, Ni; Clinton, Steven K; Liu, Zhihua; Wang, Yongquan; Riedl, Kenneth M; Schwartz, Steven J; Zhang, Xiaoli; Pan, Zui; Chen, Tong

    2015-03-10

    Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg-1 body weight). One week after injection, mice were administered 2% (w/v) dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05). The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.

  9. Insights into the field carcinogenesis of ovarian cancer based on the nanocytology of endocervical and endometrial epithelial cells

    Science.gov (United States)

    Damania, Dhwanil; Roy, Hemant K.; Kunte, Dhananja; Hurteau, Jean A.; Subramanian, Hariharan; Cherkezyan, Lusik; Krosnjar, Nela; Shah, Maitri; Backman, Vadim

    2013-01-01

    Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late-stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at-risk women as they preferentially target low-grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (Ld). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in Ld (% fold-increase > 50%, P-value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with mico-RNA expression data. PMID:23436651

  10. Gene expression correlation analysis predicts involvement of high- and low-confidence risk genes in different stages of prostate carcinogenesis.

    Science.gov (United States)

    Yano, Kojiro

    2010-12-01

    Whole genome association studies have identified many loci associated with the risk of prostate cancer (PC). However, very few of the genes associated with these loci have been related to specific processes of prostate carcinogenesis. Therefore I inferred biological functions associated with these risk genes using gene expression correlation analysis. PC risk genes reported in the literature were classified as having high (Plow (Phigh-confidence genes and other genes in the microarray dataset, whereas correlation between low-confidence genes and other genes in PC showed smaller decrease. Genes involved in developmental processes were significantly correlated with all risk gene categories. Ectoderm development genes, which may be related to squamous metaplasia, and genes enriched in fetal prostate stem cells (PSCs) showed strong association with the high-confidence genes. The association between the PSC genes and the low-confidence genes was weak, but genes related to neural system genes showed strong association with low-confidence genes. The high-confidence risk genes may be associated with an early stage of prostate carcinogenesis, possibly involving PSCs and squamous metaplasia. The low-confidence genes may be involved in a later stage of carcinogenesis. © 2010 Wiley-Liss, Inc.

  11. Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats.

    Science.gov (United States)

    Xie, Xiao-Li; Gi, Min; Fujioka, Masaki; Doi, Kenichiro; Yamano, Shotaro; Tachibana, Hirokazu; Fang, He; Kakehashi, Anna; Wanibuchi, Hideki

    2015-09-01

    Ethanol-extracted propolis (EEP) is used for medical, dietetic and cosmetic purposes. In this study, the effects of EEP on urinary bladder carcinogenesis, its underlying mechanism and in vivo genotoxicity were investigated. In experiment 1, rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 2 or 4 weeks followed by dietary administration of 0.125, 0.25, 0.5 or 1% EEP for 4 or 32 weeks, respectively. At week 6, the mRNA levels of top2a, cyclin D1 and survivin were significantly elevated in the 0.5 and 1% EEP groups. At week 36, the incidence and multiplicity of urothelial carcinomas and total tumors were markedly elevated in all EEP groups. In experiment 2, rats were fed basal diet or the 1% EEP diet for 13 weeks without carcinogen initiation. Increases in urinary precipitate, cell proliferation and incidence of simple hyperplasia were observed in the 1% EEP group. In experiment 3, dietary administration of 2.5% EEP to gpt delta rats for 13 weeks did not induce any obvious mutagenicity in the urinary bladder urothelium. Taken together, EEP enhanced BBN-initiated rat urinary bladder carcinogenesis in a non-genotoxic manner through increasing formation of urinary precipitate, enhancing cell proliferation and inhibiting apoptosis during the early stages of carcinogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Distinct response of the hepatic transcriptome to Aflatoxin B1 induced hepatocellular carcinogenesis and resistance in rats

    Science.gov (United States)

    Shi, Jiejun; He, Jiangtu; Lin, Jing; Sun, Xin; Sun, Fenyong; Ou, Chao; Jiang, Cizhong

    2016-01-01

    Aflatoxin is a natural potent carcinogen and a major cause of liver cancer. However, the molecular mechanisms of hepatocellular carcinogenesis remain largely unexplored. In this study, we profiled global gene expression in liver tissues of rats that developed hepatocellular carcinoma (HCC) from aflatoxin B1 (AFB1) administration and those that were AFB1-resistant, as well as rats without AFB1 exposure as a control. AFB1 exposure resulted in extensive perturbation in gene expression with different functions in HCC and AFB1 resistance (AR) samples. The differentially expressed genes (DEGs) in HCC sample were enriched for cell proliferation, cell adhesion and vasculature development that largely contribute to carcinogenesis. Anti-apoptosis genes were up-regulated in HCC sample whereas apoptosis-induction genes were up-regulated in AR sample. AFB1 exposure also caused extensive alteration in expression level of lncRNAs. Among all the 4511 annotated lncRNAs, half of them were highly expressed only in HCC sample and up-regulated a group of protein-coding genes with cancer-related functions: apoptosis regulation, DNA repair, and cell cycle. Intriguingly, these genes were down-regulated by lncRNAs highly expressed in AR sample. Collectively, apoptosis is the critical biological process for carcinogenesis in response to AFB1 exposure through changes in expression level of both protein-coding and lncRNA genes. PMID:27545718

  13. Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4-NQO-induced carcinogenesis.

    Science.gov (United States)

    Huang, Zhishan; Komninou, Despina; Kleinman, Wayne; Pinto, John T; Gilhooly, Elaine M; Calcagnotto, Ana; Richie, John P

    2007-04-01

    High glutathione (GSH) levels are commonly found in oral tumors and are thought to play an important role in tumorigenesis. While posttranslational binding of GSH to cellular proteins (protein glutathiolation) has recently been recognized as an important redox-sensitive regulatory mechanism, no data currently exist on this process during carcinogenesis. Our goal was to determine the effects of 4-nitroquinoline-N-oxide (4-NQO)-induced carcinogenesis on tongue levels of protein-bound and free GSH and related thiols in the rat. Male F-344 rats (6 weeks of age) were administered either 4-NQO (20 ppm) in drinking water or tap water alone (controls) for 8 weeks. Twenty-four weeks after cessation of 4-NQO, squamous cell carcinomas of the tongue were observed in all rats. The levels of both free and bound GSH in tumors, as well as in adjacent tissues, were 2- to 3-fold greater than in tongue epithelium from control rats (p tongue tissues from control rats (ptongue tissues from 4-NQO treated vs. control rats (p<0.05). Altogether, these results suggest that protein glutathiolation, together with GSH and GSSG levels, are induced during oral carcinogenesis in the rat possibly as a result of enhanced levels of oxidative stress.

  14. Strawberry Phytochemicals Inhibit Azoxymethane/Dextran Sodium Sulfate-Induced Colorectal Carcinogenesis in Crj: CD-1 Mice

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    Ni Shi

    2015-03-01

    Full Text Available Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg−1 body weight. One week after injection, mice were administered 2% (w/v dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05. The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.

  15. Gene expression profiling signatures for the diagnosis and prevention of oral cavity carcinogenesis-genome-wide analysis using RNA-seq technology.

    Science.gov (United States)

    Tang, Xiao-Han; Urvalek, Alison M; Osei-Sarfo, Kwame; Zhang, Tuo; Scognamiglio, Theresa; Gudas, Lorraine J

    2015-09-15

    We compared the changes in global gene expression between an early stage (the termination of the carcinogen treatment and prior to the appearance of frank tumors) and a late stage (frank squamous cell carcinoma (SCC)) of tongue carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral cavity and esophageal squamous cell carcinoma. Gene ontology and pathway analyses show that increases in "cell cycle progression" and "degradation of basement membrane and ECM pathways" are early events during SCC carcinogenesis and that changes in these pathways are even greater in the actual tumors. Myc, NFκB complex (NFKB1/RELA), and FOS transcription networks are the major transcriptional networks induced in early stage tongue carcinogenesis. Decreases in metabolism pathways, such as in "tricarboxylic acid cycle" and "oxidative phosphorylation", occurred only in the squamous cell carcinomas and not in the early stages of carcinogenesis. We detected increases in ALDH1A3, PTGS2, and KRT1 transcripts in both the early and late stages of carcinogenesis. The identification of the transcripts and pathways that change at an early stage of carcinogenesis provides potentially useful information for early diagnosis and for prevention strategies for human tongue squamous cell carcinomas.

  16. Punica granatum and its therapeutic implications on breast carcinogenesis: A review.

    Science.gov (United States)

    Vini, Ravindran; Sreeja, Sreeharshan

    2015-01-01

    Punica granatum has a recorded history of pharmacological properties which can be attributed to its rich reservoir of phytochemicals. Investigations in recent years have established its tremendous potential as an antitumorogenic agent against various cancers including breast cancer, which is the second leading cause of cancer-related deaths in women. The plausible role of Punica as a therapeutic agent, as an adjuvant in chemotherapy, and its dietary implications as chemopreventive agent in breast cancer have been explored. Mechanistic studies have revealed that Punica extracts and its components, individually or in combination, can modulate and target key proteins and genes involved in breast cancer. Our earlier finding also demonstrated the role of methanolic extract of pomegranate pericarp in reducing proliferation in breast cancer by binding to estrogen receptor at the same time not affecting uterine weight unlike estradiol or tamoxifen. This review analyses other plausible mechanisms of Punica in preventing the progression of breast cancer and how it can possibly be a therapeutic agent by acting at various steps of carcinogenesis including proliferation, invasion, migration, metastasis, angiogenesis, and inflammation via various molecular mechanisms.

  17. Utility of MicroRNAs and siRNAs in Cervical Carcinogenesis

    Science.gov (United States)

    Díaz-González, Sacnite del Mar; Benítez-Boijseauneau, Odelia; Gómez-Cerón, Claudia; Bermúdez-Morales, Victor Hugo; Rodríguez-Dorantes, Mauricio; Pérez-Plasencia, Carlos; Peralta-Zaragoza, Oscar

    2015-01-01

    MicroRNAs and siRNAs belong to a family of small noncoding RNAs which bind through partial sequence complementarity to 3′-UTR regions of mRNA from target genes, resulting in the regulation of gene expression. MicroRNAs have become an attractive target for genetic and pharmacological modulation due to the critical function of their target proteins in several signaling pathways, and their expression profiles have been found to be altered in various cancers. A promising technology platform for selective silencing of cell and/or viral gene expression using siRNAs is currently in development. Cervical cancer is the most common cancer in women in the developing world and sexually transmitted infection with HPV is the cause of this malignancy. Therefore, a cascade of abnormal events is induced during cervical carcinogenesis, including the induction of genomic instability, reprogramming of cellular metabolic pathways, deregulation of cell proliferation, inhibition of apoptotic mechanisms, disruption of cell cycle control mechanisms, and alteration of gene expression. Thus, in the present review article, we highlight new research on microRNA expression profiles which may be utilized as biomarkers for cervical cancer. Furthermore, we discuss selective silencing of HPV E6 and E7 with siRNAs which represents a potential gene therapy strategy against cervical cancer. PMID:25874209

  18. Molecular pathways to therapeutics: Paradigms and challenges in oncology meeting report: Carcinogenesis 2015

    Directory of Open Access Journals (Sweden)

    Ujjwala M Warawdekar

    2015-01-01

    Full Text Available The search for the most effective therapy with minimum side effects has always been the goal of oncologists and efforts to develop such therapies through understanding disease mechanisms has been the focus of many basic scientists in cancer research, leading to a common interest of convergence. The 5 th International Conference organized by the Carcinogenesis Foundation, USA and Advanced Centre for Treatment, Research and Education in Cancer (ACTREC, Tata Memorial Centre, India, was held between February 11 th and 13 th 2015, at ACTREC. During these proceedings, the scientific community engaged in oncology research discussed novel ideas emerging from the laboratory and their translation into improved clinical outcomes. However, the lack of major success in the genesis of novel cancer therapeutics that is safe and provides long-term relief to patients is a challenge that needs to be overcome. The focus of this meeting was to highlight these challenges and to encourage collaborations between scientists and clinicians and clearly a message through exemplary scientific contribution was conveyed to all the dedicated scientists and clinician that even if two decades of tireless work on a single idea does not generate a reliable and safe therapy, the combat to rein cancer must not cease. In this report we have communicated some of the outstanding work done in the areas of cancer therapeutics, biomarkers and prevention and described the salient observations associated with cancer stem cells in disease progression and some of the pathways implicated in tumor progression.

  19. Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis.

    Science.gov (United States)

    Cao, Chao; Lai, Tianwen; Li, Miao; Zhou, Hongbin; Lv, Dan; Deng, Zaichun; Ying, Songmin; Chen, Zhihua; Li, Wen; Shen, Huahao

    2016-04-05

    Oxidative stress induced by tobacco smoking is one of the main causes of DNA damage and is known to be involved in various cancers. Smoking is the leading cause of lung cancer, while the role of cigarette smoke-induced oxidative DNA damage response during lung carcinogenesis is largely unknown. In this study, we investigated oxidative DNA damage response levels in smoking and nonsmoking patients with lung cancer, and evaluated the potential diagnostic value of 8-OHdG for lung cancer. We observed a higher level of 8-OHdG expression and secretion in airways of lung cancer patients than that of noncancer controls. 8-OHdG expression was associated with the TNM stages. Additionally, cigarette smoke-induced oxidative DNA damage response was observed in bronchial epithelial cells in vitro and in vivo. A statistical significance correlation was found between the levels of 8-OHdG and smoking index. With a cut-off value of 2.86 ng/ml, 8-OHdG showed a sensitivity and specificity of 70.0% and 73.7%, respectively, to identify a patient with lung cancer. These findings not only underscore the importance of smoking in oxidative DNA damage response of lung cancer patients, but also suggest 8-OHdG as a potential diagnostic biomarker for lung cancer.

  20. The Role of Macrophage Migration Inhibitory Factor (MIF) in Ultraviolet Radiation-Induced Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimizu, Tadamichi [Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, 930-0194, Toyama (Japan)

    2010-08-09

    Ultraviolet (UV) radiation is the most common cause of physical injury to the skin due to environmental damage, and UV exposure substantially increases the risk of actinic damage to the skin. The inflammatory changes induced by acute UV exposure include erythema (sunburn) of the skin, while chronic exposure to solar UV radiation causes photo-aging, immunosuppression, and ultimately, carcinogenesis of the skin. After skin damage by UV radiation, the cells are known to secrete many cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α. and macrophage migration inhibitory factor (MIF). MIF was originally identified as a lymphokine that concentrates macrophages at inflammatory loci, and is known to be a potent activator of macrophages in vivo. MIF is considered to play an important role in cell-mediated immunity. Since the molecular cloning of MIF cDNA, MIF has been re-evaluated as a proinflammatory cytokine and pituitary-derived hormone that potentiates endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. This article reviews the latest findings on the roles of MIF with regard to UV-induced skin cancer.

  1. Imbalance between apoptosis and cell proliferation during early stages of mammary gland carcinogenesis in ACI rats

    Energy Technology Data Exchange (ETDEWEB)

    Kutanzi, Kristy R.; Koturbash, Igor [Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4 (Canada); Bronson, Roderick T. [Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115 (United States); Pogribny, Igor P., E-mail: igor.pogribny@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Kovalchuk, Olga, E-mail: olga.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4 (Canada)

    2010-12-10

    Estrogen and ionizing radiation are well-documented human breast carcinogens, yet the exact mechanisms of their deleterious effects on mammary gland remain to be discerned. Here we analyze the balance between cellular proliferation and apoptosis in the mammary glands of rats exposed to estrogen and X-ray radiation and the combined action of these carcinogenic agents. For the first time, we show that combined exposure to estrogen and radiation has a synergistic effect on cell proliferation in the mammary glands of ACI rats, as evidenced by a substantially greater magnitude of cell proliferation, especially after 12 and 18 weeks of treatment, when compared to mammary glands of rats exposed to estrogen or radiation alone. We also demonstrate that an imbalance between cell proliferation and apoptosis, rather than enhanced cell proliferation or apoptosis suppression alone, may be a driving force for carcinogenesis. Our studies further suggest that compromised functional activity of p53 may be one of the mechanisms responsible for the proliferation/apoptosis imbalance. In sum, the results of our study indicate that evaluation of the extent of cell proliferation and apoptosis before the onset of preneoplastic lesions may be a potential biomarker of breast cancer risk after exposure to breast carcinogens.

  2. Do Alterations in Mitochondrial DNA Play a Role in Breast Carcinogenesis?

    Directory of Open Access Journals (Sweden)

    Thomas E. Rohan

    2010-01-01

    Full Text Available A considerable body of evidence supports a role for oxidative stress in breast carcinogenesis. Due to their role in producing energy via oxidative phosphorylation, the mitochondria are a major source of production of reactive oxygen species, which may damage DNA. The mitochondrial genome may be particularly susceptible to oxidative damage leading to mitochondrial dysfunction. Genetic variants in mtDNA and nuclear DNA may also contribute to mitochondrial dysfunction. In this review, we address the role of alterations in mtDNA in the etiology of breast cancer. Several studies have shown a relatively high frequency of mtDNA mutations in breast tumor tissue in comparison with mutations in normal breast tissue. To date, several studies have examined the association of genetic variants in mtDNA and breast cancer risk. The G10398A mtDNA polymorphism has received the most attention and has been shown to be associated with increased risk in some studies. Other variants have generally been examined in only one or two studies. Genome-wide association studies may help identify new mtDNA variants which modify breast cancer risk. In addition to assessing the main effects of specific variants, gene-gene and gene-environment interactions are likely to explain a greater proportion of the variability in breast cancer risk.

  3. Do alterations in mitochondrial DNA play a role in breast carcinogenesis?

    Science.gov (United States)

    Rohan, Thomas E; Wong, Lee-Jun; Wang, Tao; Haines, Jonathan; Kabat, Geoffrey C

    2010-01-01

    A considerable body of evidence supports a role for oxidative stress in breast carcinogenesis. Due to their role in producing energy via oxidative phosphorylation, the mitochondria are a major source of production of reactive oxygen species, which may damage DNA. The mitochondrial genome may be particularly susceptible to oxidative damage leading to mitochondrial dysfunction. Genetic variants in mtDNA and nuclear DNA may also contribute to mitochondrial dysfunction. In this review, we address the role of alterations in mtDNA in the etiology of breast cancer. Several studies have shown a relatively high frequency of mtDNA mutations in breast tumor tissue in comparison with mutations in normal breast tissue. To date, several studies have examined the association of genetic variants in mtDNA and breast cancer risk. The G10398A mtDNA polymorphism has received the most attention and has been shown to be associated with increased risk in some studies. Other variants have generally been examined in only one or two studies. Genome-wide association studies may help identify new mtDNA variants which modify breast cancer risk. In addition to assessing the main effects of specific variants, gene-gene and gene-environment interactions are likely to explain a greater proportion of the variability in breast cancer risk.

  4. Role of HER2/HER3 co-receptor in breast carcinogenesis.

    Science.gov (United States)

    Way, Tzong-Der; Lin, Jen-Kun

    2005-12-01

    ErbB receptors are essential mediators of cell proliferation and differentiation. Their aberrant activation is associated with the development and severity of many cancers. Homo- and heterodimerization of ErbB receptors result in a wide variety of cellular signal transduction. Dimerization of human epidermal growth-factor receptor (HER)2 and HER3 occurs frequently and is a preferred heterodimer. The HER2/HER3 dimer constitutes a high affinity co-receptor for heregulin, which is capable of potent mitogenic signaling. HER3 is a kinase-defective protein that is phosphorylated by HER2. Tyrosine phosphorylated HER3 is able to directly couple to phosphatidylinositide 3-kinase, a lipid kinase involved in the proliferation, survival, adhesion and motility of tumor cells. The authors' research provides mechanistic evidence that apigenin induces apoptosis by depleting the HER2 protein and, in turn, suppressing the signaling of the HER2/HER3-phosphatidylinositide 3-kinase/Akt pathway. This indicates that inhibition of HER2/HER3 heterodimer function may be an especially effective and unique strategy for blocking the HER2-mediated carcinogenesis of breast cancer cells.

  5. Modeling Lung Carcinogenesis in Radon-Exposed Miner Cohorts: Accounting for Missing Information on Smoking.

    Science.gov (United States)

    van Dillen, Teun; Dekkers, Fieke; Bijwaard, Harmen; Brüske, Irene; Wichmann, H-Erich; Kreuzer, Michaela; Grosche, Bernd

    2016-05-01

    Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort-wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case-control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow-up period 1955-1998. After applying the proposed imputation technique, a biologically-based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.

  6. The CK1 family: contribution to cellular stress response and its role in carcinogenesis

    Directory of Open Access Journals (Sweden)

    Uwe eKnippschild

    2014-05-01

    Full Text Available Members of the highly conserved and ubiquitously expressed pleiotropic CK1 family play major regulatory roles in many cellular processes including DNA-processing and repair, proliferation, cytoskeleton dynamics, vesicular trafficking, apoptosis, and cell differentiation. As a consequence of cellular stress conditions, interaction of CK1 with the mitotic spindle is manifold increased pointing to regulatory functions at the mitotic checkpoint. Furthermore, CK1 is able to alter the activity of key regulatory proteins and signal integration molecules and is tightly connected to the regulation of β-catenin, p53- and MDM2-specific functions and degradation. Considering the importance of CK1 for accurate cell division and regulation of tumor suppressor functions it is not surprising that mutations and alterations in the expression and/or activity of CK1 isoforms are often detected in various tumor entities including cancer of the kidney, choriocarcinomas, breast carcinomas, oral cancer, adenocarcinomas of the pancreas, and ovarian cancer. Therefore, effort has enormously increased (i to understand the regulation of CK1 and its involvement in tumorigenesis- and tumor progression-related signal transduction pathways and (ii to develop CK1-specific inhibitors for the use in personalized therapy concepts. In this review we summarize the current knowledge regarding the regulation, functions, and interactions of CK1 family members with cellular proteins playing central roles in cellular stress-responses and carcinogenesis.

  7. Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity

    Directory of Open Access Journals (Sweden)

    Adil H.H. Bashir

    2011-07-01

    Full Text Available Carcinogenesis occurs through a series of steps from normal into benign and finally malignant phenotype. This cancer evolutionary trajectory has been accompanied by similar metabolic transformation from normal metabolism into Pasteur and/or Crabtree-Effects into Warburg-Effect and finally Cannibalism and/or Lactate-Symbiosis. Due to lactate production as an end-product of glycolysis, tumor colonies acquire new phenotypes that rely on lactate as energetic fuel. Presence of Warburg-Effect indicates that some tumor cells undergo partial (if not complete de-endosymbiosis and so cancer cells have been become unicellular microorganism (anti-Dollo’s Law specially when they evolve to develop cannibalism as way of metabolism while oxidative types of cells that rely on lactate, as their energetic fuel, might represent extra-endosymbiosis. Thus, at the end, the cancer colony could be considered as integrated metabolic ecosystem. Proper understanding of tumor metabolism will contribute to discover potential anticancer agents besides conventional chemotherapy.

  8. Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity)

    Energy Technology Data Exchange (ETDEWEB)

    Alfarouk, Khalid O., E-mail: Alfarouk@Hala-alfarouk.org [Department of Evolution of Tumor Metabolism and Pharmacology, Hala Alfarouk Cancer Center, Khartoum 11123 (Sudan); Shayoub, Mohammed E.A. [Department of Pharmaceutics, Faculty of Pharmacy, University of Khartoum, Khartoum 11111 (Sudan); Muddathir, Abdel Khalig [Department of Pharmacognosy, Faculty of Pharmacy, University of Khartoum, Khartoum 11111 (Sudan); Elhassan, Gamal O. [General Directorate of Pharmacy, Federal Ministry of Health, Khartoum 11111 (Sudan); Bashir, Adil H.H. [Department of Evolution of Tumor Metabolism and Pharmacology, Hala Alfarouk Cancer Center, Khartoum 11123 (Sudan); Al Jawda Medical Hospital, Khartoum 11111 (Sudan)

    2011-07-22

    Carcinogenesis occurs through a series of steps from normal into benign and finally malignant phenotype. This cancer evolutionary trajectory has been accompanied by similar metabolic transformation from normal metabolism into Pasteur and/or Crabtree-Effects into Warburg-Effect and finally Cannibalism and/or Lactate-Symbiosis. Due to lactate production as an end-product of glycolysis, tumor colonies acquire new phenotypes that rely on lactate as energetic fuel. Presence of Warburg-Effect indicates that some tumor cells undergo partial (if not complete) de-endosymbiosis and so cancer cells have been become unicellular microorganism (anti-Dollo's Law) specially when they evolve to develop cannibalism as way of metabolism while oxidative types of cells that rely on lactate, as their energetic fuel, might represent extra-endosymbiosis. Thus, at the end, the cancer colony could be considered as integrated metabolic ecosystem. Proper understanding of tumor metabolism will contribute to discover potential anticancer agents besides conventional chemotherapy.

  9. Chemopreventive effects of the juice of Vitis coignetiae Pulliat on two-stage mouse skin carcinogenesis.

    Science.gov (United States)

    Arimoto-Kobayashi, Sakae; Zhang, Xiaomeng; Yuhara, Yuta; Kamiya, Tomonori; Negishi, Tomoe; Okamoto, Goro

    2013-01-01

    Our study revealed the inhibitory effect of Vitis coignetiae Pulliat, known as Yamabudo in Japan, at the stages of multi-step carcinogenesis. The juice of Vitis coignetiae (Y-grape juice) was antimutagenic toward dimethylbenzo[a]anthracene (DMBA), aflatoxin B1, and benzo[a]pyrene in the Ames test. The Y-grape juice was also antigenotoxic in the micronucleus test using HepG2 cells toward DMBA and aflatoxin B1. Topical and oral administration of the Y-grape juice to mice inhibited the induction of inflammation of 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical and oral administration of the Y-grape juice significantly decreased the incidence and mean number of tumors in mice skin with the 2-stage tumorigenesis protocol. To elucidate the mechanisms underlying the antiinflammatory and antitumor promotion activity of the Y-grape juice, the effect of Y-grape juice on cyclooxygenase-2 (COX-2) activity in mouse ear treated with TPA was studied. Both topical and oral application of the Y-grape juice inhibited the TPA-induced increase in COX-2 activity. Caftaric acid, isolated and identified from the Y-grape juice, was antimutagenic toward DMBA and prevented TPA-induced inflammation in mice, suggesting caftaric acid participates in chemopreventive effect/activities of Y-grape juice.

  10. Boolean Network Model for Cancer Pathways: Predicting Carcinogenesis and Targeted Therapy Outcomes

    Science.gov (United States)

    Fumiã, Herman F.; Martins, Marcelo L.

    2013-01-01

    A Boolean dynamical system integrating the main signaling pathways involved in cancer is constructed based on the currently known protein-protein interaction network. This system exhibits stationary protein activation patterns – attractors – dependent on the cell's microenvironment. These dynamical attractors were determined through simulations and their stabilities against mutations were tested. In a higher hierarchical level, it was possible to group the network attractors into distinct cell phenotypes and determine driver mutations that promote phenotypic transitions. We find that driver nodes are not necessarily central in the network topology, but at least they are direct regulators of central components towards which converge or through which crosstalk distinct cancer signaling pathways. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recently performed for several human cancers. Furthermore, our results demonstrate that cell phenotypes can evolve towards full malignancy through distinct sequences of accumulated mutations. In particular, the network model supports routes of carcinogenesis known for some tumor types. Finally, the Boolean network model is employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies were additive in their effects and that the association of targeted drugs is necessary for cancer eradication. PMID:23922675

  11. Potent chemopreventive effect of mangiferin on lung carcinogenesis in experimental Swiss albino mice

    Directory of Open Access Journals (Sweden)

    Peramaiyan Rajendran

    2014-01-01

    Full Text Available Aim of the Study: In the present study the effects of mangiferin were tested against lung cancer-bearing mice in both the pre-initiation and post-initiation periods. Materials and Methods: Healthy male Swiss albino mice (6-8 weeks old were used throughout the study. The animals were treated with mangiferin (100 mg/kg body weight dissolved in corn oil two weeks before (pre-initiation and the twelfth week after (post-initiation the establishment of B (a P (50 mg/kg body weight-induced lung carcinoma. Results: The body weight decreased and the lung weight and levels of xenobiotic and liver marker enzymes markedly increased in the carcinogen-administered animals; and mangiferin treatment brought the values of these parameters back to the near-normal ones. The activities of lysosomal enzymes in the animals with B (a P-induced experimental lung carcinogenesis were also assessed. In these animals there was an increase in the activities of lysosomal enzymes such as acidphosphatase, β-glucuronidase, N-acetyl glucosaminidase, and β-galactosidase. Conclusion: Supplementation with mangiferin attenuated all these alterations, thus indicating its anticancer effect. Overall, the above data showed that the anticancer effect of mangiferin as a chemopreventive agent was pronounced.

  12. HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.

    Science.gov (United States)

    Williams, Michael D; Zhang, Xing; Belton, Amy S; Xian, Lingling; Huso, Tait; Park, Jeong-Jin; Siems, William F; Gang, David R; Resar, Linda M S; Reeves, Raymond; Hill, Herbert H

    2015-03-01

    Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.

  13. Radionuclides in cigarettes may lead to carcinogenesis via p16{sup INK4a} inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Prueitt, Robyn L.; Goodman, Julie E. [Gradient Corporation, 20 University Road, Cambridge, MA 02138 (United States); Valberg, Peter A. [Gradient Corporation, 20 University Road, Cambridge, MA 02138 (United States)], E-mail: pvalberg@gradientcorp.com

    2009-02-15

    It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including {alpha}-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16{sup INK4a} (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.

  14. Radionuclides in cigarettes may lead to carcinogenesis via p16(INK4a) inactivation.

    Science.gov (United States)

    Prueitt, Robyn L; Goodman, Julie E; Valberg, Peter A

    2009-02-01

    It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including alpha-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16(INK4a) (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.

  15. Role of environmental chemicals, processed food derivatives, and nutrients in the induction of carcinogenesis.

    Science.gov (United States)

    Persano, Luca; Zagoura, Dimitra; Louisse, Jochem; Pistollato, Francesca

    2015-10-15

    In recent years it has been hypothesized that cancer stem cells (CSCs) are the actual driving force of tumor formation, highlighting the need to specifically target CSCs to successfully eradicate cancer growth and recurrence. Particularly, the deregulation of physiological signaling pathways controlling stem cell proliferation, self-renewal, differentiation, and metabolism is currently considered as one of the leading determinants of cancer formation. Given their peculiar, slow-dividing phenotype and their ability to respond to multiple microenvironmental stimuli, stem cells appear to be more susceptible to genetic and epigenetic carcinogens, possibly undergoing mutations resulting in tumor formation. In particular, some animal-derived bioactive nutrients and metabolites known to affect the hormonal milieu, and also chemicals derived from food processing and cooking, have been described as possible carcinogenic factors. Here, we review most recent literature in this field, highlighting how some environmental toxicants, some specific nutrients and their secondary products can induce carcinogenesis, possibly impacting stem cells and their niches, thus causing tumor growth.

  16. Identification of novel genes involved in gastric carcinogenesis by suppression subtractive hybridization.

    Science.gov (United States)

    Mottaghi-Dastjerdi, N; Soltany-Rezaee-Rad, M; Sepehrizadeh, Z; Roshandel, G; Ebrahimifard, F; Setayesh, N

    2015-01-01

    Gastric cancer (GC) is one of the most common and life-threatening types of malignancies. Identification of the differentially expressed genes in GC is one of the best approaches for establishing new diagnostic and therapeutic targets. Furthermore, these investigations could advance our knowledge about molecular biology and the carcinogenesis of this cancer. To screen for the overexpressed genes in gastric adenocarcinoma, we performed suppression subtractive hybridization (SSH) on gastric adenocarcinoma tissue and the corresponding normal gastric tissue, and eight genes were found to be overexpressed in the tumor compared with those of the normal tissue. The genes were ribosomal protein L18A, RNase H2 subunit B, SEC13, eukaryotic translation initiation factor 4A1, tetraspanin 8, cytochrome c oxidase subunit 2, NADH dehydrogenase subunit 4, and mitochondrially encoded ATP synthase 6. The common functions among the identified genes include involvement in protein synthesis, involvement in genomic stability maintenance, metastasis, metabolic improvement, cell signaling pathways, and chemoresistance. Our results provide new insights into the molecular biology of GC and drug discovery: each of the identified genes could be further investigated as targets for prognosis evaluation, diagnosis, treatment, evaluation of the response to new anticancer drugs, and determination of the molecular pathogenesis of GC.

  17. Carcinogenesis, prevention and early detection of gastric cancer: where we are and where we should go.

    Science.gov (United States)

    González, Carlos A; Agudo, Antonio

    2012-02-15

    Helicobacter pylori is the most common cause of gastric cancer (GC), though smoking, alcohol, diet, genetics and epigenetic factors may also have a role in the occurrence of the disease. Why H. pylori cause GC in only a minority of those infected remains unknown. Although mechanisms of H. pylori-induced carcinogenesis are not yet well understood, several genotypes of H. pylori have been associated with strain virulence and disease risk. Primary prevention of GC should be addressed by avoiding exposure to factors that increase the risk and to promote factors associated with decrease risk. Vaccines against H. pylori are an ongoing promise and not yet available. Chemoprevention through vitamin supplementation has shown no benefit. Screening and eradication of H. pylori in the general population is not advised. Given that GC is a multiple-steps process, the identification of patients with preneoplastic lesions with high risk of progression, and periodic endoscopic surveillance of them represents the most effective way for early diagnosis of GC. However, clinical guidelines for surveillance are lacking and there are no clear criteria to classify patients into high or low risk of progressing to GC. No study has shown the potential usefulness of combining the information on the type of preneoplastic lesions, genetic and epigenetic, lifestyle and virulence bacterial factors in order to identify high risk patients who need more intensive surveillance. The integration of all this information, in a prediction model requires further research and could be the most important contribution for reducing the burden of GC.

  18. Folate levels in mucosal tissue but not methylenetetrahydrofolate reductase polymorphisms are associated with gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Yu-Rong Weng; Dan-Feng Sun; Jing-Yuan Fang; Wei-Qi Gu; Hong-Yin Zhu

    2006-01-01

    AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation.METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls.Folate concentrations in these tissues were detected by the FOL ACS: 180 automated chemiluminescence system.MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP).RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16INK4A in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21WAF1 in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype.CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesis through hypomethylation and overexpression of c-myc.

  19. EXPRESSION OF P16 AND CYCLIN D1 IN THE COURSE OF CARCINOGENESIS OF THE STOMACH

    Institute of Scientific and Technical Information of China (English)

    CHEN Yu-long; XU Feng; LI Yan-jie

    1999-01-01

    Objective: To determine p16 and cyclin D1 expression in the specimen of gastric carcinoma, atypic hyperplasia, atrophic gastritis, superficial gastritis and normal gastric mucosa. Methods: Using immunohistochemical method (ABC), the samples of 58 adenocarcinomas, 22 atypic hyperplasias, 28 atrophic gastritis,27 superficial gastritis and 15 gastric epitheliums were analyzed. Results: Positive immunostaining rate for p16 protein was the highest in normal gastric mucosa and decreased with the lesions progressing from superficial gastritis to atrophic gastritis to atypital hyperplasia and to adenocarcinoma (85%, 78.6%, 31.8%,48.3% respectively); Positive immunostaining of cyclin D1 can observed in atrophic gastritis. With the lesions progressing from atrophic gastritis to atypical hyperplasia to adenocarcinoma, its expression rate increased (17.9%, 36.4%, 53.4% respectively), and there was a significant difference between adenocarcinoma and atrophic gastritis group (P<0.05). An interesting observation was that inverse expression between p16and cyclin D1, was shown in most of gastric cancer detected. Conclusion: It is indicated that p16 and cyclin D1 play an important role in the gastric carcinogenesis, the inverse expression between p16 and cyclin D1 suggested that there is a suppression trend in them.

  20. Alterations in Gastric Microbiota After H. Pylori Eradication and in Different Histological Stages of Gastric Carcinogenesis

    Science.gov (United States)

    Li, Tung Hiu; Qin, Youwen; Sham, Pak Chung; Lau, K.S.; Chu, Kent-Man; Leung, Wai K.

    2017-01-01

    The role of bacteria other than Helicobacter pylori (HP) in the stomach remains elusive. We characterized the gastric microbiota in individuals with different histological stages of gastric carcinogenesis and after receiving HP eradication therapy. Endoscopic gastric biopsies were obtained from subjects with HP gastritis, gastric intestinal metaplasia (IM), gastric cancer (GC) and HP negative controls. Gastric microbiota was characterized by Illumina MiSeq platform targeting the 16 S rDNA. Apart from dominant H. pylori, we observed other Proteobacteria including Haemophilus, Serratia, Neisseria and Stenotrophomonas as the major components of the human gastric microbiota. Although samples were largely converged according to the relative abundance of HP, a clear separation of GC and other samples was recovered. Whilst there was a strong inverse association between HP relative abundance and bacterial diversity, this association was weak in GC samples which tended to have lower bacterial diversity compared with other samples with similar HP levels. Eradication of HP resulted in an increase in bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to individuals without HP. In conclusion, HP colonization results in alterations of gastric microbiota and reduction in bacterial diversity, which could be restored by antibiotic treatment. PMID:28322295

  1. Critical pathogenic steps to high risk Helicobacter pylori gastritis and gastric carcinogenesis.

    Science.gov (United States)

    Lee, Inchul

    2014-06-07

    Helicobacter pylori (H. pylori) gastritis may progress to high risk gastropathy and cancer. However, the pathological progression has not been characterized in detail. H. pylori induce persistent inflammatory infiltration. Neutrophils are unique in that they directly infiltrate into foveolar epithelium aiming the proliferative zone specifically. Neutrophilic proliferative zone foveolitis is a critical pathogenic step in H. pylori gastritis inducing intensive epithelial damage. Epithelial cells carrying accumulated genomic damage and mutations show the Malgun (clear) cell change, characterized by large clear nucleus and prominent nucleolus. Malgun cells further undergo atypical changes, showing nuclear folding, coarse chromatin, and multiple nucleoli. The atypical Malgun cell (AMC) change is a novel premalignant condition in high risk gastropathy, which may progress and undergo malignant transformation directly. The pathobiological significance of AMC in gastric carcinogenesis is reviewed. A new diagnosis system of gastritis is proposed based on the critical pathologic steps classifying low and high risk gastritis for separate treatment modality. It is suggested that the regulation of H. pylori-induced neutrophilic foveolitis might be a future therapeutic goal replacing bactericidal antibiotics approach.

  2. Genetic characteristics of mitochondrial DNA was associated with colorectal carcinogenesis and its prognosis.

    Directory of Open Access Journals (Sweden)

    Jae-Ho Lee

    Full Text Available Clinical value of mitochondrial DNA has been described in colorectal cancer (CRC. To clarify its role in colorectal carcinogenesis, mitochondrial microsatellite instability (mtMSI and other markers were investigated in CRCs and their precancerous lesions, as a multitier genetic study. DNA was isolated from paired normal and tumoral tissues in 78 tubular adenomas (TAs, 34 serrated polyps (SPs, and 100 CRCs. mtMSI, nucleus microsatellite instability (nMSI, KRAS mutation, and BRAF mutation were investigated in these tumors and their statistical analysis was performed. mtMSI was found in 30% of CRCs and 21.4% of precancerous lesions. Mitochondrial copy number was higher in SPs than TAs and it was associated with mtMSI in low grade TAs. KRAS and BRAF mutations were mutually exclusive in TAs and SPs. CRCs with mtMSI showed shorter overall survival times than the patients without mtMSI. In CRCs without nMSI or BRAF mutation, mtMSI was a more accurate marker for predicting prognosis. The genetic change of mitochondrial DNA is an early and independent event in colorectal precancerous lesions and mtMSI and mitochondrial contents are associated with the tubular adenoma-carcinoma sequence, resulting in poor prognosis. This result suggested that the genetic change in mitochondrial DNA appears to be a possible prognosis marker in CRC.

  3. The significance of azo-reduction in the mutagenesis and carcinogenesis of azo dyes.

    Science.gov (United States)

    Chung, K T

    1983-04-01

    Azo dyes are widely used in textile, printing, cosmetic, drug and food-processing industries. They are also used extensively in laboratories as either biological stains or pH indicators. The extent of such use is related to the degree of industrialization. Since intestinal cancer is more common in highly industrialized countries, a possible connection may exist between the increase in the number of cancer cases and the use of azo dyes. Azo dyes can be reduced to aromatic amines by the intestinal microflora. The mutagenicity of a number of azo dyes is reviewed in this paper. They include Trypan Blue, Ponceau 3R, Pinceau 2R, Methyl Red, Methyl Yellow, Methyl Orange, Lithol Red, Orange I, Orange II, 4-Phenylazo-Naphthylamine, Sudan I, Sudan IV, Acid Alizarin Violet N, Fast Garnet GBC, Allura Red, Ponceau SX, Sunset Yellow, Tartrazine, Citrus Red No. 2, Orange B, Yellow AB, Carmoisine, Mercury Orange, Ponceau S, Versatint Blue, Phenylazophenol, Evan's Blue and their degraded aromatic amines. The significance of azo reduction in the mutagenesis and carcinogenesis of azo dyes is discussed.

  4. Identification of a nuclear protein, LRRC42, involved in lung carcinogenesis.

    Science.gov (United States)

    Fujitomo, Takashi; Daigo, Yataro; Matsuda, Koichi; Ueda, Koji; Nakamura, Yusuke

    2014-07-01

    On the basis of the gene expression profiles of 120 lung cancer cases using a cDNA microarray containing 27,648 genes or expressed sequence tags (ESTs), we identified LRRC42 (Leucine-rich repeat containing 42) to be significantly upregulated in the majority of lung cancers. Northern blot analysis demonstrated that LRRC42 was expressed only in testis among normal tissues examined. Knockdown of LRRC42 expression by siRNA against LRRC42 significantly suppressed the growth of lung cancer cells. On the other hand, stable induction of LRRC42 expression significantly promoted cell growth. LRRC42, which was found to localize in the nucleus of mammalian cells, is likely to interact with and stabilize GATAD2B (GATA zinc finger domain-containing 2B) and MBD3 (Methyl-CpG-binding domain protein 3) proteins that could contribute to lung cancer cell proliferation partly through the regulation of p21Waf1/Cip1. Our findings suggest that LRRC42 overexpression as well as its interaction with LRRC42-GATAD2B might play essential roles in lung carcinogenesis, and be a promising molecular target for lung cancer therapy.

  5. Immunological and Biochemical Markers in Oral Carcinogenesis: The Public Health Perspective

    Directory of Open Access Journals (Sweden)

    Sunali Khanna

    2008-12-01

    Full Text Available Oral health is an integral component of general health and well being and a basic human right. Dental public health is probably the most challenging specialty of dentistry. Because of the lack of adequate resources among other factors, many people are likely to suffer from dental diseases. Despite great improvements in the oral health status of populations across the world, the burden and impact of dental diseases are still high. This is particularly true among underprivileged groups in both developed and developing communities. Oral diseases and conditions, including oral cancer, oral manifestations of HIV/AIDS, dental trauma, craniofacial anomalies, and noma, all have broad impacts on health and well-being. Oral cancer, the sixth most common cancer worldwide continues to be most prevalent cancer related to the consumption of tobacco, alcohol and other carcinogenic products. Nevertheless, significant reduction in mortality can be achieved by advances in early diagnosis and implementation of multidisciplinary treatment programs leading to improvement of survivorship and better quality of life. The present study was designed to evaluate the immunologic and biochemical markers in oral carcinogenesis using circulating immune complexes (CIC, copper, iron, and selenium concentrations as assessment endpoints. Study results indicated an increase in CIC and copper levels, and a decrease in iron and selenium concentrations in oral cancer patients compared to controls. The implications of these findings for public health are discussed.

  6. Myenteric denervation in gastric carcinogenesis: differential modulation of nitric oxide and annexin-A1.

    Science.gov (United States)

    Polli-Lopes, Ana Cláudia; Estofolete, Cássia F; Oliani, Sonia M; Zucoloto, Sérgio; Cunha, Fernando Q; Gil, Cristiane D

    2013-01-01

    This study evaluated the properties of endogenous nitric oxide synthases (NOS) and annexin-A1 (ANXA1) and determined how they can be exploited in the N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and myenteric denervation model. Male Wistar rats were treated with MNNG and/or aminoguanidine (AG) for 20 weeks. In another set of experiments, rats with nondenervated and denervated stomachs were treated with MNNG or water for 28 weeks. Fragments of the pyloric region were processed for histopathology, NOS activity, and immunohistochemistry to explore the activity and expression of constitutive (cNOS) and inducible (iNOS) NO synthase and their relationship with annexin-A1 (ANXA1) expression. NO inhibition by AG increased the percentage of animals with adenocarcinomas (~29%) compared with the untreated MNNG group (~4%). Myenteric denervation did not alter NOS activity. cNOS activity was significantly greater in nondernervated and denervated stomachs with or without lesions (Pactivity (Pactivity in normal stomachs and outside the lesion area was considerably higher than inside it (Pmyenteric denervation. In conclusion, NO protects against the development of gastric adenocarcinomas. The pattern of ANXA1 expression was not associated with NOS activity or expression, suggesting that NO and ANXA1 act in gastric tumors in disparate pathways.

  7. Differential Regulation of a Fibroblast Growth Factor-Binding Protein during Skin Carcinogenesis and Wound Healing

    Directory of Open Access Journals (Sweden)

    Andreas Kurtz

    2004-09-01

    Full Text Available The initiation of premalignant lesions is associated with subtle cellular and gene expression changes. Here we describe a severe combined immunodeficient mouse xenograft model with human adult skin and compare chemical carcinogenesis and wound healing. We focus on a secreted binding protein for fibroblast growth factors (FGF-BP that enhances the activity of locally stored FGFs and is expressed at high levels in human epithelial cancers. Carcinogen treatment of murine skin induced papilloma within 6 weeks, whereas the human skin grafts displayed no obvious macroscopic alterations. Microscopic studies of the human skin, however, showed p53-positive keratinocytes in the epidermis, increased angiogenesis in the dermis of the treated skin, enhanced proliferation of keratinocytes in the basal layer, and an increase of FGF-BP protein and mRNA expression. In contrast, after surgical wounding of human skin grafts or of mouse skin, FGF-BP expression was upregulated within a few hours and returned to control levels after 2 days with wound closure. Enhanced motility of cultured keratinocytes and dermal fibroblasts by FGF-BP supports a role in wound healing. We conclude that adult human skin xenografts can be used to identify early molecular events during malignant transformation as well as transient changes during wound healing.

  8. Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link.

    Science.gov (United States)

    Hursting, Stephen D; Lashinger, Laura M; Wheatley, Karrie W; Rogers, Connie J; Colbert, Lisa H; Nunez, Nomeli P; Perkins, Susan N

    2008-08-01

    The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the US. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects on the carcinogenesis process and mechanistic targets of interventions that modulate energy balance, such as reduced-calorie diets and physical activity, have not been well characterized. The purpose of this review is to provide a strong foundation for the translation of mechanism-based research in this area by describing key animal and human studies of energy balance modulations involving diet or physical activity and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention is placed on signaling through the insulin and insulin-like growth factor-1 receptors, including components of the Akt and mammalian target of rapamycin (mTOR) signaling pathways downstream of these growth factor receptors. These pathways have emerged as potential targets for disrupting the obesity-cancer link. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.

  9. Metabolism of phenylhydroquinone by prostaglandin (H) synthase: possible implications in o-phenylphenol carcinogenesis.

    Science.gov (United States)

    Kolachana, P; Subrahmanyam, V V; Eastmond, D A; Smith, M T

    1991-01-01

    o-Phenylphenol (OPP) and its sodium salt sodium ortho-phenylphenate (NaOPP) are broad spectrum fungicides and antibacterial agents. Both are urinary bladder and renal carcinogens in the Fischer 344 rat. OPP is converted by mixed-function oxidases in the liver to phenylhydroquinone (PHQ). Since appreciable amounts of prostaglandin (H) synthase (PGS) are found in rat bladder and kidney-medullary papilla, the target sites of OPP- and NaOPP-induced tumors, we hypothesized that a secondary PGS-mediated activation of PHQ to phenylbenzoquinone (PBQ) may occur in the bladder and kidney. We have studied the metabolism of PHQ by PGS in the presence of arachidonic acid and hydrogen peroxide as co-factors. These studies showed that PHQ is indeed metabolized to a product having identical spectral and electrochemical properties to PBQ. The disappearance of PHQ with time was stoichiometric to the formation of PBQ. Less than 10% of PHQ was converted to PBQ in the absence of enzyme, indicating that auto-oxidation may play only a minor role in the conversion of PHQ to PBQ. Similar results were obtained when PGS was replaced with either myeloperoxidase or horseradish peroxidase and hydrogen peroxide as co-factor. These studies suggest that the peroxidative metabolism of PHQ by PGS to the reactive PBQ could play an important role in OPP-induced urinary bladder and kidney carcinogenesis in rats.

  10. Involvement of inflammatory factors in pancreatic carcinogenesis and preventive effects of anti-inflammatory agents.

    Science.gov (United States)

    Takahashi, Mami; Mutoh, Michihiro; Ishigamori, Rikako; Fujii, Gen; Imai, Toshio

    2013-03-01

    Chronic inflammation is known to be a risk for many cancers, including pancreatic cancer. Heavy alcohol drinking and cigarette smoking are major causes of pancreatitis, and epidemiological studies have shown that smoking and chronic pancreatitis are risk factors for pancreatic cancer. Meanwhile, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are elevated in pancreatitis and pancreatic cancer tissues in humans and in animal models. Selective inhibitors of iNOS and COX-2 suppress pancreatic cancer development in a chemical carcinogenesis model of hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). In addition, hyperlipidemia, obesity, and type II diabetes are also suggested to be associated with chronic inflammation in the pancreas and involved in pancreatic cancer development. We have shown that a high-fat diet increased pancreatic cancer development in BOP-treated hamsters, along with aggravation of hyperlipidemia, severe fatty infiltration, and increased expression of adipokines and inflammatory factors in the pancreas. Of note, fatty pancreas has been observed in obese and/or diabetic cases in humans. Preventive effects of anti-hyperlipidemic/anti-diabetic agents on pancreatic cancer have also been shown in humans and animals. Taking this evidence into consideration, modulation of inflammatory factors by anti-inflammatory agents will provide useful data for prevention of pancreatic cancer.

  11. Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective.

    Science.gov (United States)

    Feng, Hui-Yi; Chen, Yang-Chao

    2016-09-07

    The role of bile acids in colorectal cancer has been well documented, but their role in pancreatic cancer remains unclear. In this review, we examined the risk factors of pancreatic cancer. We found that bile acids are associated with most of these factors. Alcohol intake, smoking, and a high-fat diet all lead to high secretion of bile acids, and bile acid metabolic dysfunction is a causal factor of gallstones. An increase in secretion of bile acids, in addition to a long common channel, may result in bile acid reflux into the pancreatic duct and to the epithelial cells or acinar cells, from which pancreatic adenocarcinoma is derived. The final pathophysiological process is pancreatitis, which promotes dedifferentiation of acinar cells into progenitor duct-like cells. Interestingly, bile acids act as regulatory molecules in metabolism, affecting adipose tissue distribution, insulin sensitivity and triglyceride metabolism. As a result, bile acids are associated with three risk factors of pancreatic cancer: obesity, diabetes and hypertriglyceridemia. In the second part of this review, we summarize several studies showing that bile acids act as cancer promoters in gastrointestinal cancer. However, more question are raised than have been solved, and further oncological and physiological experiments are needed to confirm the role of bile acids in pancreatic cancer carcinogenesis.

  12. Fifty years of tobacco carcinogenesis research: from mechanisms to early detection and prevention of lung cancer.

    Science.gov (United States)

    Hecht, Stephen S; Szabo, Eva

    2014-01-01

    The recognition of the link between cigarette smoking and lung cancer in the 1964 Surgeon General's Report initiated definitive and comprehensive research on the identification of carcinogens in tobacco products and the relevant mechanisms of carcinogenesis. The resultant comprehensive data clearly illustrate established pathways of cancer induction involving carcinogen exposure, metabolic activation, DNA adduct formation, and consequent mutation of critical genes along with the exacerbating influences of inflammation, cocarcinogenesis, and tumor promotion. This mechanistic understanding has provided a framework for the regulation of tobacco products and for the development of relevant tobacco carcinogen and toxicant biomarkers that can be applied in cancer prevention. Simultaneously, the recognition of the link between smoking and lung cancer paved the way for two additional critical approaches to cancer prevention that are discussed here: detection of lung cancer at an early, curable stage, and chemoprevention of lung cancer. Recent successes in more precisely identifying at-risk populations and in decreasing lung cancer mortality with helical computed tomography screening are notable, and progress in chemoprevention continues, although challenges with respect to bringing these approaches to the general population exist. Collectively, research performed since the 1964 Report demonstrates unequivocally that the majority of deaths from lung cancer are preventable.

  13. Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies.

    Science.gov (United States)

    Anderson, Lucy M

    2004-09-01

    Perinatal carcinogenesis as a cross-disciplinary concern is the subject of this special issue of Toxicology and Applied Pharmacology, which consists of a total of eight reviews or commentaries in the areas of epidemiology, risk assessment, and animal models. Some of the conclusions from these articles, and the Questions and Answers section that follows most of them, are summarized here. There is adequate reason to suspect that perinatal exposures contribute to human cancer risk, both childhood cancers, and those appearing later in life. The latter type of risk may actually be quantitatively the more important, and involve a wide range of types of effects, but has received only limited attention. With regard to childhood cancers, fetal irradiation and diethylstilbestrol exposure are known etiological agents, and it is likely, but not yet certain, there are additional external causes of a portion of these. Some current focal points of interest here include nitroso compounds, DNA topoisomerase inhibitors, viruses, anti-AIDS drugs, and endocrine disruptors. Regulatory agencies must rely heavily on animal data for estimation of human risk due to perinatal exposures to chemicals, and the quantity and quality of these data presently available for this purpose are greatly limiting. Correctly designed conventional animal studies with suspect chemicals are still needed. Furthermore, genetically engineered mouse models for childhood cancers, especially medulloblastoma, have become available, and could be used for screening of candidate causative agents for this cancer type, and for better understanding of gene-environment interactions.

  14. The effect of childbirth on carcinogenesis of DMBA-induced breast cancer in female SD rats.

    Science.gov (United States)

    Zhao, Ji-An; Chen, Jin-Jun; Ju, Ying-Chao; Wu, Jian-Hua; Geng, Cui-Zhi; Yang, Hui-Chai

    2011-11-01

    Many epidemiologic and clinical studies have indicated that the frequency of breast cancer was lower in parous women than in nulliparous women. Moreover, the incidence of breast cancer has been reported to be lower in women with early childbirth than in women with late childbirth. To verify the effect of childbirth and the age at first childbirth on carcinogenesis and progression of breast cancer, we induced breast cancer by 7,12-dimethylbenanthracene (DMBA) in 120 female Sprague-Dawley (SD) rats, and divided them into control or experimental (DMBA-treated) nulliparous, early childbirth, and late childbirth groups to observe the incidence, latency, and size of breast cancer. Argyrophilic nucleolar organizer regions (AgNOR) count and the expression of C-erbB-2, proliferating cell nuclear antigen (PCNA), Ki-67, and minichromosome maintenance protein 2 (MCM2) in breast cancer tissues were detected by immunohistochemistry. The breast cancer incidences were 95.0%, 16.7%, and 58.8% in the experimental nulliparous, early childbirth, and late childbirth groups, respectively (all P induced breast cancer.

  15. Utility of MicroRNAs and siRNAs in Cervical Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Sacnite del Mar Díaz-González

    2015-01-01

    Full Text Available MicroRNAs and siRNAs belong to a family of small noncoding RNAs which bind through partial sequence complementarity to 3′-UTR regions of mRNA from target genes, resulting in the regulation of gene expression. MicroRNAs have become an attractive target for genetic and pharmacological modulation due to the critical function of their target proteins in several signaling pathways, and their expression profiles have been found to be altered in various cancers. A promising technology platform for selective silencing of cell and/or viral gene expression using siRNAs is currently in development. Cervical cancer is the most common cancer in women in the developing world and sexually transmitted infection with HPV is the cause of this malignancy. Therefore, a cascade of abnormal events is induced during cervical carcinogenesis, including the induction of genomic instability, reprogramming of cellular metabolic pathways, deregulation of cell proliferation, inhibition of apoptotic mechanisms, disruption of cell cycle control mechanisms, and alteration of gene expression. Thus, in the present review article, we highlight new research on microRNA expression profiles which may be utilized as biomarkers for cervical cancer. Furthermore, we discuss selective silencing of HPV E6 and E7 with siRNAs which represents a potential gene therapy strategy against cervical cancer.

  16. Role of nitric oxide in the pathogenesis ofBarrett's-associated carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    Barrett's esophagus (BE), a premalignant condition toBarrett's adenocarcinoma (BAC), is closely associatedwith chronic inflammation due to gastro-esophagealreflux. Caudal type homeobox 2 (CDX2), a representativemarker of BE, is increased during the metaplasticand neoplastic transformation of BE. Nitric oxide (NO)has been proposed to be a crucial mediator of Barrett'scarcinogenesis. We previously demonstrated that CDX2 might be induced directly under stimulation oflarge amounts of NO generated around the gastroesophagealjunction (GEJ) by activating epithelial growthfactor receptor in a ligand-independent manner. Thus,we reviewed recent developments on the role of NOin Barrett's carcinogenesis. Notably, recent studieshave reported that microbial communities in the distalesophagus are significantly different among groupswith a normal esophagus, reflux esophagitis, BE orBAC, despite there being no difference in the bacterialquantity. Considering that microorganism componentscan be one of the major sources of large amounts ofNO, these studies suggest that the bacterial compositionin the distal esophagus might play an important rolein regulating NO production during the carcinogenicprocess. Controlling an inflammatory reaction due togastro-esophageal reflux or bacterial composition aroundthe GEJ might help prevent the progression of Barrett'scarcinogenesis by inhibiting NO production.

  17. Atomic Bomb Survivors Life-Span Study: Insufficient Statistical Power to Select Radiation Carcinogenesis Model.

    Science.gov (United States)

    Socol, Yehoshua; Dobrzyński, Ludwik

    2015-01-01

    The atomic bomb survivors life-span study (LSS) is often claimed to support the linear no-threshold hypothesis (LNTH) of radiation carcinogenesis. This paper shows that this claim is baseless. The LSS data are equally or better described by an s-shaped dependence on radiation exposure with a threshold of about 0.3 Sievert (Sv) and saturation level at about 1.5 Sv. A Monte-Carlo simulation of possible LSS outcomes demonstrates that, given the weak statistical power, LSS cannot provide support for LNTH. Even if the LNTH is used at low dose and dose rates, its estimation of excess cancer mortality should be communicated as 2.5% per Sv, i.e., an increase of cancer mortality from about 20% spontaneous mortality to about 22.5% per Sv, which is about half of the usually cited value. The impact of the "neutron discrepancy problem" - the apparent difference between the calculated and measured values of neutron flux in Hiroshima - was studied and found to be marginal. Major revision of the radiation risk assessment paradigm is required.

  18. Animal models of chemical carcinogenesis: driving breakthroughs in cancer research for 100 years

    Science.gov (United States)

    Kemp, Christopher J.

    2016-01-01

    Chemical carcinogenesis studies in animals have directly contributed to a reduction of cancer burden in the human population through their ability to identify carcinogens from the workplace, diet, and environment. Reduced exposure to these carcinogens through lifestyle changes, government regulation, or change in industry practices has reduced cancer incidence in exposed populations. In addition to providing the first experimental evidence for the link between chemical and radiation exposure and cancer, animal models of environmentally induced cancer have and will continue to provide important insight into the causes, mechanisms, and conceptual frameworks of cancer. More recently, combining chemical carcinogens with genetically engineered mouse models (GEMMs) has emerged as an invaluable approach to study the complex interaction between genotype and environment that contributes to cancer development. In the future, animal models of environmentally induced cancer are likely to provide insight into areas such as the epigenetic basis of cancer, genetic modifiers of cancer susceptibility, the systems biology of cancer, inflammation and cancer, and cancer prevention. PMID:26430259

  19. Arecoline N-oxide: its mutagenicity and possible role as ultimate carcinogen in areca oral carcinogenesis.

    Science.gov (United States)

    Lin, Kuo-Hui; Lin, Ching-Yuan; Liu, Chin-Chih; Chou, Ming-Young; Lin, Jen-Kun

    2011-04-13

    The areca nut is the most widely consumed psychoactive substance in Taiwan, India, and Southeast Asia. It is considered to be an environmental risk factor for the development of oral submucous fibrosis and cancer. Arecoline, the major alkaloid of areca nut, has been known to cause cytotoxicity and genotoxicity in various systems. However, the active compound accounting for arecoline-induced damage in normal human oral cells is still uncharacterized. The present study was undertaken to identify the active metabolite of arecoline that might induce damage in human oral tissues and cause mutagenicity in Salmonella typhimurium tester strains TA 100 and TA 98. It is interesting to find that the major metabolite of arecoline, arecoline N-oxide, is moderately mutagenic to these Salmonella tester strains. This mutagenicity was potently inhibited by sulfhydryl compounds, namely, glutathione, N-acetylcysteine, and cysteine, whereas methionine is inactive in this inhibition. The mutagenicity of arecoline N-oxide was strongly inhibited by the N-oxide reducing agent titanium trichloride. The possible role of arecoline N-oxide in the induction of oral carcinogenesis by areca nut chewing is discussed.

  20. Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis

    Science.gov (United States)

    Suzuki, Shugo; Mori, Yukiko; Nagano, Aya; Naiki-Ito, Aya; Kato, Hiroyuki; Nagayasu, Yuko; Kobayashi, Mizuho; Kuno, Toshiya; Takahashi, Satoru

    2016-01-01

    Pioglitazone (PGZ), a peroxisome proliferator-activated receptor γ agonist, which is known as a type 2 diabetes drug, inhibits cell proliferation in various cancer cell lines, including prostate carcinomas. This study focused on the effect of PGZ on prostate carcinogenesis using a transgenic rat for an adenocarcinoma of prostate (TRAP) model. Adenocarcinoma lesions as a percentage of overall lesions in the ventral prostate were significantly reduced by PGZ treatment in a dose-dependent manner. The number of adenocarcinomas per given area in the ventral prostate was also significantly reduced by PGZ treatment. The Ki67 labeling index in the ventral prostate was also significantly reduced by PGZ. Decreased cyclin D1 expression in addition to the inactivation of both p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)κB were detected in PGZ-treated TRAP rat groups. In LNCaP, a human androgen-dependent prostate cancer cell line, PGZ also inhibited cyclin D1 expression and the activation of both p38 MAPK and NFκB. The suppression of cultured cell growth was mainly regulated by the NFκB pathway as detected using specific inhibitors in both LNCaP and PC3, a human androgen-independent prostate cancer cell line. These data suggest that PGZ possesses a chemopreventive potential for prostate cancer. PMID:27973395

  1. Correlation of neomycin, faecal neutral and acid sterols with colon carcinogenesis in rats.

    Science.gov (United States)

    Panda, S K; Chattoraj, S C; Broitman, S A

    1999-06-01

    High fat diets have been implicated in incidence of colon cancer both in epidemiological and animal studies. Present investigation deals with the incidence, location and numbers of large and small bowel tumours induced by 1,2-dimethyl hydrazine (DMH) in rats fed high fat diets and neomycin. Neomycin was used to modify the faecal sterol metabolism and the relationship of the high fat diet and faecal neutral and acid sterols to the large bowel tumorigenesis was evaluated. DMH administered rats were fed with (a) 20% safflower oil; (b) 20% safflower oil and neomycin; (c) 20% safflower oil, cholesterol and cholic acid; and (d) 20% safflower oil, cholesterol, cholic acid and neomycin. Neomycin was found to be associated with both increase and decrease of tumour numbers. The faecal sterols lithocholic and deoxycholic acids were found to have no participation, while cholesterol and cholic acid were found to decrease with increase in tumour numbers. However, faecal coprostanol has been found to have a significant positive correlation with tumorigenesis in all dietary groups. Therefore coprostanol might possibly be associated with colon carcinogenesis in DMH-fed rats and cholesterol metabolism in gut appears to be related to the development of tumours.

  2. Differential protective effects of red wine polyphenol extracts (RWEs) on colon carcinogenesis.

    Science.gov (United States)

    Mazué, Frédéric; Delmas, Dominique; Murillo, Genoveva; Saleiro, Diana; Limagne, Emeric; Latruffe, Norbert

    2014-04-01

    Various epidemiological studies have shown that a regular and moderate consumption of red wine is correlated with a decreased relative risk of developing coronary heart disease and cancer. These health benefits are commonly attributed to high contents of polyphenols, particularly resveratrol, representing important sources of antioxidants. However, resveratrol does not seem to be the only bioactive compound present in the wine which contains numerous other polyphenols. The present study investigates the efficiency of red wine extracts (RWEs), containing different polyphenols, on colon cancer cell proliferation in vitro and on colonic aberrant crypt foci (ACF) in vivo. Proliferation, cell cycle analysis and incidence of ACF were monitored to examine the effects of RWEs. RWEs derived from a long vinification process exhibit superior anti-proliferative activity in colon cancer cells and prevent the appearance of ACF in mice. Interestingly, quercetin and resveratrol, representing two major bio-active polyphenols, exhibit synergistic anti-proliferative effects. These data suggest that the efficacy of RWEs on colon carcinogenesis may depend on the polyphenolic content, synergistic interaction of bio-active polyphenols and modulation of cellular uptake of polyphenols.

  3. Prevention of mammary carcinogenesis in MMTV-neu mice by cruciferous vegetable constituent benzyl isothiocyanate.

    Science.gov (United States)

    Warin, Renaud; Chambers, William H; Potter, Douglas M; Singh, Shivendra V

    2009-12-15

    Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, inhibits growth of human breast cancer cells in culture. The present study provides in vivo evidence for efficacy of BITC for prevention of mammary cancer in MMTV-neu mice. Administration of BITC at 1 and 3 mmol/kg diet for 25 weeks markedly suppressed the incidence and/or burden of mammary hyperplasia and carcinoma in female MMTV-neu mice without causing weight loss or affecting neu protein level. For example, cumulative incidence of hyperplasia/carcinoma was significantly lower in mice fed BITC-supplemented diets compared with control mice (P = 0.01 by Fisher's test). The BITC-mediated prevention of mammary carcinogenesis correlated with suppression of cell proliferation and increased apoptosis. The average number of Ki-67-positive cells in the carcinoma lesions of 3 mmol BITC group was lower by approximately 21% (P cells in the tumor. Although BITC treatment increased cytotoxicity of natural killer (NK) cells in vitro, dietary feeding of BITC failed to augment NK cell lytic activity in an ex vivo assay. The present study demonstrating efficacy of BITC against mammary cancer in an animal model provides impetus to determine its activity in a clinical setting.

  4. The Potential Protective Effects of Polyphenols in Asbestos-Mediated Inflammation and Carcinogenesis of Mesothelium

    Directory of Open Access Journals (Sweden)

    Monica Benvenuto

    2016-05-01

    Full Text Available Malignant Mesothelioma (MM is a tumor of the serous membranes linked to exposure to asbestos. A chronic inflammatory response orchestrated by mesothelial cells contributes to the development and progression of MM. The evidence that: (a multiple signaling pathways are aberrantly activated in MM cells; (b asbestos mediated-chronic inflammation has a key role in MM carcinogenesis; (c the deregulation of the immune system might favor the development of MM; and (d a drug might have a better efficacy when injected into a serous cavity thus bypassing biotransformation and reaching an effective dose has prompted investigations to evaluate the effects of polyphenols for the therapy and prevention of MM. Dietary polyphenols are able to inhibit cancer cell growth by targeting multiple signaling pathways, reducing inflammation, and modulating immune response. The ability of polyphenols to modulate the production of pro-inflammatory molecules by targeting signaling pathways or ROS might represent a key mechanism to prevent and/or to contrast the development of MM. In this review, we will report the current knowledge on the ability of polyphenols to modulate the immune system and production of mediators of inflammation, thus revealing an important tool in preventing and/or counteracting the growth of MM.

  5. The Potential Protective Effects of Polyphenols in Asbestos-Mediated Inflammation and Carcinogenesis of Mesothelium.

    Science.gov (United States)

    Benvenuto, Monica; Mattera, Rosanna; Taffera, Gloria; Giganti, Maria Gabriella; Lido, Paolo; Masuelli, Laura; Modesti, Andrea; Bei, Roberto

    2016-05-09

    Malignant Mesothelioma (MM) is a tumor of the serous membranes linked to exposure to asbestos. A chronic inflammatory response orchestrated by mesothelial cells contributes to the development and progression of MM. The evidence that: (a) multiple signaling pathways are aberrantly activated in MM cells; (b) asbestos mediated-chronic inflammation has a key role in MM carcinogenesis; (c) the deregulation of the immune system might favor the development of MM; and (d) a drug might have a better efficacy when injected into a serous cavity thus bypassing biotransformation and reaching an effective dose has prompted investigations to evaluate the effects of polyphenols for the therapy and prevention of MM. Dietary polyphenols are able to inhibit cancer cell growth by targeting multiple signaling pathways, reducing inflammation, and modulating immune response. The ability of polyphenols to modulate the production of pro-inflammatory molecules by targeting signaling pathways or ROS might represent a key mechanism to prevent and/or to contrast the development of MM. In this review, we will report the current knowledge on the ability of polyphenols to modulate the immune system and production of mediators of inflammation, thus revealing an important tool in preventing and/or counteracting the growth of MM.

  6. Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach.

    Directory of Open Access Journals (Sweden)

    Neha Nanda

    Full Text Available Doxycycline (DOX exhibits anti-inflammatory, anti-tumor, and pro-apoptotic activity and is being tested in clinical trials as a chemotherapeutic agent for several cancers, including colon cancer.In the current study, the chemotherapeutic activity of doxycycline was tested in a rat model of colon carcinogenesis, induced by colon specific cancer promoter, 1,2, dimethylhydrazine (DMH as well as study the effect of DOX-alone on a separate group of rats.Doxycycline administration in DMH-treated rats (DMH-DOX unexpectedly increased tumor multiplicity, stimulated progression of colonic tumor growth from adenomas to carcinomas and revealed metastasis in small intestine as determined by macroscopic and histopathological analysis. DOX-alone treatment showed markedly enhanced chronic inflammation and reactive hyperplasia, which was dependent upon the dose of doxycycline administered. Moreover, immunohistochemical analysis revealed evidence of inflammation and anti-apoptotic action of DOX by deregulation of various biomarkers.These results suggest that doxycycline caused chronic inflammation in colon, small intestine injury, enhanced the efficacy of DMH in tumor progression and provided a mechanistic link between doxycycline-induced chronic inflammation and tumorigenesis. Ongoing studies thus may need to focus on the molecular mechanisms of doxycycline action, which lead to its inflammatory and tumorigenic effects.

  7. Role of Free Radicals, Oxidative Stress and Xenobiotics in Carcinogenesis by Environmental Pollutants

    Directory of Open Access Journals (Sweden)

    Dibyajyoti Saha

    2014-09-01

    Full Text Available Carcinogenesis by many small molecular weight chemicals involves either a direct action of the chemical on cellular DNA or metabolism of the parent chemical to an active or ultimate form, which can than react with cellular DNA to produce a permanent chemical change in a DNA structure. A free radical is an atom or molecule that has one or more unpaired electron(s. These are highly reactive species capable of wide spread, indiscriminate oxidation and per oxidation of proteins, lipids and DNA which can lead to significant cellular damage and even tissue and/or organ failure. . Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. Xenobiotics are a compound that is foreign to the body. Xenobiotics can produce a variety of biological effects, including pharmacologic responses, toxicity, genes, immunologic reactions and cancer. Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. This communication highlights the role of carcinogens as environmental pollutants with the possible mechanism of free radicals, oxidative stress and xenobiotics.

  8. GSTM1, GSTT1, and NQO1 polymorphisms in cervical carcinogenesis.

    Science.gov (United States)

    Nunobiki, Osamu; Ueda, Masatsugu; Akise, Hikari; Izuma, Shinji; Torii, Kiyo; Okamoto, Yoshiaki; Tanaka, Ichiro; Noda, Sadamu; Akashi, Kyoko; Higashida, Taro

    2015-07-01

    The aim of the study is to investigate the clinical significance of glutathione-S-transferase GSTM1, GSTT1, and NQO1 c.609C>T (rs1800566) genetic polymorphisms in cervical carcinogenesis. GSTM1, GSTT1, and NQO1 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 192 cervical smear in exfoliated cervical cell samples using polymerase chain reaction (PCR) system and real-time polymerase chain reaction (PCR) system. The 19 patients with high-grade squamous intraepithelial lesion had statistically higher frequency of null GSTT1 genotype than 9 with low-grade squamous intraepithelial lesion (LSIL) among the 67 patients with high-risk HPV (P = 0.024). The 24 patients with HSIL had also statistically higher frequency of NQO1 (CT+TT) genotype than 14 with LSIL among the 67 patients with high-risk HPV (P = 0.024). GSTT1 null and NQO1 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population.

  9. A stochastic model of radiation carcinogenesis: Latent time distributions and their properties

    Energy Technology Data Exchange (ETDEWEB)

    Klebanov, L.V.; Yakovlev, A.Yu. (St. Petersburg Technical Univ. (Russian Federation)); Rachev, S.T. (Univ. of California, Santa Barbara (United States))

    1993-01-01

    A stochastic model of radiation carcinogenesis is proposed that has much in common with the ideas suggested by M. Pike as early as 1966. The model allows one to obtain a parametric family of substochastic-type distributions for the time of tumor latency that provides a description of the rate of tumor development and the number of affected individuals. With this model it is possible to interpret data on tumor incidence in terms of promotion and progression processes. The basic model is developed for a prolonged irradiation at a constant dose rate and includes short-term irradiation as a special case. A limiting form of the latent time distribution for short-term irradiation at high doses is obtained. This distribution arises in the extreme value theory within the random minima framework. An estimate for the rate of convergence to a limiting distributions is given. Based on the proposed latent time distributions, long-term predictions of carcinogenic risk do not call for information about irradiation dose. As shown by computer simulation studies and real data analysis, the parametric estimation of carcinogenic risk appears to be robust to the loss of statistical information caused by the right-hand censoring of time-to-tumor observations. It seems likely that this property, although revealed by means of a purely empirical procedure, may be useful in selecting a model for the practical purpose of risk prediction. 44 refs., 3 figs., 1 tab.

  10. DNA interstrand cross-link induced by estrogens as well as their complete and synergic carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The estrogens show negative activity in Ames test, but estrodiol and diethylstilbestrol in estrogens both are carcinogens based upon animal experiments and epidemiological investigation. It is concluded from the di-region theory, a mechanism conception put forward by one of the present authors, that the carcinogenesis of estrogens is switched on by the covalent cross-link between complementary DNA bases induced by them. We verified for the first time by the DNA alkaline elution method that both estrodiol and diethylstilbestrol cause covalent cross-link between DNA-protein and DNA interstrands after metabolic activation with dosage correlation, but neither the non-carcinogens cholesterol nor pyrene can lead to these sorts of cross-link in the same condition. It has been known that there is a synergetic effect between estrogen and pollution of polycyclic aromatic hydrocarbons. Although non-carcinogenic pyrene alone cannot induce cross-link, its addition with equal molar quantity to estrodiol culture causes synergically the total and DNA interstrand cross-link ratios to be respectively four and three times more than the ones in the cultivation with estrodiol only. It is shown that not only the estrodiol set off the formation of pyrene bi-radicals, but also the pyrene radicals arouse conversely the production of estrodiol bi-radicals.

  11. Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis.

    Science.gov (United States)

    Sena, Paola; Mariani, Francesco; Benincasa, Marta; De Leon, Maurizio Ponz; Di Gregorio, Carmela; Mancini, Stefano; Cavani, Francesco; Smargiassi, Alberto; Palumbo, Carla; Roncucci, Luca

    2014-01-01

    The aim of the present study was to determine whether BCL6 is expressed during malignant transformation of the large bowel and to assess whether, and to what extent, immunoreactivity is related to the different stages of neoplastic progression. Samples of normal colorectal mucosa (n=22), microadenomas (n=22) and colorectal cancer (n=22), were analyzed by immunohistochemistry, immunofluorescence coupled with confocal microscopy and western blotting. Our results clearly outlined the marked increase occurring in both intensity and density of BCL6 protein expression in the normal mucosa-microadenoma-carcinoma sequence. Immunohistochemistry and immunofluorescence analyses showed that BCL6 is expressed at low levels in normal mucosa and increases in microadenoma and in cancer with statistical significance. These results were confirmed by western blotting data. The increasing expression of BCL6 in human colorectal cancer development suggests the involvement of BCL6 in tumor progression, from the earliest stages of carcinogenesis with significant increase in cancer. The enhanced understanding of the biological role of BCL6, previously shown to exert a key role in lymphomagenesis, may lead to a re-evaluation of this protein and may highlight the importance of performing further studies in order to identify novel therapeutic targets for colorectal cancer.

  12. Teorie inteligence a jejich význam pro pedagogickou teorii a praxi

    OpenAIRE

    KOTLÍN, Roman

    2013-01-01

    The thesis deals with theories of intelligence and their significance for pedagogical theory and practice. The first part of the thesis describes theories of intelligence, specific theories of intelligence, mental retardation, causes of mental retardation, and focus on the relationship between theories of intelligence and pedagogical theory and practice. The second section presents an overview of current educational theories and practices, the education of gifted children and education of men...

  13. Karanie z mocy ustawy o przeciwdziałaniu narkomanii z perspektywy wybranych teorii kary

    Directory of Open Access Journals (Sweden)

    Jakub Sukiennik

    2015-12-01

    Full Text Available Increasing amount of legislation is being passed to regulate economic and social relations. It seems that in certain areas, its implementation can be logically justified. However, in the case of increasing criminalisation of drug-related activities that occurred during the Transformation of 1989, this leads to excessive paternalism and raises problems of interpretation. The object of this study will be drug prohibition designed to protect public health. This institution restricts freedom, especially personal liberty in the sense of personal rights and of the right to dispose of economic assets. Consumption of these substances generates negative externalities, whose formation is an argument in favour of state intervention. The aims of this article are to answer whether prohibition as a method of regulating the drug market, adopted in the 90's, seems to be effective and socially desirable from the point of view of utilitarian, retributive and abolitionist theories of punishment.

  14. Dual-self theory a její implikace pro ekonomickou teorii

    OpenAIRE

    Mrňávek, Vít

    2013-01-01

    Standard economic theory of intertemporal preferences cannot fully capture depth of such a complex phenomenon as procrastination is. An analytical comparison of theoretical approaches of discounted utility and dual-self theory to procrastination, this work investigated the credibility of explanation of its main aspects: utility of activities, timing of rewards and efforts, estimates of future preferences and self-regulation. The analysis implies that the classical economic paradigm of human b...

  15. „Cinemagraphs” Jamie Beck w kontekście dramatycznej teorii literatury

    Directory of Open Access Journals (Sweden)

    Ewelina Woźniak

    2012-01-01

    Full Text Available The purpose of this article is to present works of a New York photographer Jamie Beck, who developed a new type of moving photography – cinemagraphs, and look at her work from the perspective of the dramatic theory of literature. Jamie Beck in her works redefines many notions related to the visual realm. Movement and time relationship, the model identity and the impact of material on the image perception are the most interesting problems, that are connected with cinemagraphs. All these issues are analyzed in relation to fields dealing with image: André Rouille’s and Roland Barthes’ photographic theories, art history represented by Georges Didi- Huberman and Rudolf Arnheim’s “the psychology of creative eye”.

  16. Ku teoretycznej wielości (w sprawie teorii słabych)

    OpenAIRE

    Januszkiewicz, Michał

    2005-01-01

    This article refers to the problems of disputes over the concept of a literary character and theory (in humanities). The reference to the historical perspective becomes an occasion for the presentation of an attitude which stems from post-modern reflection: the metaphysical (essential) claims are put forward both to the subject and to the manner of studies, they are lifted for the sake of pragmatic and hermeneutic interpretations within this which the author calls weak theories (a...

  17. Obserwacja rzeczywistości a tworzenie teorii w myśli Panajotisa Kondylisa

    OpenAIRE

    Horst, Falk; Verykios, Konstantin; Zieliński, Lech

    2015-01-01

    Observation of Reality and Theory Creation in Panagiotis Kondylis’ Thought In the first part of the paper the authors present an outline of the Polish perception of thoughts and ideas of Panagiotis Kondylis which has started to develop only recently. This is followed by demonstrating major issues present in the output of this  Greek philosopher who was strongly linked both with Greece (Athens) and with Germany (Heidelberg). The paper closes with a discussion of Kondylis’ concept of theory cre...

  18. Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications

    Directory of Open Access Journals (Sweden)

    Kyrgidis Athanassios

    2010-01-01

    Full Text Available Background :The classification and prognostic assessment of melanoma is currently based on morphologic and histopathologic biomarkers. Availability of an increasing number of molecular biomarkers provides the potential for redefining diagnostic and prognostic categories and utilizing pharmacogenomics for the treatment of patients. The aim of the present review is to provide a basis that will allow the construction-or reconstruction-of future melanoma research. Methods: We critically review the common medical databases (PubMed, EMBASE, Scopus and Cochrane CENTRAL for studies reporting on molecular biomarkers for melanoma. Results are discussed along the hallmarks proposed for malignant transformation by Hanahan and Weinberg. We further discuss the genetic basis of melanoma with regard to the possible stem cell origin of melanoma cells and the role of sunlight in melanoma carcinogenesis. Results: Melanocyte precursors undergo several genome changes -UV-induced or not- which could be either mutations or epigenetic. These changes provide stem cells with abilities to self-invoke growth signals, to suppress anti-growth signals, to avoid apoptosis, to replicate without limit, to invade, proliferate and sustain angiogenesis. Melanocyte stem cells are able to progressively collect these changes in their genome. These new potential functions, drive melanocyte precursors to the epidermis were they proliferate and might cause benign nevi. In the epidermis, they are still capable of acquiring new traits via changes to their genome. With time, such changes could add up to transform a melanocyte precursor to a malignant melanoma stem cell. Conclusions : Melanoma cannot be considered a "black box" for researchers anymore. Current trends in the diagnosis and prognosis of melanoma are to individualize treatment based on molecular biomarkers. Pharmacogenomics constitute a promising field with regard to melanoma patients′ treatment. Finally, development of novel

  19. Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis.

    Science.gov (United States)

    Smith, Martyn T; Guyton, Kathryn Z; Gibbons, Catherine F; Fritz, Jason M; Portier, Christopher J; Rusyn, Ivan; DeMarini, David M; Caldwell, Jane C; Kavlock, Robert J; Lambert, Paul F; Hecht, Stephen S; Bucher, John R; Stewart, Bernard W; Baan, Robert A; Cogliano, Vincent J; Straif, Kurt

    2016-06-01

    A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health

  20. Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium.

    Science.gov (United States)

    Pierre, Fabrice; Santarelli, Raphaëlle; Taché, Sylviane; Guéraud, Françoise; Corpet, Denis E

    2008-05-01

    Red meat consumption is associated with increased risk of colorectal cancer. We have previously shown that haemin, Hb and red meat promote carcinogen-induced preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF) in rats. We have also shown that dietary Ca, antioxidant mix and olive oil inhibit haemin-induced ACF promotion, and normalize faecal lipoperoxides and cytotoxicity. Here we tested if these strategies are effective also against red meat promotion in dimethylhydrazine-induced rats. Three diets with 60 % beef meat were supplemented with calcium phosphate (31 g/kg), antioxidant agents (rutin and butylated hydroxyanisole, 0.05 % each) and olive oil (5 %). ACF, MDF, faecal water cytotoxicity, thiobarbituric acid reactive substances (TBARS) and urinary 1,4-dihydroxynonane mercapturic acid (DHN-MA) were measured. Beef meat diet increased the number of ACF (+30 %) and MDF (+100 %) (P Promotion was associated with increased faecal water TBARs ( x 4) and cytotoxicity ( x 2), and urinary DHN-MA excretion ( x 15). Ca fully inhibited beef meat-induced ACF and MDF promotion, and normalized faecal TBARS and cytotoxicity, but did not reduce urinary DHN-MA. Unexpectedly, high-calcium control diet-fed rats had more MDF and ACF in the colon than low-Ca control diet-fed rats. Antioxidant mix and olive oil did not normalize beef meat promotion nor biochemical factors. The results confirm that haem causes promotion of colon carcinogenesis by red meat. They suggest that Ca can reduce colorectal cancer risk in meat-eaters. The results support the concept that toxicity associated with the excess of a useful nutrient may be prevented by another nutrient.

  1. Expression of TFF2 and Helicobacter pylori infection in carcinogenesis of gastric mucosa

    Institute of Scientific and Technical Information of China (English)

    Guo-Yong Hu; Bao-Ping Yu; Wei-Guo Dong; Mu-Qi Li; Jie-Ping Yu; He-Sheng Luo; Zong-Xue Rang

    2003-01-01

    AIM: To investigate the expression of TFF2 and Helicobacter pyloriinfection in carcinogenesis of gastric mucosa.METHODS: The expression of TFF2 was immunohistochemically analyzed in paraffin-embedded samples from 119 patients with endoscopic biopsy and subtotal gastrectomy specimens of gastric mucosal lesions, including 16 cases of chronic superficial gastritis (CSG), 20 chronic atrophic gastritis (CAG),35 intestinal metaplasia (IN), 23 gastric epithelial dysplasia (GED) and 25 gastric carcinoma (CA), and Helicobacter pylori infection was detected by Warthin-Starry staining.RESULTS: 1:TFF2 was located in the cytoplasm of gastrk mucous neck cell. The expression of TFF2 was 100 %,100 %, 0, 56.5 % and 0 in CSGs, CAGs, INs, GEDs and CAs, respectively. 2: The value of TFF2 positive cell density in CSG with Helicobacter pyloriinfection was higher than that without Helicobacter pyloriinfection. (52.89±7.27vs46.49±13.04, P>0.05); But the value of TFF2 positive cell density in CAG and GED with Helicobacter pyloriinfection was significantly lower than that without Helicobacter pylori infection (18.17±4.09 vs 37.93±13.80, P<0.01 and 14.44±9.32 vs 24.84±10.22, P<0.05).CONCLUSION: Increase of TFF2 expression in CSG is perhaps associated with the protective mechanism after gastric mucosal injury. Decrease of TFF2 expression in CAG possibly attributes to the decrease in the number of gastric gland cell expressing TFF2. Re-expression of TFF2 in gastric epithelial dysplasia implies that TFF2 possibly contributes to the initiation of gastric carcinoma. The effect of Helicobacter pylori on the expression of TFF2 depends on the status of gastric mucosa.

  2. Monitoring pancreatic carcinogenesis by the molecular imaging of cathepsin E in vivo using confocal laser endomicroscopy.

    Directory of Open Access Journals (Sweden)

    Hui Li

    Full Text Available The monitoring of pancreatic ductal adenocarcinoma (PDAC in high-risk populations is essential. Cathepsin E (CTSE is specifically and highly expressed in PDAC and pancreatic intraepithelial neoplasias (PanINs, and its expression gradually increases along with disease progression. In this study, we first established an in situ 7,12-dimethyl-1,2-benzanthracene (DMBA-induced rat model for PanINs and PDAC and then confirmed that tumorigenesis properties in this model were consistent with those of human PDAC in that CTSE expression gradually increased with tumor development using histology and immunohistochemistry. Then, using in vivo imaging of heterotopically implanted tumors generated from CTSE- overexpressing cells (PANC-1-CTSE in nude mice and in vitro imaging of PanINs and PDAC in DMBA-induced rats, the specificity of the synthesized CTSE-activatable probe was verified. Quantitative determination identified that the fluorescence signal ratio of pancreatic tumor to normal pancreas gradually increased in association with progressive pathological grades, with the exception of no significant difference between PanIN-II and PanIN-III grades. Finally, we monitored pancreatic carcinogenesis in vivo using confocal laser endomicroscopy (CLE in combination with the CTSE-activatable probe. A prospective double-blind control study was performed to evaluate the accuracy of this method in diagnosing PDAC and PanINs of all grades (>82.7%. This allowed us to establish effective diagnostic criteria for CLE in PDAC and PanINs to facilitate the monitoring of PDAC in high-risk populations.

  3. Expression of proline-rich Akt-substrate PRAS40 in cell survival pathway and carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Bei HUANG; Gavin PORTER

    2005-01-01

    Aim: To study the expression of proline-rich Akt-substrate PRAS40 in the cell survival pathway and tumor progression. Methods: The effects of three key kinase inhibitors on PRAS40 activity in the cell survival pathway, serum withdrawal,H2O2 and overexpression of Akt were tested. The expression of PRAS40, Akt, Raf and 14-3-3 in normal cells and cancer cell lines was determined by Western blot.Results: The PI3K inhibitors worthmannin and Ly294002, but not rapamycin, completely inhibited the phosphorylation of Akt and PRAS40. The phosphorylation level of Akt decreased after serum withdrawal and treatment with the MEK inhibitor Uo126, but increased after treatment with H2O2 at low concentration, whereas none of these treatments changed PRAS40 activity. 14-3-3 is a PRAS40 binding protein, and the expression of 14-3-3, like that of PRAS40, was higher in HeLa cells than in HEK293 cells; PRAS40 had a stronger phosphorylation activity in A549 and HeLa cancer cells than in HEK293 normal cells. In the breast cancer model (MCF10A/MCF7) and lung cancer model (BEAS/H1198/H1170) we also found the same result: PRAS40 was constitutively active in H1198/H1170 and MCF7 premalignant and malignant cancer cells, but weakly expressed in MCF10A and BEAS normal cell. We also discussed PRAS40 activity in other NSCLC cell lines.Conclusion: The PI3K-Akt survival pathway is the main pathway that PRAS40 is involved in; PRAS40 is a substrate for Akt, but can also be activated by an Aktindependent mechanisms. PRAS40 activation is an early event during breast and lung carcinogenesis.

  4. DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis.

    Science.gov (United States)

    Fahrer, Jörg; Frisch, Janina; Nagel, Georg; Kraus, Alexander; Dörsam, Bastian; Thomas, Adam D; Reißig, Sonja; Waisman, Ari; Kaina, Bernd

    2015-10-01

    Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O (6)-methylguanine (O (6)-MeG) and N-methylated purines, which are repaired by O (6)-MeG-DNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG)-initiated base excision repair, respectively. In view of recent evidence of nonlinear mutagenicity for NOC-like compounds, the question arises as to the existence of threshold doses in CRC formation. Here, we set out to determine the impact of DNA repair on the dose-response of alkylation-induced CRC. DNA repair proficient (WT) and deficient (Mgmt (-/-), Aag (-/-) and Mgmt (-/-)/Aag (-/-)) mice were treated with azoxymethane (AOM) and dextran sodium sulfate to trigger CRC. Tumors were quantified by non-invasive mini-endoscopy. A non-linear increase in CRC formation was observed in WT and Aag (-/-) mice. In contrast, a linear dose-dependent increase in tumor frequency was found in Mgmt (-/-) and Mgmt (-/-)/Aag (-/-) mice. The data were corroborated by hockey stick modeling, yielding similar carcinogenic thresholds for WT and Aag (-/-) and no threshold for MGMT lacking mice. O (6)-MeG levels and depletion of MGMT correlated well with the observed dose-response in CRC formation. AOM induced dose-dependently DNA double-strand breaks in colon crypts including Lgr5-positive colon stem cells, which coincided with ATR-Chk1-p53 signaling. Intriguingly, Mgmt (-/-) mice displayed significantly enhanced levels of γ-H2AX, suggesting the usefulness of γ-H2AX as an early genotoxicity marker in the colorectum. This study demonstrates for the first time a non-linear dose-response for alkylation-induced colorectal carcinogenesis and reveals DNA repair by MGMT, but not AAG, as a key node in determining a carcinogenic threshold.

  5. HPV infection and the alterations of the pRB pathway in oral carcinogenesis.

    Science.gov (United States)

    Lim, Kue Peng; Hamid, Sharifah; Lau, Shin-Hin; Teo, Soo-Hwang; Cheong, Sok Ching

    2007-06-01

    Inactivation of the retinoblastoma (pRB) pathway is a common event in oral squamous cell carcinoma particularly through the aberrant expression of the components within this pathway. This study examines the alterations of molecules within the pRB pathway by looking at the presence of homozygous deletions in p16(INK4A) and the expression patterns of pRB, cyclin D1 and CDK4, as well as the presence of human papillomavirus (HPV) in our samples. In our study, 5/20 samples demonstrated deletions of p16(INK4A) exon 1alpha. pRB overexpression was found in 20/20 samples, the expression was mainly observed in all layers of the epithelia, particularly in the basal layer where cells are actively dividing and aberrant pRB expression was found in 12/20 samples. Cyclin D1 and CDK4 overexpression was detected in 6/20 and 2/20 samples respectively in comparison to hyperplasias where both proteins were either not expressed or expressed at minimal levels (pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16(INK4A) and overexpression of pRB, cyclin D1 and CDK4. Collectively, this data demonstrates that alterations in the pRB pathway are a common event and involve the aberration of more than one molecule within the pathway. Furthermore, the involvement of HPV in all our samples suggests that HPV infection may play an important role in oral carcinogenesis.

  6. Field cancerization in mammary carcinogenesis - Implications for prevention and treatment of breast cancer.

    Science.gov (United States)

    Rivenbark, Ashley G; Coleman, William B

    2012-12-01

    The natural history of breast cancer unfolds with the development of ductal carcinoma in situ (DCIS) in normal breast tissue, and evolution of this pre-invasive neoplasm into invasive cancer. The mechanisms that drive these processes are poorly understood, but evidence from the literature suggests that mammary carcinogenesis may occur through the process of field cancerization. Clinical observations are consistent with the idea that (i) DCIS may arise in a field of altered breast epithelium, (ii) narrow surgical margins do not remove the entire altered field (contributing to recurrence and/or disease progression), and (iii) whole-breast radiation therapy is effective in elimination of the residual field of altered cells adjacent to the resected DCIS. Molecular studies suggest that the field of altered breast epithelial cells may carry cancer-promoting genetic mutations (or other molecular alterations) or cancer promoting epimutations (oncogenic alterations in the epigenome). In fact, most breast cancers develop through a succession of molecular events involving both genetic mutations and epimutations. Hence, in hereditary forms of breast cancer, the altered field reflects the entire breast tissue which is composed of cells with a predisposing molecular lesion (such as a BRCA1 mutation). In the example of a BRCA1-mutant patient, it is evident that local resection of a DCIS lesion or localized but invasive cancer will not result in elimination of the altered field. In sporadic breast cancer patients, the mechanistic basis for the altered field may not be so easily recognized. Nonetheless, identification of the nature of field cancerization in a given patient may guide clinical intervention. Thus, patients with DCIS that develops in response to an epigenetic lesion (such as a hypermethylation defect affecting the expression of tumor suppressor genes) might be treated with epigenetic therapy to normalize the altered field and reduce the risk of secondary occurrence of

  7. Tumor suppressor function of Betaig-H3 gene in radiation carcinogenesis

    Science.gov (United States)

    Zhao, Y. L.; Piao, C. Q.; Hei, T. K.

    Interaction between cell and extracellular matrix (ECM) plays a crucial role in tumor invasiveness and metastasis. Using an immortalized human bronchial epithelial (BEP2D) cell model, we showed previously that expression of a list of genes including Betaig-h3 (induced by transforming growth factor-β) DCC (deleted in colorectal cancer), p21 cip1, c-fos , Heat shock protein (HSP27) and cytokeratin 14 were differentially expressed in several independently generated, radiation-induced tumor cell lines (TL1-TL5) relative to parental BEP2D cells. Our previous data further demonstrated that loss of tumor suppressor gene(s) as a likely mechanism of radiation carcinogenesis. In the present study, we chose Betaig-h3 and DCC that were downregulated in tumorigenic cells for further study. Restored expression of Betaig-h3 gene, not DCC gene, by transfecting cDNA into tumor cells resulted in a significant reduction in tumor growth. While integrin receptor α5β1 was overexpressed in tumor cells, its expression was corrected to the level found in control BEP2D cells after Betaig-h3 transfection. These data suggest that Betaig-h3 gene is involved in tumor progression by regulating integrin α5β1 receptor. Furthermore, exogenous TGF-β1 induced expression of Betaig-h3 gene and inhibited the growth of both control and tumorigenic BEP2D cells. Therefore, downregulation of Betaig-h3 gene may results from the decreased expression of upstream mediators such as TGF-β. The findings provide strong evidence that the Betaig-h3 gene has tumor suppressor function in radiation-induced tumorigenic human bronchial epithelial cells and suggest a potential target for interventional therapy.

  8. DNA lesions, inducible DNA repair, and cell division: Three key factors in mutagenesis and carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ames, B.N.; Shigenaga, M.K. [Univ. of California, Berkeley, CA (United States); Gold, L.S. [Lawrence Berkeley National Lab., CA (United States)

    1993-12-01

    DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10{sup 6} oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).

  9. Chronic psychosocial stress increases the risk for inflammation-related colon carcinogenesis in male mice.

    Science.gov (United States)

    Peters, Sebastian; Grunwald, Nicole; Rümmele, Petra; Endlicher, Esther; Lechner, Anja; Neumann, Inga D; Obermeier, Florian; Reber, Stefan O

    2012-07-01

    Patients with inflammatory bowel diseases (IBDs) have a higher risk of developing colorectal cancer (CRC) than the general population. Furthermore, chronic psychosocial stress increases the likelihood of developing IBD and multiple types of malignant neoplasms, including CRC. Here, for the first time, we investigate the effects of chronic psychosocial stress in male mice on an artificially induced CRC, by employing the chronic subordinate colony (CSC) housing paradigm in combination with the reliable azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC model. Colonoscopy revealed that CSC mice showed accelerated macroscopic suspect lesions. In addition, more CSC mice developed low-grade dysplasia (LGD) and/or high-grade dysplasia (HGD) in the colonic tissue compared to the single-housed control mice (SHC). CSC mice showed an increased number of Ki67+ and a decreased number of terminal deoxynucleotidyl transferase dUTP nick end labeling epithelial cells in colonic tissue. Colonic liver receptor homolog-1 (LRH-1), cyclooxygenase II (COXII), tumor necrosis factor, forkhead box P3 (FoxP3) mRNA as well as colonic ß-catenin, COXII, and LRH-1 protein expression were also increased in CSC compared with SHC mice. Although the number of CD4+ Th cells was increased, a tendency toward a decreased colonic interferon-γ (IFN-γ) mRNA expression was observed. Furthermore, despite an increased percentage of CD3+ cells and CD3+/FoxP3+ double-positive cells within mesenteric lymph node cells of CSC mice, IFN-γ secretion from these cells was unaffected. Altogether, our results suggest that chronic psychosocial stress increases the risk for AOM/DSS-induced and, thus, inflammation-related CRC. Finally, assessment of additional time points may test whether the shift from tumor-protective Th1 cell to regulatory T-cell immunity represents a consequence of increased carcinogenesis or a causal factor involved in its development.

  10. Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis

    Science.gov (United States)

    Smith, Martyn T.; Guyton, Kathryn Z.; Gibbons, Catherine F.; Fritz, Jason M.; Portier, Christopher J.; Rusyn, Ivan; DeMarini, David M.; Caldwell, Jane C.; Kavlock, Robert J.; Lambert, Paul F.; Hecht, Stephen S.; Bucher, John R.; Stewart, Bernard W.; Baan, Robert A.; Cogliano, Vincent J.; Straif, Kurt

    2015-01-01

    basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713–721; http://dx.doi.org/10.1289/ehp.1509912 PMID:26600562

  11. Effect of spices on lipid metabolism in 1,2-dimethylhydrazine-induced rat colon carcinogenesis.

    Science.gov (United States)

    Nalini, N; Manju, V; Menon, V P

    2006-01-01

    Colon cancer is the second most common cancer among men and women worldwide. We investigated the effect of red chilli (Capsicum annum L.), cumin (Cuminum cyminum L.), and black pepper (Piper nigrum L.) on colon cancer induced in rats by a colon-specific carcinogen, 1,2-dimethylhydrazine (DMH). Colon cancer was induced by subcutaneous injection of DMH at a dosage of 20 mg/kg of body weight (15 doses, at 1-week intervals). The rats were continued with the standard pellet diet and supplemented red chilli [C. annum L., 0.015% (wt/wt) mixed with the diet], cumin seeds [C. cyminum L., 1.25% (wt/wt) mixed with the diet], and black pepper (P. nigrum L., 0.5% (wt/wt) mixed with the diet] throughout the experimental period. After the total experimental period of 32 weeks (including 2 weeks of acclimatization) the incidence and number of tumors in the colon were observed to be significantly higher in the rats administered DMH and/or red chillis, as compared with the cumin + DMH and black pepper + DMH groups. No tumors were observed in the control, cumin + DMH, or black pepper + DMH groups. The levels of fecal bile acids and neutral sterols in 24-hour fecal samples were significantly decreased in DMH + chilli-administered rats, while the excretion of fecal bile acids and neutral sterols was significantly increased in cumin + DMH- and black pepper + DMH-administered rats. In DMH-, chilli-, and chilli + DMH-administered rats the levels of cholesterol, cholesterol/phospholipid ratio, and 3-hydroxy-3-methylglutaryl-CoA reductase activity were decreased in cumin + DMH- and black pepper + DMH-treated rats. The phospholipid levels were reduced in the DMH, chilli, and chilli + DMH groups as compared with the cumin + DMH and black pepper + DMH groups. Our results show that chilli supplementation promotes colon carcinogenesis, whereas cumin or black pepper suppresses colon carcinogensis in the presence of the procarcinogen DMH.

  12. Chemopreventive effect of zingerone against colon carcinogenesis induced by 1,2-dimethylhydrazine in rats.

    Science.gov (United States)

    Vinothkumar, Rajenderan; Vinothkumar, Rajamanickam; Sudha, Mani; Nalini, Namasivayam

    2014-09-01

    Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butane], one of the active phenolic components isolated from Zingiber officinale, has antioxidant and anticarcinogenic properties. In our study, we have evaluated the effect of different doses of zingerone on lipid peroxidation (thiobarbituric acid-reactive substances, lipid hydroxyl radical and conjugated dienes), tissue enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase), and nonenzymatic antioxidants (reduced glutathione, vitamin E, vitamin C), and also the formation of aberrant crypt foci (ACF) in male albino Wistar rats with colon cancer induced using 1,2-dimethylhydrazine (DMH). The rats were divided into six groups. Group 1 served as a control group and received a modified pellet diet; the rats in group 2 received a modified pellet diet along with zingerone (40 mg/kg b.w., orally every day); groups 3-6 were administered DMH (20 mg/kg b.w., subcutaneously) once a week for the first 4 weeks; and groups 4-6 received zingerone at three different doses of 10, 20 and 40 mg/kg b.w., respectively, every day for 16 weeks. Increased tumour incidence and ACF formation were accompanied by a decrease in the tissue lipid peroxidation, enzymatic and nonenzymatic antioxidant activities observed in the colon of DMH-treated rats. Supplementation with zingerone in DMH-treated rats led to a significant decrease in the tumour incidence and ACF formation with simultaneous modulation in the level of tissue lipid peroxidation and antioxidant status. Thus, in conclusion, we can suggest that zingerone effectively inhibits DMH-induced colon carcinogenesis in male Wistar rats.

  13. The effect of childbirth on carcinogenesis of DMBA-induced breast cancer in female SD rats

    Institute of Scientific and Technical Information of China (English)

    Ji-An Zhao; Jin-Jun Chen; Ying-Chao Ju; Jian-Hua Wu; Cui-Zhi Geng; Hui-Chai Yang

    2011-01-01

    Many epidemiologic and clinical studies have indicated that the frequency of breast cancer was lower in parous women than in nulliparous women.Moreover,the incidence of breast cancer has been reported to be lower in women with early childbirth than in women with late childbirth.To verify the effect of childbirth and the age at first childbirth on carcinogenesis and progression of breast cancer,we induced breast cancer by 7,12-dimethylbenanthracene (DMBA) in 120 female Sprague-Dawley (SD) rats,and divided them into control or experimental (DMBA-treated) nulliparous,early childbirth,and late childbirth groups to observe the incidence,latency,and size of breast cancer.Argyrophilic nucleolar organizer regions (AgNOR) count and the expression of C-erbB-2,proliferating cell nuclear antigen (PCNA),Ki-67,and minichromosome maintenance protein 2 (MCM2) in breast cancer tissues were detected by immunohistochemistry.The breast cancer incidences were 95.0%,16.7%,and 58.8% in the experimental nulliparous,early childbirth,and late childbirth groups,respectively (all P < 0.05).Between any two of these groups,the latency was significantly different,but tumor size was similar.AgNOR count and the expression of C-erbB-2,PCNA,Ki-67,and MCM2 were significantly higher in the experimental nulliparous group than in the experimental early or late childbirth groups (P < 0.05),but no significant differences were observed between the latter two groups.Taken together,the results suggest that childbirth,especially early childbirth,can reduce the incidence and postpone the onset of DMBA-induced breast cancer.

  14. ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway.

    Science.gov (United States)

    Shan, Weiwei; Wang, Chao; Zhang, Zhenbo; Luo, Xuezhen; Ning, Chengcheng; Yu, Yinhua; Feng, Youji; Gu, Chao; Chen, Xiaojun

    2015-03-01

    The purpose of the study was to explore the role and mechanism of ataxia-telangiectasia mutated (ATM) protein in endometrial carcinogenesis. A reverse-phase protein array (RPPA) was used to analyze the expression of ATM signal pathway proteins in Ishikawa and progesterone-insensitive Ishikawa. ATM expression was detected in endometrium specimens by immunohistochemistry, including 8 cases with proliferative endometrium, 6 cases with secretory endometrium, 10 cases with simple hyperplasia (SH), 13 cases of complex hyperplasia (CH), 11 cases of endometrial atypical hyperplasia (EAH), and 83 cases with type I endometrial cancer. The relationship between ATM expression and other clinicopathological indicators was also examined in type I endometrial cancer patients. The mechanisms of ATM were explored in vitro with the endometrial cell lines Ishikawa and RL95-2. A cell counting kit-8 (CCK-8) test and Western blot analysis were performed to test proliferation and protein expression. Statistical analysis was performed with SPSS19.0. The significance level was set at 0.05. ATM was increased with medroxyprogesterone acetate (MPA) stimulation in Ishikawa in RPPA. ATM expression gradually decreased in endometrial hyperplasic lesions compared with the normal proliferative and secretory endometrium and was the lowest in type I endometrial cancer. ATM expression was negatively correlated with pathological grades in type I endometrial cancer. In vitro, ATM silencing retarded proliferation inhibition in Ishikawa and RL95-2 treated with MPA. ATM silencing could down-regulate the MPA-stimulated signal proteins, including Chk2, P53, and caspase-3 in vitro. MPA might exert its role through activating the ATM-associated pathway, ATM-Chk2-P53-caspase-3 (active), preserving normal endometrium and protecting it from malignancies. ATM might be a promising indicator for endometrial hyperplasia and cancer.

  15. High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis.

    Science.gov (United States)

    Gaddy, Jennifer A; Radin, Jana N; Loh, John T; Zhang, Feng; Washington, M Kay; Peek, Richard M; Algood, Holly M Scott; Cover, Timothy L

    2013-06-01

    Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA(+) H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/high-salt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1β (IL-1β), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains.

  16. MicroRNA, SND1, and alterations in translational regulation in colon carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tsuchiya, Naoto [Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Nakagama, Hitoshi, E-mail: hnakagam@ncc.go.jp [Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Early Oncogenesis Research Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan)

    2010-11-10

    Post-transcriptional regulation of gene expression by microRNA (miRNA) has recently attracted major interest in relation to its involvement in cancer development. miRNA is a member of small non-coding RNA, consists of 22-24 nucleotides and regulates expression of target mRNA species in a post-transcriptional manner by being incorporated with RNA-induced silencing complex (RISC). Staphylococcal nuclease homology domain containing 1 (SND1), a component of RISC, is frequently up-regulated in human colon cancers and also chemically induced colon cancers in animals. We here showed that SDN1 is involved in miRNA-mediated gene suppression and overexpression of SND1 in colon cancer cells causes down-regulation of APC without altering APC mRNA levels. As for the miRNA expression profile in human colon cancer, miR-34a was among the list of down-regulated miRNA. Expression of miR-34a is tightly regulated by p53, and ectopic expression of miR-34a in colon cancer cells causes remarkable reduction of cell proliferation and induces senescence-like phenotypes. MiR-34a also participates in the positive feedback loop of the p53 tumor suppressor network. This circuitry mechanism for p53 activation is of interest in understanding the tumor suppressive function of miR-34a in colon carcinogenesis. miRNA should also be considered as novel anti-cancer agents in tumor suppressive therapeutic applications.

  17. Estimation of risk based on multiple events in radiation carcinogenesis of rat skin

    Science.gov (United States)

    Burns, F. J.; Jin, Y.; Garte, S. J.; Hosselet, S.

    1994-10-01

    In the multistage theory of carcinogenesis, cells progress to cancer through a series of discrete, irreversible, heritable genetic alterations or mutations. However data on radiation-induced cancer incidence in rat skin suggests that some part of an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to the following radiations: 1. an electron beam (LET = 0.34 keV/um, 2. a neon ion beam (LET = 25 keV/um and 3. an argon ion beam (LET = 125 keV/um. The latter 2 beams were generated by the Bevalac at the Lawrence Berkeley Laboratory, Berkeley, CA. About 6.0 cm2 of skin was irradiated per rat. The rats were observed every 6 weeks for at least 78 weeks and tumors were scored at first occurrence. Several histological types of cancer, including squamous and basal cell carcinomas, were induced. The cancer yield versus radiation dose was fitted by the quadratic equation (Y (D) = CLD + BD2), and the parameters C and B were estimated for each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated in all tumors tested, although only a small proportion of neon-induced tumors showed similar activation. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces carcinogenically relevant lesions via 2 repairable events at low LET and via a non-repairable, linked event pathway at high LET; either pathway may advance the cell by 1 stage in the multistage model. The model, if validated, permits the direct calculation of cancer risk in rat skin in a way that can be subjected to experimental testing.

  18. Anal Neoplasia in Inflammatory Bowel Disease: Classification Proposal, Epidemiology, Carcinogenesis, and Risk Management Perspectives.

    Science.gov (United States)

    Wisniewski, Andrew; Fléjou, Jean-Francois; Siproudhis, Laurent; Abramowitz, Laurent; Svrcek, Magali; Beaugerie, Laurent

    2017-08-01

    Patients with inflammatory bowel disease [IBD] may develop, similarly to individuals from general population, rare cases of human papilloma virus [HPV]-related anal canal squamous cell carcinoma [SCC] and intra-epithelial precursor lesions, as well as very rare cases of anal canal adenocarcinoma. Patients with chronic perianal Crohn's disease [CD] are at substantial risk of developing SCC or adenocarcinoma from the fistula-lining epithelium, as well as SCC or adenocarcinoma arising from chronic anorectal ulcerations or strictures. Based on this lesion stratification, we provide in this review tailored incidence estimates and we propose an IBD-specific classification of all types of anal neoplasia that may occur in patients with IBD. After reviewing putative carcinogenesis of all types of neoplasia, we conclude that HPV vaccination could reduce the incidence of HPV-related lesions, although an anal screening programme related to these lesions is not mandatory on the sole basis of IBD. By contrast, we point out that all patients with chronic perianal CD should be explored in depth, including biopsies under anaesthesia and fistula curettage when necessary, in case of any change in anal symptoms ─in particular new, increasing, unexplained pain. Finally, we conclude that there is an urgent need for elaborating and evaluating surveillance algorithms in patients with chronic perianal CD, in order to avoid cancers with late diagnosis and poor prognosis. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Effect of nisin and doxorubicin on DMBA-induced skin carcinogenesis--a possible adjunct therapy.

    Science.gov (United States)

    Preet, Simran; Bharati, Sanjay; Panjeta, Anshul; Tewari, Rupinder; Rishi, Praveen

    2015-11-01

    In view of the emergence of multidrug-resistant cancer cells, there is a need for therapeutic alternatives. Keeping this in mind, the present study was aimed at evaluating the synergism between nisin (an antimicrobial peptide) and doxorubicin (DOX) against DMBA-induced skin carcinogenesis. The possible tumoricidal activity of the combination was evaluated in terms of animal bioassay observations, changes in hisotological architecture of skin tissues, in situ apoptosis assay (TUNEL assay) and in terms of oxidant and antioxidant status of the skin tissues. In vivo additive effect of the combination was evidenced by larger decreases in mean tumour burden and tumour volume in mice treated with the combination than those treated with the drugs alone. Histological observations indicated that nisin-DOX therapy causes chromatin condensation and marginalisation of nuclear material in skin tissues of treated mice which correlated well with the results of TUNEL assay wherein a marked increase in the rate of apoptosis was revealed in tissues treated with the combination. A slightly increased oxidative stress in response to the adjunct therapy as compared to dox-alone-treated group was revealed by levels of lipid peroxidation (LPO) and nitrite generation in skin tissue-treated mice. An almost similar marginal enhancement in superoxide dismutase levels corresponding with a decrease in catalase activity could also be observed in nisin + DOX-treated groups as compared to nisin and dox-alone-treated groups. These results point towards the possible use of nisin as an adjunct to doxorubicin may help in developing alternate strategies to combat currently developing drug resistance in cancer cells.

  20. Association of Betel Nut with Carcinogenesis: Revisit with a Clinical Perspective

    Science.gov (United States)

    Sharan, Rajeshwar N.; Mehrotra, Ravi; Choudhury, Yashmin; Asotra, Kamlesh

    2012-01-01

    Abstract Betel nut (BN), betel quid (BQ) and products derived from them are widely used as a socially endorsed masticatory product. The addictive nature of BN/BQ has resulted in its widespread usage making it the fourth most abused substance by humans. Progressively, several additives, including chewing tobacco, got added to simple BN preparations. This addictive practice has been shown to have strong etiological correlation with human susceptibility to cancer, particularly oral and oropharyngeal cancers. The PUBMED database was searched to retrieve all relevant published studies in English on BN and BQ, and its association with oral and oropharyngeal cancers. Only complete studies directly dealing with BN/BQ induced carcinogenesis using statistically valid and acceptable sample size were analyzed. Additional relevant information available from other sources was also considered. This systematic review attempts to put in perspective the consequences of this widespread habit of BN/BQ mastication, practiced by approximately 10% of the world population, on oral cancer with a clinical perspective. BN/BQ mastication seems to be significantly associated with susceptibility to oral and oropharyngeal cancers. Addition of tobacco to BN has been found to only marginally increase the cancer risk. Despite the widespread usage of BN/BQ and its strong association with human susceptibility to cancer, no serious strategy seems to exist to control this habit. The review, therefore, also looks at various preventive efforts being made by governments and highlights the multifaceted intervention strategies required to mitigate and/or control the habit of BN/BQ mastication. PMID:22912735

  1. Association of betel nut with carcinogenesis: revisit with a clinical perspective.

    Directory of Open Access Journals (Sweden)

    Rajeshwar N Sharan

    Full Text Available Betel nut (BN, betel quid (BQ and products derived from them are widely used as a socially endorsed masticatory product. The addictive nature of BN/BQ has resulted in its widespread usage making it the fourth most abused substance by humans. Progressively, several additives, including chewing tobacco, got added to simple BN preparations. This addictive practice has been shown to have strong etiological correlation with human susceptibility to cancer, particularly oral and oropharyngeal cancers.The PUBMED database was searched to retrieve all relevant published studies in English on BN and BQ, and its association with oral and oropharyngeal cancers. Only complete studies directly dealing with BN/BQ induced carcinogenesis using statistically valid and acceptable sample size were analyzed. Additional relevant information available from other sources was also considered.This systematic review attempts to put in perspective the consequences of this widespread habit of BN/BQ mastication, practiced by approximately 10% of the world population, on oral cancer with a clinical perspective. BN/BQ mastication seems to be significantly associated with susceptibility to oral and oropharyngeal cancers. Addition of tobacco to BN has been found to only marginally increase the cancer risk. Despite the widespread usage of BN/BQ and its strong association with human susceptibility to cancer, no serious strategy seems to exist to control this habit. The review, therefore, also looks at various preventive efforts being made by governments and highlights the multifaceted intervention strategies required to mitigate and/or control the habit of BN/BQ mastication.

  2. The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis.

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    Ingerslev, Kasper; Hogdall, Estrid; Schnack, Tine Henrichsen; Skovrider-Ruminski, Wojciech; Hogdall, Claus; Blaakaer, Jan

    2017-01-01

    The etiological cause of ovarian cancer is poorly understood. It has been theorized that bacterial or viral infection as well as pelvic inflammatory disease could play a role in ovarian carcinogenesis. To review the literature on studies examining the association between ovarian cancer and bacterial or viral infection or pelvic inflammatory disease. Database search through MEDLINE, applying the medical subject headings: "Ovarian neoplasms", AND "Chlamydia infections", "Neisseria gonorrhoeae", "Mycoplasma genitalium", "Papillomaviridae", or "pelvic inflammatory disease". Corresponding searches were performed in EMBASE, and Web of Science. The literature search identified 935 articles of which 40 were eligible for inclusion in this review. Seven studies examined the association between bacterial infection and ovarian cancer. A single study found a significant association between chlamydial infection and ovarian cancer, while another study identified Mycoplasma genitalium in a large proportion of ovarian cancer cases. The remaining studies found no association. Human papillomavirus detection rates varied from 0 to 67% and were generally higher in the Asian studies than in studies from Western countries. Cytomegalovirus was the only other virus to be detected and was found in 50% of cases in a case-control study. The association between ovarian cancer and pelvic inflammatory disease was examined in seven epidemiological studies, two of which, reported a statistically significant association. Data indicate a potential association between pelvic inflammatory disease and ovarian cancer. An association between ovarian cancer and high-risk human papillomavirus genotypes may exist in Asia, whereas an association in Western countries seems unlikely due to the low reported prevalence. Potential carcinogenic bacteria were found, but results were inconsistent, and further research is warranted.

  3. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.

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    Schulz, Manon D; Atay, Ciğdem; Heringer, Jessica; Romrig, Franziska K; Schwitalla, Sarah; Aydin, Begüm; Ziegler, Paul K; Varga, Julia; Reindl, Wolfgang; Pommerenke, Claudia; Salinas-Riester, Gabriela; Böck, Andreas; Alpert, Carl; Blaut, Michael; Polson, Sara C; Brandl, Lydia; Kirchner, Thomas; Greten, Florian R; Polson, Shawn W; Arkan, Melek C

    2014-10-23

    Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.

  4. PRL-3, an emerging marker of carcinogenesis, is strongly associated with poor prognosis.

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    Guzińska-Ustymowicz, Katarzyna; Pryczynicz, Anna

    2011-01-01

    PRL-3 protein belongs to the family of protein tyrosine phosphatases with unique COOH-terminal prenylation motif, which determines the functions of this protein and its location in the cell. Numerous research studies revealed that apart from performing the poorly investigated physiological role, PRL-3 takes part in the process of carcinogenesis. Specifically, it is involved in reconstructing of the cytoskeleton, regulating adhesion and cell cycle of the cancer cells, and in epithelial-mesenchymal transition. Through these mechanisms PRL-3 protein participates in invasion, migration, metastasis and angiogenesis. Numerous studies indicate that PRL-3 expression is particularly important in colorectal, as well as in gastric, ovarian and breast carcinomas. Recently, several studies on PRL-3 protein in other types of cancer have been published. They reveal a significant role of this protein in the process of angiogenesis and metastasis. It has been proven that a higher expression of PRL-3 correlates with tumor progression and its severity. While the degree of overexpression of PRL-3 varies in different types of tumors, most research shows that in the metastases of these tumors, whether to the lymph nodes or to other organs, the level of expression is extremely high. Overexpression of PRL-3 protein was repeatedly confirmed in metastases, but not with primary tumors. PRL-3 seems to be an adequate marker in diagnosing the stage of tumor advancement for various types of carcinomas, especially for colorectal carcinoma investigated thoroughly in this study. PRL-3 overexpression predicts poor prognosis in patients with various carcinomas and is a promising target in the cancer treatment.

  5. Cancer stem cells in Helicobacter pylori infection and aging: Implications for gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Edi; Levi; Paula; Sochacki; Nabiha; Khoury; Bhaumik; B; Patel; Adhip; PN; Majumdar

    2014-01-01

    AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells(CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and Helicobacter pylori(H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old(young) with 22 mo(aged) old Fischer-344 rats. For human studies, gastric biop-sies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells. RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia. CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.

  6. Avian WNT4 in the female reproductive tracts: potential role of oviduct development and ovarian carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Chul-Hong Lim

    Full Text Available The wingless-type MMTV integration site family of proteins (WNTs is highly conserved secreted lipid-modified signaling molecules that play a variety of pivotal roles in developmental events such as embryogenesis, tissue homeostasis and cell polarity. Although, of these proteins, WNT4 is known to be involved in genital development in fetuses of mammalian species, its role is unknown in avian species. Therefore, in this study, we investigated expression profiles, as well as hormonal and post-transcriptional regulation of WNT4 expression in the reproductive tract of female chickens. Results of this study demonstrated that WNT4 is most abundant in the stromal and luminal epithelial cells of the isthmus and shell gland of the oviduct, respectively. WNT4 is also most abundant in the glandular epithelium of the shell gland of the oviduct of laying hens at 3 h post-ovulation during the laying cycle. In addition, treatment of young chicks with diethylstilbestrol (DES, a synthetic estrogen agonist stimulated WNT4 only in the glandular epithelial cells of the isthmus and shell gland of the oviduct. Moreover, results of our study demonstrated that miR-1786 influences WNT4 expression via specific binding sites in its 3'-UTR. On the other hand, our results also indicate that WNT4 is expressed predominantly in the glandular epithelium of cancerous ovaries, but not in normal ovaries of hens. Collectively, these results indicate cell-specific expression of WNT4 in the reproductive tract of chickens and that it likely has crucial roles in development and function of oviduct as well as initiation of ovarian carcinogenesis in laying hens.

  7. Flavonoids Extracted from Licorice Prevents Colitis-Associated Carcinogenesis in AOM/DSS Mouse Model.

    Science.gov (United States)

    Huo, Xiaowei; Liu, Dongyu; Gao, Li; Li, Liyong; Cao, Li

    2016-08-24

    Inflammatory bowel disease (IBD) is generally considered as a major risk factor in the progression of colitis-associated carcinogenesis (CAC). Thus, it is well accepted that ameliorating inflammation creates a potential to achieve an inhibitory effect on CAC. Licorice flavonoids (LFs) possess strong anti-inflammatory activity, making it possible to investigate its pharmacologic role in suppressing CAC. The purpose of the present study was to evaluate the anti-tumor potential of LFs, and further explore the underlying mechanisms. Firstly, an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model was established and administered with or without LFs for 10 weeks, and then the severity of CAC was examined macroscopically and histologically. Subsequently, the effects of LFs on expression of proteins associated with apoptosis and proliferation, levels of inflammatory cytokine, expression of phosphorylated-Janus kinases 2 (p-Jak2) and phosphorylated-signal transducer and activator of transcription 3 (p-Stat3), and activation of nuclear factor-κB (NFκB) and P53 were assessed. We found that LFs could significantly reduce tumorigenesis induced by AOM/DSS. Further study revealed that LFs treatment substantially reduced activation of NFκB and P53, and subsequently suppressed production of inflammatory cytokines and phosphorylation of Jak2 and Stat3 in AOM/DSS-induced mice. Taken together, LFs treatment alleviated AOM/DSS induced CAC via P53 and NFκB/IL-6/Jak2/Stat3 pathways, highlighting the potential of LFs in preventing CAC.

  8. Inflammation-Related Carcinogenesis and Prevention in Esophageal Adenocarcinoma Using Rat Duodenoesophageal Reflux Models

    Energy Technology Data Exchange (ETDEWEB)

    Fujimura, Takashi, E-mail: tphuji@staff.kanazawa-u.ac.jp; Oyama, Katsunobu; Sasaki, Shozo; Nishijima, Koji; Miyashita, Tomoharu; Ohta, Tetsuo [Gastroenterologic Surgery, Kanazawa University Hospital, Kanazawa, Japan, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 (Japan); Koichi, Miwa [Houju Memorial Hospital, Nomi, Japan, 11-71 Midorigaoka, Nomi, Ishikawa 923-1226 (Japan); Takanori, Hattori [Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Otsu, Japan, Seta Tsukinowa-cho, Otsu, Shiga 520-2192 (Japan)

    2011-08-10

    Development from chronic inflammation to Barrett's adenocarcinoma is known as one of the inflammation-related carcinogenesis routes. Gastroesophageal reflux disease induces regurgitant esophagitis, and esophageal mucosa is usually regenerated by squamous epithelium, but sometimes and somewhere replaced with metaplastic columnar epithelium. Specialized columnar epithelium, so-called Barrett's epithelium (BE), is a risk factor for dysplasia and adenocarcinoma in esophagus. Several experiments using rodent model inducing duodenogastroesophageal reflux or duodenoesophageal reflux revealed that columnar epithelium, first emerging at the proliferative zone, progresses to dysplasia and finally adenocarcinoma, and exogenous carcinogen is not necessary for cancer development. It is demonstrated that duodenal juice rather than gastric juice is essential to develop esophageal adenocarcinoma in not only rodent experiments, but also clinical studies. Antireflux surgery and chemoprevention by proton pump inhibitors, nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, green tea, retinoic acid and thioproline showed preventive effects on the development of Barrett's adenocarcinoma in rodent models, but it remains controversial whether antireflux surgery could regress BE and prevent esophageal cancer in clinical observation. The Chemoprevention for Barrett's Esophagus Trial (CBET), a phase IIb, multicenter, randomized, double-masked study using celecoxib in patients with Barrett's dysplasia failed to prove to prevent progression of dysplasia to cancer. The AspECT (Aspirin Esomeprazole Chemoprevention Trial), a large multicenter phase III randomized trial to evaluate the effects of esomeprazole and/or aspirin on the rate of progression to high-grade dysplasia or adenocarcinoma in patients with BE is now ongoing.

  9. Medium-term multi-organ carcinogenesis bioassay of ethyl tertiary-butyl ether in rats.

    Science.gov (United States)

    Hagiwara, Akihiro; Doi, Yuko; Imai, Norio; Nakashima, Hironao; Ono, Takahiro; Kawabe, Mayumi; Furukawa, Fumio; Tamano, Seiko; Nagano, Kasuke; Fukushima, Shoji

    2011-11-18

    The modifying potential of ethyl tertiary-butyl ether (ETBE) on tumor development was investigated in a medium-term multi-organ carcinogenesis bioassay using male F344 rats. Animals were sequentially given 5 carcinogens with different target sites in the first 4 weeks for multi-organ initiation. After one week they received ETBE by gavage at dose levels of 0 (control), 300 or 1000mg/kg/day until experimental week 28. Further groups were also given ETBE at doses of 0 or 1000mg/kg/day without prior carcinogen application. Incidences and multiplicities of follicular cell hyperplasias and neoplasms in the thyroid were significantly increased at dose levels of more than 300mg/kg/day. Combined incidences of squamous cell hyperplasias and papillomas of the forestomach were also significantly increased at 300 and 1000mg/kg/day. Incidences and multiplicities of adenocarcinomas in the colon were increased at 1000mg/kg/day. The numbers and areas of glutathione S-transferase placental form (GST-P) positive foci per unit area of the liver sections, and the incidence of hepatocellular adenomas were also significantly increased at 1000mg/kg/day, along with multiplicities of atypical hyperplasias of renal tubules of the kidney and the incidence of papillomatosis of the urinary bladder. This latter lesion was also seen at low incidence at 1000mg/kg/day without initiation. Thus, the current results indicate that ETBE has tumor promoting potential for the thyroid and forestomach at dose levels of 300mg/kg/day and more, and for the colon, liver, kidney and urinary bladder at 1000mg/kg/day, under the present experimental conditions.

  10. Early-Stage Induction of SWI/SNF Mutations during Esophageal Squamous Cell Carcinogenesis.

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    Hidetsugu Nakazato

    Full Text Available The SWI/SNF chromatin remodeling complex is frequently inactivated by somatic mutations of its various components in various types of cancers, and also by aberrant DNA methylation. However, its somatic mutations and aberrant methylation in esophageal squamous cell carcinomas (ESCCs have not been fully analyzed. In this study, we aimed to clarify in ESCC, what components of the SWI/SNF complex have somatic mutations and aberrant methylation, and when somatic mutations of the SWI/SNF complex occur. Deep sequencing of components of the SWI/SNF complex using a bench-top next generation sequencer revealed that eight of 92 ESCCs (8.7% had 11 somatic mutations of 7 genes, ARID1A, ARID2, ATRX, PBRM1, SMARCA4, SMARCAL1, and SMARCC1. The SMARCA4 mutations were located in the Forkhead (85Ser>Leu and SNF2 family N-terminal (882Glu>Lys domains. The PBRM1 mutations were located in a bromodomain (80Asn>Ser and an HMG-box domain (1,377Glu>Lys. For most mutations, their mutant allele frequency was 31-77% (mean 61% of the fraction of cancer cells in the same samples, indicating that most of the cancer cells in individual ESCC samples had the SWI/SNF mutations on one allele, when present. In addition, a BeadChip array analysis revealed that a component of the SWI/SNF complex, ACTL6B, had aberrant methylation at its promoter CpG island in 18 of 52 ESCCs (34.6%. These results showed that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.

  11. Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene.

    Science.gov (United States)

    Song, Xiaoyu; Siriwardhana, Nalin; Rathore, Kusum; Lin, Degui; Wang, Hwa-Chain Robert

    2010-05-01

    Breast cancer is the most common type of cancer among women in northern America and northern Europe; dietary prevention is a cost-efficient strategy to reduce the risk of this disease. To identify dietary components for the prevention of human breast cancer associated with long-term exposure to environmental carcinogens, we studied the activity of grape seed proanthocyanidin extract (GSPE) in suppression of cellular carcinogenesis induced by repeated exposures to low doses of environmental carcinogens. We used combined carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), at picomolar concentrations, to repeatedly treat noncancerous, human breast epithelial MCF10A cells to induce cellular acquisition of cancer-related properties of reduced dependence on growth factors, anchorage-independent growth, and acinar-conformational disruption. Using these properties as biological target endpoints, we verified the ability of GSPE to suppress combined NNK- and B[a]P-induced precancerous cellular carcinogenesis and identified the minimal, noncytotoxic concentration of GSPE required for suppressing precancerous cellular carcinogenesis. We also identified that hydroxysteroid-11-beta-dehydrogenase 2 (HSD11B2) may play a role in NNK- and B[a]P-induced precancerous cellular carcinogenesis, and its expression may act as a molecular target endpoint in GSPE's suppression of precancerous cellular carcinogenesis. And, the ability of GSPE to reduce gene expression of cytochrome-P450 enzymes CYP1A1 and CYP1B1, which can bioactivate NNK and B[a]P, possibly contributes to the preventive mechanism for GSPE in suppression of precancerous cellular carcinogenesis. Our model system with biological and molecular target endpoints verified the value of GSPE for the prevention of human breast cell carcinogenesis induced by repeated exposures to low doses of multiple environmental carcinogens. (c) 2010 Wiley-Liss, Inc.

  12. Insights into the field carcinogenesis of ovarian cancer based on the nanocytology of endocervical and endometrial epithelial cells.

    Science.gov (United States)

    Damania, Dhwanil; Roy, Hemant K; Kunte, Dhananja; Hurteau, Jean A; Subramanian, Hariharan; Cherkezyan, Lusik; Krosnjar, Nela; Shah, Maitri; Backman, Vadim

    2013-09-01

    Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late-stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at-risk women as they preferentially target low-grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (Ld ). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in Ld (% fold-increase > 50%, p-value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with micro-RNA expression data.

  13. HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure.

    Science.gov (United States)

    Stypula-Cyrus, Yolanda; Damania, Dhwanil; Kunte, Dhananjay P; Cruz, Mart Dela; Subramanian, Hariharan; Roy, Hemant K; Backman, Vadim

    2013-01-01

    Normal cell function is dependent on the proper maintenance of chromatin structure. Regulation of chromatin structure is controlled by histone modifications that directly influence chromatin architecture and genome function. Specifically, the histone deacetylase (HDAC) family of proteins modulate chromatin compaction and are commonly dysregulated in many tumors, including colorectal cancer (CRC). However, the role of HDAC proteins in early colorectal carcinogenesis has not been previously reported. We found HDAC1, HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. Furthermore, we observed that HDAC2 up-regulation is one of the earliest events in CRC carcinogenesis and observed this in human field carcinogenesis, the azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a novel and important early event in CRC, which may serve as a biomarker. HDAC inhibitors (HDACIs) interfere with tumorigenic HDAC activity; however, the precise mechanisms involved in this process remain to be elucidated. We confirmed that HDAC inhibition by valproic acid (VPA) targeted the more aggressive cell line. Using nuclease digestion assays and transmission electron microscopy imaging, we observed that VPA treatment induced greater changes in chromatin structure in the more aggressive cell line. Furthermore, we used the novel imaging technique partial wave spectroscopy (PWS) to quantify nanoscale alterations in chromatin. We noted that the PWS results are consistent with the biological assays, indicating a greater effect of VPA treatment in the more aggressive cell type. Together, these results demonstrate the importance of HDAC activity in early carcinogenic events and the unique role of higher-order chromatin structure in determining cell tumorigenicity.

  14. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect.

    Science.gov (United States)

    San-Millán, Iñigo; Brooks, George A

    2017-02-01

    Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production ('lactagenesis'), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate-producing ('lactagenic') cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a 'lactormone') with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery. © The Author 2016. Published by Oxford University Press.

  15. Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer.

    Science.gov (United States)

    Lando, Malin; Holden, Marit; Bergersen, Linn C; Svendsrud, Debbie H; Stokke, Trond; Sundfør, Kolbein; Glad, Ingrid K; Kristensen, Gunnar B; Lyng, Heidi

    2009-11-01

    Integrative analysis of gene dosage, expression, and ontology (GO) data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these patients were also analyzed with the Illumina expression method to confirm the gene expression results. An independent cohort of 41 patients was used for validation of gene expressions associated with clinical outcome. Statistical analysis identified 29 recurrent gains and losses and 3 losses (on 3p, 13q, 21q) associated with poor outcome after chemoradiotherapy. The intratumor heterogeneity, assessed from the gene dosage profiles, was low for these alterations, showing that they had emerged prior to many other alterations and probably were early events in carcinogenesis. Integration of the alterations with gene expression and GO data identified genes that were regulated by the alterations and revealed five biological processes that were significantly overrepresented among the affected genes: apoptosis, metabolism, macromolecule localization, translation, and transcription. Four genes on 3p (RYBP, GBE1) and 13q (FAM48A, MED4) correlated with outcome at both the gene dosage and expression level and were satisfactorily validated in the independent cohort. These integrated analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. Further mapping of the connections among genetic events, drivers, and biological processes suggested that each individual event stimulates specific processes in carcinogenesis through the coordinated control of multiple genes. The present results may provide novel therapeutic opportunities of both early and advanced stage cervical cancers.

  16. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response.

    Science.gov (United States)

    Ericksen, Russell E; Rose, Shannon; Westphalen, Christoph Benedikt; Shibata, Wataru; Muthupalani, Sureshkumar; Tailor, Yagnesh; Friedman, Richard A; Han, Weiping; Fox, James G; Ferrante, Anthony W; Wang, Timothy C

    2014-03-01

    To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.

  17. Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice.

    Science.gov (United States)

    Miyazaki, Tsuneyuki; Shirakami, Yohei; Kubota, Masaya; Ideta, Takayasu; Kochi, Takahiro; Sakai, Hiroyasu; Tanaka, Takuji; Moriwaki, Hisataka; Shimizu, Masahito

    2016-03-01

    Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects.

  18. Carcinogenesis switched on by DNA cross-link between complementary bases aroused by aflatoxin and N-nitroso compounds

    Institute of Scientific and Technical Information of China (English)

    DAI Qianhuan; LU Ping; PENG Shaohua; ZHANG Qingrong

    2003-01-01

    The di-region theory put forward by Dai Qianhuan, a molecular mechanism of chemical carcinogenesis, concluded that the carcinogenesis induced by most of the environmental carcinogens is switched on by the cross-linking between DNA complementary bases aroused by the bifunctional alkylation of their metabolic intermediates. It was evidenced in this paper with DNA filter elution method that one carcinogenic mycotoxin, aflatoxin G1, four carcinogenic N-nitroso compounds, N-nitrosodiethyl-amine, N-nitrosodibutyl-amine, N-nitrosomorpholine and N-nitrosopyrrolidine, one carcinogenic diazo color, 4-dimethylaminodiazobenzene and one carcinogenic nitrogen-containing heterocyclic compound, quinoline, all induced DNA interstrands cross-linking with dosage correlation after metabolic activation. However, the non-carcinogens in corresponding series for control, aflatoxin B2, N-nitroso-diphenylamine, 4′-bromo-4-dimethylaminodiazobenzene and isoquinoline, cannot induce DNA interstrands cross-linking at all in the same condition. A method for the determination of cross-linking ratio between DNA complementary bases in total DNA interstrands cross-linking, which has no monitoring measure as yet, has been established for the first time based upon a 24 hour repairing experiment. The DNA complementary pair cross-linking ratio induced by a metabolized carcinogen is correlated with its carcinogenic potential. It may be concluded that the mutations including point and frameshift mutagenesis induced by aflatoxin and other carcinogens are switched on by their corresponding cross-linking base pair between complementary bases. Therefore, the di-region theory is a reasonable molecular mechanism for chemical, endogenous and physical carcinogenesis.

  19. Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats

    Science.gov (United States)

    Kakehashi, Anna; Yoshida, Midori; Tago, Yoshiyuki; Ishii, Naomi; Okuno, Takahiro; Gi, Min; Wanibuchi, Hideki

    2016-01-01

    Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA) initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w.)/day) PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG), respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3%, and more pronouncedly, at 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA. PMID:27827907

  20. Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis

    Directory of Open Access Journals (Sweden)

    Van Veldhuizen Peter J

    2011-01-01

    Full Text Available Abstract Background Despite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood. Results We show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1. Conclusions In conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.

  1. A novel mouse model for colitis-associated colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sulfate sodium

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo Wang; Dong-Fei Wang; Bing-Jian Lv; Jian-Min Si

    2004-01-01

    AIM: To develop an efficient animal colitis-associated carcinogenesis model and to detect the expression of β-catenin and p53 in this new model.METHODS: Dysplasia and cancer were investigated in mice pretreated with a single intraperitoneal injection of 20 mg/kg body mass of 1,2-dimethylhydrazine prior to three repetitive oral administrations of 30 g/L dextran sulfate sodium to give conditions similar to the clinically observed active and remission phases. Immunohistochemical staining of β-catenin and p53 was performed on paraffin-imbedded specimens of animals with cancer and/or dysplasia, those without dysplasia and the normal control animals.RESULTS: At wk 11, four early-invasive adenocarcinomas and 36 dysplasia were found in 10 (90.9%) of the 11 mice that underwent 1,2-dimethylhydrazine-pretreatment with 3 cycles of 30 g/L dextran sulfate sodium-exposure. Dysplasia and/or cancer occurred as flat lesions or as dysplasia-associated lesion or mass (DALM) as observed in humans. Colorectal carcinogenesis occurred primarily on the distal portion of the large intestine. No dysplasia and/or cancer lesion was observed in the control groups with 1,2-dimethylhydrazine pretreatment or 3 cycles of 30 g/L dextran sulfate sodium exposure alone. Immunohistochemical investigation revealed that β-catenin was translocated from cell membrane to cytoplasm and/or nucleus in 100% of cases with dysplasia and neoplasm, while normal membrane staining was observed in cases without dysplasia and the normal control animals. Nuclear expression of p53 was not detected in specimens.CONCLUSION: A single dose of procarcinogen followed by induction of chronic ulcerative colitis results in a high incidence of colorectal dysplasia and cancer. Abnormal expression of β-catenin occurs frequently in dysplasia and cancer. This novel mouse model may provide an excellent vehicle for studying colitis-related colon carcinogenesis.

  2. Prevention of azoxymethane/dextran sodium sulfate-induced mouse colon carcinogenesis by processed Aloe vera gel.

    Science.gov (United States)

    Im, Sun-A; Kim, Ji-Wan; Kim, Hee-Suk; Park, Chan-Su; Shin, Eunju; Do, Seon-Gil; Park, Young In; Lee, Chong-Kil

    2016-11-01

    The preventive effect of a processed Aloe vera gel (PAG) on colon carcinogenesis was examined using an azoxymethane (AOM)-initiated and dextran sodium sulfate (DSS)-promoted mouse colon carcinogenesis model. Oral administration of PAG (200, or 400mg/kg/day) significantly reduced the multiplicity of colonic adenomas and adenocarcinomas compared with the AOM/DSS only-treated mice. In the mice treated with 400mg/kg of PAG, adenoma and adenocarcinoma development was reduced to 80% and 60%, respectively, compared to 100% in the PAG-untreated AOM/DSS-treated mice. Western blot analysis using colon extracts showed that PAG reduced the activation of nuclear factor kappa B (NF-κB), resulting in the inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression. PAG appeared to inhibit the NF-κB activation through the activation of peroxisome proliferator-activated receptor gamma. PAG also inhibited the expression and phosphorylation of signal transducer and activator of transcription 3, which is known to connect inflammation and cancer. In addition, PAG inhibited cell cycle progression-inducing cellular factors, such as extracellular signal-regulated kinases 1/2, cyclin-dependent kinase 4, and cyclin D1. On the other hand, PAG increased the expression of Caudal-related homeobox transcription factor 2, which is known to be a tumor suppressor in colorectal cancer. These findings show that PAG suppresses colitis-related colon carcinogenesis by inhibiting both chronic inflammation and cell cycle progression in the colon. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure.

    Directory of Open Access Journals (Sweden)

    Yolanda Stypula-Cyrus

    Full Text Available Normal cell function is dependent on the proper maintenance of chromatin structure. Regulation of chromatin structure is controlled by histone modifications that directly influence chromatin architecture and genome function. Specifically, the histone deacetylase (HDAC family of proteins modulate chromatin compaction and are commonly dysregulated in many tumors, including colorectal cancer (CRC. However, the role of HDAC proteins in early colorectal carcinogenesis has not been previously reported. We found HDAC1, HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. Furthermore, we observed that HDAC2 up-regulation is one of the earliest events in CRC carcinogenesis and observed this in human field carcinogenesis, the azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a novel and important early event in CRC, which may serve as a biomarker. HDAC inhibitors (HDACIs interfere with tumorigenic HDAC activity; however, the precise mechanisms involved in this process remain to be elucidated. We confirmed that HDAC inhibition by valproic acid (VPA targeted the more aggressive cell line. Using nuclease digestion assays and transmission electron microscopy imaging, we observed that VPA treatment induced greater changes in chromatin structure in the more aggressive cell line. Furthermore, we used the novel imaging technique partial wave spectroscopy (PWS to quantify nanoscale alterations in chromatin. We noted that the PWS results are consistent with the biological assays, indicating a greater effect of VPA treatment in the more aggressive cell type. Together, these results demonstrate the importance of HDAC activity in early carcinogenic events and the unique role of higher-order chromatin structure in determining cell tumorigenicity.

  4. Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats

    Directory of Open Access Journals (Sweden)

    Anna Kakehashi

    2016-11-01

    Full Text Available Pueraria mirifica (PM, a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w./day PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG, respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3%, and more pronouncedly, at 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA.

  5. Carcinogenesis and Inflammatory Effects of Plutonium-Nitrate Retention in an Exposed Nuclear Worker and Beagle Dogs.

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, Christopher E. [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Wang, Xihai [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Robinson, Robert J. [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Brooks, Antone L. [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Lovaglio, Jamie A. [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Patton, Kristin M. [Battelle Toxicology Northwest, Richland, WA (United States); McComish, Stacey [United States Transuranium and Uranium Registries, Washington State University, College of Pharmacy, Richland, WA (United States); Tolmachev, Sergei Y. [United States Transuranium and Uranium Registries, Washington State University, College of Pharmacy, Richland, WA (United States); Morgan, William F. [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

    2014-01-01

    The genetic and inflammatory response pathways elicited following plutonium exposure in archival lung tissue of an occupationally exposed human and experimentally exposed beagle dogs were investigated. These pathways include: tissue injury, apoptosis and gene expression modifications related to carcinogenesis and inflammation. In order to determine which pathways are involved, multiple lung samples from a plutonium exposed worker (Case 0269), a human control (Case 0385), and plutonium exposed beagle dogs were examined using histological staining and immunohistochemistry. Examinations were performed to identify target tissues at risk of radiation-induced fibrosis, inflammation, and carcinogenesis. Case 0269 showed interstitial fibrosis in peripheral and subpleural regions of the lung, but no pulmonary tumors. In contrast, the dogs with similar and higher doses showed pulmonary tumors primarily in brochiolo-alveolar, peripheral and subpleural alveolar regions. The TUNEL assay showed slight elevation of apoptosis in tracheal mucosa, tumor cells, and nuclear debris was present in the inflammatory regions of alveoli and lymph nodes of both the human and the dogs. The expression of apoptosis and a number of chemokine/cytokine genes was slightly but not significantly elevated in protein or gene levels compared to that of the control samples. In the beagles, mucous production was increased in the airway epithelial goblet cells and glands of trachea, and a number of chemokine/cytokine genes showed positive immunoreactivity. This analysis of archival tissue from an accidentally exposed worker and in a large animal model provides valuable information on the effects of long-term retention of plutonium in the respiratory tract and the histological evaluation study may impact mechanistic studies of radiation carcinogenesis.

  6. Promotion of liver and kidney carcinogenesis by ethyl tertiary-butyl ether (ETBE) in male Wistar rats.

    Science.gov (United States)

    Hagiwara, Akihiro; Doi, Yuko; Imai, Norio; Suguro, Mayuko; Kawabe, Mayumi; Furukawa, Fumio; Tamano, Seiko; Nagano, Kasuke; Fukushima, Shoji

    2015-10-01

    Tumor-promoting effects of ethyl tertiary-butyl ether (ETBE) were investigated in a 2-stage carcinogenesis bioassay with regard to hepatic and renal carcinogenesis in rats. Male 6-week-old Wistar rats were given drinking water containing N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN), as an initiator, at a dose of 500 ppm for 2 weeks. Starting one week thereafter, the animals were administered ETBE at dose levels of 0 (control), 100, 300, 500 or 1,000 mg/kg/day by gavage for 19 weeks from week 4 to 22. Necropsy of all rats was performed at week 23, and livers and kidneys were examined histopathologically. Incidences of hepatocellular adenomas, and those of combined hepatocellular adenomas and carcinomas were significantly elevated in rats given 1,000 mg/kg/day ETBE, but not 100‒500 mg/kg/day ETBE, and there was a significant increase in the average numbers of lesions. No significant differences in incidences and average numbers of renal tubule neoplasms were found in rats administered 100‒1,000 mg/kg/day ETBE. However, the average numbers of atypical tubule hyperplasias, considered to be preneoplastic lesions, were significantly increased in rats given ETBE at 1,000 mg/kg/day, but not in rats given 500 mg/kg/day or lower doses. Thus, these results imply that ETBE has hepatic and renal tumor-promoting activities that affect EHEN-induced carcinogenesis in male rats, and the no-observed-effect level is 500 mg/kg/day under the present experimental conditions.

  7. Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

    Directory of Open Access Journals (Sweden)

    Kimura Shioko

    2012-12-01

    Full Text Available Abstract Background The CCAAT/enhancer binding proteins (C/EBPs play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. Methods A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined. Results A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse. Conclusions The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.

  8. The Applicability of a Short-term Test for Detection of Modifying Effects of Dietary Factors in Rodent Colon Carcinogenesis

    DEFF Research Database (Denmark)

    Kristiansen, Eva

    HCl or AOM for their modulating effect on the development of aberrant crypt foci (ACF). Furthermore the heterocyclic amines IQ and PhIP were introduced in the assay as inducers of ACF in mice and rats and their role in colon carcinogenesis in mice was investigated. ACF were found to be induced...... in rodent colon by the colon carcinogens DMH-2HC1, AOM, IQ, and PhIP and it was shown that the incidence of the induced ACF could be modulated by dietary components such as sucrose, dietary fibre, and starch....

  9. Inhibitory Effects of Gymnema (Gymnema sylvestre Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Ken Yasukawa

    2014-01-01

    Full Text Available Ethanol extracts of gymnema (Gymnema sylvestre leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50–555 nmol/ear.

  10. Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis

    OpenAIRE

    Ken Yasukawa; Sakiko Okuda; Yasuhito Nobushi

    2014-01-01

    Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice....

  11. Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis.

    Science.gov (United States)

    Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

    2014-01-01

    Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50-555 nmol/ear.

  12. Early diagnosis of colorectal cancer in rats with DMH induced carcinogenesis by means of urine autofluorescence analysis.

    Science.gov (United States)

    Šteffeková, Zuzana; Birková, Anna; Bomba, Alojz; Mareková, Mária

    2014-01-01

    Cancer is one of the most highlighted topics of current research. Early detection of this disease allows more effective therapy, hence higher chance of cure. Application of fluorescence spectral techniques into oncological diagnostic is one of the potential alternatives. Chemically induced carcinogenesis in rats is widely used model for exploration of various aspects of colorectal cancer. This study shows value of discriminate analysis of urine fluorescent fingerprint between healthy control group of rats and those with dimethylhydrazine induced early lesions of colorectal cancer. Using fluorescence spectroscopy, significant difference (P < 0.05) between both of group was achieved.

  13. Mucin-depleted foci (MDF) in the colon of rats treated with azoxymethane (AOM) are useful biomarkers for colon carcinogenesis.

    Science.gov (United States)

    Femia, Angelo Pietro; Dolara, Piero; Caderni, Giovanna

    2004-02-01

    Crypt foci with absent or scant mucous production (mucin-depleted foci, MDF) were recently described by our group in the colon of azoxymethane (AOM)-treated rats. Since MDF are dysplastic and easy to quantify, we think that MDF are pre-neoplastic lesions that could be used as biomarkers for carcinogenesis. To test this hypothesis, we studied MDF in azoxymethane (AOM)-initiated rats treated with cholic acid (CHA), a promoter of colon carcinogenesis or with piroxicam (PXC), a colon cancer-inhibiting drug. Aberrant crypt foci (ACF) were determined as well. F344 male rats were treated with AOM (15 mg/kg x 2, s.c.) and then divided into: controls, which were fed AIN76 diet; CHA group, which was fed AIN76 diet containing CHA 0.5% w/w; PXC group, which was fed AIN76 diet containing PXC 0.02% w/w. Ten weeks after the first dose of AOM, the total number of MDF was significantly increased in rats treated with CHA (PMDF/colon were 6.10 +/- 1.26, 10.59 +/- 1.96 and 1.31 +/- 0.21 in controls, CHA and PXC groups, respectively, means +/- SE). The multiplicity of MDF was also increased in CHA-treated rats. On the contrary, ACF multiplicity was significantly decreased by CHA. In PXC-treated rats there were fewer ACF with lower multiplicity. The effect of PXC was also investigated 15 weeks after the first AOM dose and the results showed that the total number of MDF in the PXC group was significantly lower than in controls. The number of 'large' MDF, formed by 12 or more crypts, was also reduced (PMDF were 1.7 +/- 0.5 and 0.4 +/- 0.2 in control and PXC groups, respectively). Since CHA promotes and PXC reduces colon cancer, MDF are correlated with carcinogenesis and can be proposed as endpoints to study the modulation of colon carcinogenesis in short-term experiments.

  14. PBX1 attributes as a determinant of connexin 32 downregulation in Helicobacter pylori-related gastric carcinogenesis.

    Science.gov (United States)

    Liu, Xiao-Ming; Xu, Can-Xia; Zhang, Lin-Fang; Huang, Li-Hua; Hu, Ting-Zi; Li, Rong; Xia, Xiu-Juan; Xu, Lin-Yong; Luo, Ling; Jiang, Xiao-Xia; Li, Ming

    2017-08-07

    To clarify the mechanisms of connexin 32 (Cx32) downregulation by potential transcriptional factors (TFs) in Helicobacter pylori (H. pylori)-associated gastric carcinogenesis. Approximately 25 specimens at each developmental stage of gastric carcinogenesis [non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric carcinoma (GC)] with H. pylori infection [H. pylori (+)] and 25 normal gastric mucosa (NGM) without H. pylori infection [H. pylori (-)] were collected. After transcriptional factor array analysis, the Cx32 and PBX1 expression levels of H. pylori-infected tissues from the developmental stages of GC and NGM with no H. pylori infection were measured by real-time polymerase chain reaction (RT-PCR) and Western blot analysis. Regarding H. pylori-infected animal models, the Cx32 and PBX1 mRNA expression levels and correlation between the gastric mucosa from 10 Mongolian gerbils with long-term H. pylori colonization and 10 controls were analyzed. PBX1 and Cx32 mRNA and protein levels were further studied under the H. pylori-infected condition as well as PBX1 overexpression and knockdown conditions in vitro. Incremental PBX1 was first detected by TF microarray in H. pylori-related gastric carcinogenesis. The identical trend of PBX1 and Cx32 expression was confirmed in the developmental stages of H. pylori-related clinical specimens. The negative correlation of PBX1 and Cx32 was confirmed in H. pylori-infected Mongolian gerbils. Furthermore, decreased PBX1 expression was detected in the normal gastric epithelial cell line GES-1 with H. pylori infection. Enforced overexpression or RNAi-mediated knockdown of PBX1 contributed to the diminished or restored Cx32 expression in GES-1 and the gastric carcinoma cell line BGC823, respectively. Finally, dual-luciferase reporter assay in HEK293T cells showed that Cx32 promoter activity decreased by 30% after PBX1 vector co-transfection, indicating PBX1 as a transcriptional downregulator

  15. Identification of a long non-coding RNA NR_026689 associated with lung carcinogenesis induced by NNK

    OpenAIRE

    Wu, Jianjun; Li, Xun; Xu, Yiqin; Yang, Ti; Yang, Qiaoyuan; Yang, Chengfeng; Jiang, Yiguo

    2016-01-01

    Long non-coding RNAs (lncRNA) are thought to be important epigenetic regulators involved in the development of a variety of cancers. Alterations in lncRNA expression are associated with exposure to chemical carcinogens. However, it is still unclear whether lncRNA expression during lung carcinogenesis is induced by chemical carcinogens. In this study, using NNK-induced rat lung cancer model established by our previous study, we determined the lncRNA expression profiles, and an alteration in ln...

  16. Beta-catenin accelerates human papilloma virus type-16 mediated cervical carcinogenesis in transgenic mice.

    Directory of Open Access Journals (Sweden)

    Gülay Bulut

    Full Text Available Human papilloma virus (HPV is the principal etiological agent of cervical cancer in women, and its DNA is present in virtually all of these tumors. However, exposure to the high-risk HPV types alone is insufficient for tumor development. Identifying specific collaborating factors that will lead to cervical cancer remains an unanswered question, especially because millions of women are exposed to HPV. Our earlier work using an in vitro model indicated that activation of the canonical Wnt pathway in HPV-positive epithelial cells was sufficient to induce anchorage independent growth. We therefore hypothesized that constitutive activation of this pathway might function as the "second hit." To address this possibility, we developed two double-transgenic (DT mouse models, K14-E7/ΔN87βcat and K14-HPV16/ΔN87βcat that express either the proteins encoded by the E7 oncogene or the HPV16 early region along with constitutively active β-catenin, which was expressed by linking it to the keratin-14 (K14 promoter. We initiated tumor formation by treating all groups with estrogen for six months. Invasive cervical cancer was observed in 11% of the K14-ΔN87βcat mice, expressing activated β-catenin and in 50% of the animals expressing the HPV16 E7 oncogene. In double-transgenic mice, coexpression of β-catenin and HPV16 E7 induced invasive cervical cancer at about 7 months in 94% of the cases. We did not observe cervical cancer in any group unless the mice were treated with estrogen. In the second model, K14-HPV16 mice suffered cervical dysplasias, but this phenotype was not augmented in HPV16/ΔN87βcat mice. In summary, the phenotypes of the K14-E7/ΔN87βcat mice support the hypothesis that activation of the Wnt/β-catenin pathway in HPV-associated premalignant lesions plays a functional role in accelerating cervical carcinogenesis.

  17. Influence of Ionizing Radiation on Stromal-Epithelial Communication in Esophageal Carcinogenesis

    Science.gov (United States)

    Huff, Janice; Patel, Zarana; Grugan, Katharine; Rustgi, Anil; Cucinotta, Francis A.

    Esophageal cancer is the 6th leading cause of cancer death worldwide and is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. A connection with ionizing radiation exposure is revealed by the high excess relative risk for esophageal squamous cell carcinoma observed in the survivors of the atomic bomb detonations in Japan. Esophageal carcinomas are also seen as secondary malignancies in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely responsive to treatment. In normal epithelium, the stromal microenvironment is essential for the maintenance and modulation of cell growth and differentiation. Cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibrob-lasts (Okawa et al., Genes Dev. 2007. 21: 2788-2803). We examined how irradiation of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. These assays were conducted in modified Boyden chambers using conditioned media from irradiated fibroblasts. Our results using low LET gamma radiation showed a dose-dependent increase in migration of epithelial

  18. The Histogenesis of the Third Pathway of Colonic Carcinogenesis in Rats.

    Science.gov (United States)

    Rubio, Carlos A

    2017-03-01

    Conventional (tubular or villous) adenomas, and the more recently described serrated adenomas, are non-invasive neoplasias that precede colon carcinomas in carcinogen-treated rats. In contrast, the histological steps antedating carcinomas in gut-associated lymphoid tissue (GALT) in rats, i.e. the third pathway of colonic carcinogenesis, remain unidentified. Aim of the study was to investigate the histological changes preceding colonic GALT carcinomas in Sprague-Dawley (SD) rats. Archived sections from previous experiments showing GALT mucosal domains in 292 rats were re-evaluated: 276 were injected with 1,2-dimethylhydrazine (DMH) suspended in ethylenedia-minetetra-acetic acid (EDTA), and 16 were controls (8 EDTA-treated, and 8 untreated). A total of 402 colonic GALT mucosal domains were found in the 292 rats: 382 in 276 DMH-treated, 10 in eight EDTA-treated, and 10 in eight-untreated rats. In DMH-treated rats, corrupted crypts (CCS; i.e. with asymmetric fission or abnormal crypt-alignment) were recorded in 50% of the GALT domains (15% had no dysplasia and 35% had epithelial dysplasia). Adenomas on top of GALT domains were found in 7%, and GALT carcinomas in 53%. Histology of the 146 colonic GALT carcinomas revealed highly differentiated carcinomas or signet-ring cell carcinomas. EDTA-treated and untreated animals showed no dysplastic CCS, or other neoplasia. This study demonstrated that GALT mucosal domains in carcinogen-treated rats often develop dysplastic CCS. Non-dysplastic CCS appear to act as scaffolds for the top-down replacement/transformation by dysplastic cells. Importantly, highly differentiated carcinomas were seen to evolve from dysplastic CCS and from adenomas, and signet-ring cell carcinomas from dysplastic goblet cells present at the base of crypts. This is the first study showing that non-invasive neoplastic lesions (dysplastic CCS and adenomas) antedate colonic GALT carcinomas in DMH-treated SD rats. The DMH-SD paradigm permits detailed study of

  19. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation.

    Science.gov (United States)

    Katoh, Y; Katoh, M

    2009-09-01

    Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.

  20. miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis.

    Science.gov (United States)

    Benderska, Natalya; Dittrich, Anna-Lena; Knaup, Sabine; Rau, Tilman T; Neufert, Clemens; Wach, Sven; Fahlbusch, Fabian B; Rauh, Manfred; Wirtz, Ralph M; Agaimy, Abbas; Srinivasan, Swetha; Mahadevan, Vijayalakshmi; Rümmele, Petra; Rapti, Emmanouela; Gazouli, Maria; Hartmann, Arndt; Schneider-Stock, Regine

    2015-09-01

    Longstanding ulcerative colitis (UC) bears a high risk for development of UC-associated colorectal carcinoma (UCC). The inflammatory microenvironment influences microRNA expression, which in turn deregulates target gene expression. microRNA-26b (miR-26b) was shown to be instrumental in normal tissue growth and differentiation. Thus, we aimed to investigate the impact of miR-26b in inflammation-associated colorectal carcinogenesis. Two different cohorts of patients were investigated. In the retrospective group, a tissue microarray with 38 samples from 17 UC/UCC patients was used for miR-26b in situ hybridization and quantitative reverse transcription polymerase chain reaction analyses. In the prospective group, we investigated miR-26b expression in 25 fresh-frozen colon biopsies and corresponding serum samples of 6 UC and 15 non-UC patients, respectively. In silico analysis, Ago2-RNA immunoprecipitation, luciferase reporter assay, quantitative reverse transcription polymerase chain reaction examination, and miR-26b mimic overexpression were employed for target validation. miR-26b expression was shown to be upregulated with disease progression in tissues and serum of UC and UCC patients. Using miR-26b and Ki-67 expression levels, an UCC was predicted with high accuracy. We identified 4 novel miR-26b targets (DIP1, MDM2, CREBBP, BRCA1). Among them, the downregulation of the E3 ubiquitin ligase DIP1 was closely related to death-associated protein kinase stabilization along the normal mucosa-UC-UCC sequence. In silico functional pathway analysis revealed that the common cellular pathways affected by miR-26b are highly related to cancerogenesis and the development of gastrointestinal diseases. We suggest that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. Because miR-26b expression is downregulated in sporadic colon cancer, it could discriminate between UCC and the sporadic cancer type.

  1. hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis

    Directory of Open Access Journals (Sweden)

    Snijders Peter JF

    2010-06-01

    Full Text Available Abstract Background Activation of telomerase resulting from deregulated hTERT expression is a key event during high-risk human papillomavirus (hrHPV-induced cervical carcinogenesis. In the present study we examined hTERT promoter activity and its relation to DNA methylation as one of the potential mechanisms underlying deregulated hTERT transcription in hrHPV-transformed cells. Methods Using luciferase reporter assays we analyzed hTERT promoter activity in primary keratinocytes, HPV16- and HPV18-immortalized keratinocyte cell lines and cervical cancer cell lines. In the same cells as well as cervical specimens we determined hTERT methylation by bisulfite sequencing analysis of the region spanning -442 to +566 (relative to the ATG and quantitative methylation specific PCR (qMSP analysis of two regions flanking the hTERT core promoter. Results We found that in most telomerase positive cells increased hTERT core promoter activity coincided with increased hTERT mRNA expression. On the other hand basal hTERT promoter activity was also detected in telomerase negative cells with no or strongly reduced hTERT mRNA expression levels. In both telomerase positive and negative cells regulatory sequences flanking both ends of the core promoter markedly repressed exogenous promoter activity. By extensive bisulfite sequencing a strong increase in CpG methylation was detected in hTERT positive cells compared to cells with no or strongly reduced hTERT expression. Subsequent qMSP analysis of a larger set of cervical tissue specimens revealed methylation of both regions analyzed in 100% of cervical carcinomas and 38% of the high-grade precursor lesions, compared to 9% of low grade precursor lesions and 5% of normal controls. Conclusions Methylation of transcriptionally repressive sequences in the hTERT promoter and proximal exonic sequences is correlated to deregulated hTERT transcription in HPV-immortalized cells and cervical cancer cells. The detection of DNA

  2. Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis.

    Science.gov (United States)

    Qi, Cuiling; Lan, Haimei; Ye, Jie; Li, Weidong; Wei, Ping; Yang, Yang; Guo, Simei; Lan, Tian; Li, Jiangchao; Zhang, Qianqian; He, Xiaodong; Wang, Lijing

    2014-07-01

    Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2'-deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous

  3. Nucleos(t)ide analogues causes HBV S gene mutations and carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Meng-Lan Wang; Hong Tang

    2016-01-01

    BACKGROUND: The long-term use of nucleos(t)ide analogues causes drug resistance and mutations in the HBV reverse tran-scriptase (RT) region of the polymerase gene. The RT region overlaps the HBV surface gene (S gene) and therefore, the mutations in the RT region simultaneously modify S gene se-quence. Certain mutations in the RT region bring about trun-cated S proteins because the corresponding changed S gene en-codes a stop codon which results in the loss of a large portion of the C-terminal hydrophobic region of HBV surface protein. The rtA181T/sW172*, rtM204I/sW196* and rtV191I/sW182*are the most frequently reported drug-resistant mutations with C-terminal truncation, these mutations have oncogenic potential. DATA SOURCES: PubMed and Web of Science were searched using terms: “hepatitis B virus”, “HBV drug resistance muta-tion”, “HBV surface protein”, “HBV truncation”, “hepatocel-lular carcinoma”, “rtA181T/sW172*”, “rtM204I/sW196*”,“rtV191I/sW182*”, and relevant articles published in English in the past decades were reviewed. RESULTS: The rtA181T/sW172* and rtV191I/sW182* mu-tants occurred more frequently than the rtM204I/sW196* mu-tant both in chronic hepatitis B patients and the HBV-related hepatocellular carcinoma tissues. Although these mutations occur naturally, nucleos(t)ide analogues therapy is the main driving force. These mutations may exist alone or coexist with other HBV mutations. All these three mutants impair the vi-rion secretion and result in HBV surface protein retention and serum HBV DNA level reduction. These mutations possess potential carcinogenic properties. The three mutations are re-sistant to more than one nucleos(t)ide analogue and therefore, it is dififcult to treat the patients with the truncated mutations. CONCLUSIONS: Nucleos(t)ide analogues induce drug resis-tance and HBV S gene truncated mutations. These mutations have potential carcinogenesis.

  4. Carcinogenesis of asbestos switched on by inducing cross-linkage between DNA complementary pair bases

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Since the beginning of the 1980s, Dai Qianhuan predicted based upon his di-region theory that the carcinogenesis switched on by the so-called physical carcinogenic factors including radiation, asbestos and foreign matter implantation, is just initiated through the cross-linking between DNA complementary pair bases induced by them. In this note, it was evidenced with the DNA filter elution method that the oxygenase activated by asbestos induces the cross-linking between DNA inter-strands and DNA-protein with dosage correlation, in which over 80% of DNA inter-strand cross-link ratio account for the total cross-link ratio. Obviously, both of the cross-linkages are just induced by hydroxyl free radical, HO@, because the ferrous ion increased the cross-link ratios up to several times through Fenton reaction and vitamin C inhibited the cross-link ratios with factors of 8-9 by destroying the hydroxyl radical. Non-carcinogen but with lower free radical formation energy, pyrene, by culturing with asbestos gave 3-4 times cross-link ratios than the original ratios induced by asbestos only. Estradiol, an endogenous carcinogen, as a bio-electrophilic species but with higher free radical formation energy by culturing with asbestos, gave only 1.2 time cross-link ratios than expected ones. Ferrous ion which can increase HO@ concentration through Fenton reaction, increased the ratios to 2-2.5 times in the former case but only 1.2 time in the latter case. Vitamin C, a free radical scavenger, gave a powerful inhibition to the cross-linking with a factor of 8-11 in the former case but a weak inhibition with a factor of 1.2 only in the latter case. So, it is evidenced further that the cross-linkages induced by asbestos are originated from hydroxyl radical. Reasonable structures of the cross-linking products induced by asbestos or hydroxyl radical have been depicted based upon AM1 MO theory. These structures have been verified further by a reasonable explanation of the mutational

  5. [Biology of cancer cell-stroma interaction in carcinogenesis and cancer progression].

    Science.gov (United States)

    Fujita, S; Sugihara, H; Ito, R; Tsuchihashi, Y

    1984-03-01

    Cancer cells are dependent on physical and chemical supports of stroma no less than non-cancerous cells and tissues are. The role of stroma should, therefore, be important in genesis and progression of cancers growing in vivo. But this aspect underlying carcinogenesis and manifestation of human cancers has long been neglected or attracted less attention in the investigations of oncology. Focusing particular attention on parenchyma-stromal interaction in gastrointestinal mucosa, the authors have found that, quite unexpectedly, in normal gastric as well as intestinal mucosa of all the animal species so for studied, vascularity is always poorly developed in the generative cell zones. Cross-sectional area of vascular bed is markedly reduced in this zone. Application of Hagen-Poiseulle law revealed that the reduced total cross-sectional area, resulting in a rapid drop in hydrostatic pressure, creates here a situation particularly favorable for proliferating cell population. Since the transport of water soluble material together with tissue fluid through the capillary wall is driven by the hydrostatic pressure, the generative cell zones are found to be present at the site where the turnover of the material is the most active. Before the zone of the rapid pressure drop, there appears zone of relatively high intravascular hydrostatic pressure, where secretory function seems to be facilitated. This zone, as is well known, corresponds to glandular portion of the mucosa. After the zone of the rapid pressure drop (in surface of the mucosa), zone of a low intravascular hydrostatic pressure appears, where absorptive function is to be facilitated. Within such zones, in gastric mucosa surface epithelium and in intestinal mucosa absorptive villi cells are located. It is likely that architecture of gastrointestinal epithelium and vascular pattern in the stroma is closely correlated and that the former is determined, at least partly, by the latter. When human gastric mucosa shows

  6. Influence of Ionizing Radiation on Stromal-Epithelial Intercellular Communication in Esophageal Carcinogenesis

    Science.gov (United States)

    Patel, Zarana S.; Kalabis, Jiri; Rustgi, Anil K.; Cucinotta, Francis A.; Huff, Janice L.

    2010-01-01

    Esophageal cancer is the 6th leading cause of cancer death worldwide. Its development is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. An association with ionizing radiation exposure is revealed by the high excess relative risk for squamous cell carcinoma of the esophagus observed in the survivors of the atomic bomb detonations in Japan. It is also seen as a secondary malignancy in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely curable. The stromal microenvironment plays an essential role in the maintenance and modulation of normal epithelial cell growth and differentiation and cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibroblasts (Okawa et al., Genes & Dev. 2007. 21: 2788-2803). We examined how radiation treatment of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. Chemotactic and haptotactic migration of epithelial cells stimulated by conditioned media from irradiated fibroblasts was measured using assays conducted in Transwell cell culture chambers. Our results using

  7. Na+,HCO3--cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted pH gradient across the plasma membrane

    DEFF Research Database (Denmark)

    Lee, Soojung; Mele, Marco; Vahl, Pernille

    2015-01-01

    and promoting cancer cell metabolism, proliferation, migration, and invasion. We investigated the effects of breast carcinogenesis on the mechanisms of cellular pH control using multicellular epithelial organoids freshly isolated from human primary breast carcinomas and matched normal breast tissue...... (~0.3 units of magnitude) in steady-state intracellular pH of human primary breast carcinomas compared to normal breast tissue. Na(+)/H(+)-exchange activity and steady-state intracellular pH in the absence of CO2/HCO3 (-) were practically unaffected by breast carcinogenesis. These effects were evident....... Intracellular pH was measured by fluorescence microscopy, while protein expression was investigated by immunofluorescence imaging and immunoblotting. We found that cellular net acid extrusion increased during human breast carcinogenesis due to enhanced Na(+),HCO3 (-)-cotransport, which created an alkaline shift...

  8. Circadian variations of clock gene Per2 and cell cycle genes in different stages of carcinogenesis in golden hamster buccal mucosa.

    Science.gov (United States)

    Tan, Xue-Mei; Ye, Hua; Yang, Kai; Chen, Dan; Wang, Qing-Qing; Tang, Hong; Zhao, Ning-Bo

    2015-05-07

    Previous studies have suggested that the expression of clock genes have circadian rhythms, and many cell cycle genes are regulated by clock genes. The disruption of circadian rhythms appears to be associated with the acceleration of cancer development. To investigate the circadian patterns of the clock gene Per2 and of cell cycle genes p53, Cyclin D1, CDK1 and Cyclin B1 in different stages of carcinogenesis, the daily mRNA profiles of these genes were detected by real-time RT-PCR in dimethylbenzanthracene-induced cancer, in precancerous lesions and in normal tissues. Per2, p53, Cyclin D1 and CDK1 showed circadian rhythms in the 3 different stages of carcinogenesis, whereas the circadian rhythm of Cyclin B1 was absent in the precancerous lesions. The mesors and amplitudes of Per2 and p53 were decreased (P circadian pattern variations of these genes in different stages of carcinogenesis.

  9. Chemopreventive potential of fungal taxol against 7, 12-dimethylbenz[a]anthracene induced mammary gland carcinogenesis in Sprague Dawley rats.

    Science.gov (United States)

    Gokul Raj, Kathamuthu; Chidambaram, Ranganathan; Varunkumar, Krishnamoorthy; Ravikumar, Vilwanathan; Pandi, Mohan

    2015-11-15

    Breast cancer is the second most prevalent cancer and foremost global public health problem. The present study was designed to appraise the chemopreventive potential of fungal taxol against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinogenesis in Sprague Dawley rats. After 90 days of tumor induction, fungal and authentic taxol were given intraperitoneally once in a week for four weeks. Infrared thermal imaging analysis, serum biochemical parameters such as lipid peroxidase (LPO), creatinine, enzymic and non enzymic antioxidants, liver markers tests such as alanine transaminase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG) and lipoproteins was analysed. In addition, histopathological observation (breast, kidney and liver), immunohistochemical analysis (p53 and Her2/neu) and western blotting experiments (bcl-2, bax and caspase-9) were performed both in control and experimental animals. In thermal imaging, decreased temperature was observed in rat treated with fungal and authentic taxol when compared to tumor induced rats. The significant decrease in LPO, creatinine, ALT, AST, TC, TG, lipoproteins and increase in enzymic, non-enzymic antioxidants were exemplified in serum of treated groups. Further histopathology, immunohistochemical and western blot analysis (bax, cas-9 and bcl-2) of apoptotic markers in breast tissues clearly showed the anti-carcinogenic property of fungal taxol. Our findings implement that fungal taxol is a potential chemo preventive agent against DMBA induced mammary gland carcinogenesis.

  10. Mechanism of fiber carcinogenesis: from reactive radical species to silencing of the beta igH3 gene.

    Science.gov (United States)

    Hei, Tom K; Xu, An; Huang, Sarah X; Zhao, Yongliang

    2006-11-01

    Although the U.S. Environmental Protection Agency has restricted the industrial use of regulated forms of asbestos in the United States since the early 1970s, environmental exposure to asbestos remains a health concern in the United States and is a significant health issue among developing countries. Exposure to asbestos is associated with chronic pulmonary diseases and cancer of the lung, pleura, and peritoneum. The mechanism of fiber carcinogenesis is far from clear and is likely to be complex, depending on fiber dimensions, surface properties, and physical durability. The induction of reactive oxygen and nitrogen species upon phagocytosis of fibers plays an important role in fiber genotoxicity. The beta igH3, a secreted protein induced by the transforming growth factor-beta and essential for cell adhesion, is downregulated in asbestos-induced tumorigenic human bronchial epithelial cells. Ectopic expression of the beta igH3 gene abrogates the tumorigenic phenotype and suggests that the gene plays a causal role in fiber carcinogenesis. A better understanding of the carcinogenic mechanism of asbestos and other mineral fibers will provide useful information on interventional and preventive measures for asbestos-mediated diseases such as human pleural and peritoneal mesotheliomas.

  11. Safrole-DNA adducts in tissues from esophageal cancer patients: clues to areca-related esophageal carcinogenesis.

    Science.gov (United States)

    Lee, Jang-Ming; Liu, Tsung-Yung; Wu, Deng-Chyang; Tang, Hseau-Chung; Leh, Julie; Wu, Ming-Tsang; Hsu, Hsao-Hsun; Huang, Pei-Ming; Chen, Jin-Shing; Lee, Chun-Jean; Lee, Yung-Chie

    2005-01-01

    Epidemiological studies have demonstrated that areca quid chewing can be an independent risk factor for developing esophageal cancer. However, no studies are available to elucidate the mechanisms of how areca induces carcinogenesis in the esophagus. Since the areca nut in Taiwan contains a high concentration of safrole, a well-known carcinogenic agent, we analyzed safrole-DNA adducts by the 32P-postlabelling method in tissue specimens from esophageal cancer patients. In total, we evaluated 47 patients with esophageal cancer (16 areca chewers and 31 non-chewers) who underwent esophagectomy at the National Taiwan University Hospital between 1996 and 2002. Of the individuals with a history of habitual areca chewing (14 cigarette smokers and two non-smokers), one of the tumor tissue samples and five of the normal esophageal mucosa samples were positive for safrole-DNA adducts. All patients positive for safrole-DNA adducts were also cigarette smokers. Such adducts could not be found in patients who did not chew areca, irrespective of their habits of alcohol consumption or cigarette smoking (psafrole was also tested in vitro in three esophageal cell lines and four cultures of primary esophageal keratinocytes. In two of the esophageal keratinocyte cultures, adduct formation was increased by treatment with safrole after induction of cytochrome P450 by 3-methyl-cholanthrene. This paper provides the first observation of how areca induces esophageal carcinogenesis, i.e., through the genotoxicity of safrole, a component of the areca juice.

  12. Detection of the onset of ischemia and carcinogenesis by hypoxia-inducible transcription factor-based in vivo bioluminescence imaging.

    Directory of Open Access Journals (Sweden)

    Tetsuya Kadonosono

    Full Text Available An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1 is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg mice that carry HRE/ODD-luciferase (HOL gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential.

  13. Grape juice concentrate (G8000™) modulates apoptosis but not oxidative stress following rat colon carcinogenesis induced by azoxymethane.

    Science.gov (United States)

    Oshima, Celina Tizuko Fujiyama; Landman, Gilles; Paiotti, Ana Paula Ribeiro; Artigiani Neto, Ricardo; Silva, Roseane Mendes; Campanholo, Vanessa Maria De Lima Pazine; Gollucke, Andrea Pittelli Boiago; Ribeiro, Daniel Araki; Forones, Nora Manoukian

    2015-02-01

    The aim of this study was to evaluate if grape juice concentrate is able to protect against experimental colon carcinogenesis. For this purpose, a total of 35 male Wistar rats were randomly distributed into seven groups: G1: SHAM animals receiving only saline; G2: animals receiving 15 mg/kg azoxymethane (AOM); G3: animals receiving 1% grape juice concentrate 2 weeks before the administration of AOM; G4: animals receiving 2% grape juice concentrate 2 weeks before the administration of AOM; G5: animals receiving 1% grape juice concentrate 4 weeks after the last administration of AOM; G6: animals receiving 2% grape juice concentrate 4 weeks after the last administration of AOM; G7: animals receiving only 2% grape juice concentrate. The group that received 2% grape juice concentrate before induction with AOM showed the decreased expression of Bcl-2 compared to those animals that were induced by AOM (positive control). Regarding Bax, animals that received grape juice at 2% decreased Bax immunoexpression when compared to AOM group. Furthermore, animals that intake grape juice at 1% after induced by AOM decreased Bax immunoexpression as well. 8-OHdGLI did not show significant statistically differences (p > 0.05) among groups. In summary, our results demonstrate that grape juice is able to modulate rat colon carcinogenesis as a result of induction of apoptosis.

  14. Emerging role of bacteria in oral carcinogenesis: a review with special reference to perio-pathogenic bacteria

    Directory of Open Access Journals (Sweden)

    Manosha Perera

    2016-09-01

    Full Text Available Oral cancer, primarily oral squamous cell carcinoma (OSCC, continues to be a major global health problem with high incidence and low survival rates. While the major risk factors for this malignancy, mostly lifestyle related, have been identified, around 15% of oral cancer cases remain unexplained. In light of evidence implicating bacteria in the aetiology of some cancer types, several epidemiological studies have been conducted in the last decade, employing methodologies ranging from traditional culture techniques to 16S rRNA metagenomics, to assess the possible role of bacteria in OSCC. While these studies have demonstrated differences in microbial composition between cancerous and healthy tissues, they have failed to agree on specific bacteria or patterns of oral microbial dysbiosis to implicate in OSCC. On the contrary, some oral taxa, particularly Porphyromonas gingivalis and Fusobacterium nucleatum, show strong oral carcinogenic potential in vitro and in animal studies. Bacteria are thought to contribute to oral carcinogenesis via inhibition of apoptosis, activation of cell proliferation, promotion of cellular invasion, induction of chronic inflammation, and production of carcinogens. This narrative review provides a critical analysis of and an update on the association between bacteria and oral carcinogenesis and the possible mechanisms underlying it.

  15. A critical overview on the biological and molecular features of red and processed meat in colorectal carcinogenesis.

    Science.gov (United States)

    Jeyakumar, Arunan; Dissabandara, Lakal; Gopalan, Vinod

    2017-04-01

    A recent investigation by the World Health Organisation (WHO) has found that the consumption of processed meat and potentially red meat promotes carcinogenesis and can increase the risk of colorectal cancer. This literature review aims to summarise both the red and processed meat molecules associated with colorectal carcinogenesis and investigate their relationship with the pathogenic process of colorectal cancer. Literature relating to the carcinogenic effect of red and processed meat molecules was critically reviewed. There are multiple molecules present in red and processed meat with a potential carcinogenic effect on colorectal tissues. Processed meat is more carcinogenic compared to red meat because of the abundance of potent nitrosyl-heme molecules that form N-nitroso compounds. Studies have also noted that other molecules such as polycyclic aromatic hydrocarbons and heterocyclic amines have potential mechanisms for the initiation of colorectal cancer pathogenesis. The non-human sugar molecule N-glycolylneuraminic acid may account for the carcinogenic effects of pork despite its heme content being comparable to that of chicken. Red meat products, especially those that have been processed, have a wide variety of carcinogenic molecules known to increase the risk of colorectal cancer. Thus, the outcome of this review is consistent with the recent findings of WHO.

  16. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2012-01-01

    Full Text Available One of the key features of hepatocellular carcinoma (HCC is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR, a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

  17. Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis

    Science.gov (United States)

    Kim, Jong-Eun; Roh, Eunmiri; Lee, Mee Hyun; Yu, Dong Hoon; Kim, Dong Joon; Lim, Tae-Gyu; Jung, Sung Keun; Peng, Cong; Cho, Yong-Yeon; Dickinson, Sally; Alberts, Dave; Bowden, G. Tim; Einspahr, Janine; Stratton, Steven P; Curiel, Clara; Bode, Ann M.; Lee, Ki Won; Dong, Zigang

    2015-01-01

    Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure, and Fyn knockout (Fyn−/−) mice formed larger and more tumors compared to Fyn wildtype mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn as well as cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis. PMID:26686094

  18. A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model.

    Science.gov (United States)

    Zhang, Yong; Zhang, Jinhui; Wang, Lei; Quealy, Emily; Gary, Bernard D; Reynolds, Robert C; Piazza, Gary A; Lü, Junxuan

    2010-07-01

    Nonsteroidal anti-inflammatory drugs including sulindac are well documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX)-inhibitory activities cause severe gastrointestinal, renal, and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of nonsteroidal anti-inflammatory drugs and support the potential for the development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution called sulindac sulfide amide (SSA) was recently identified to be devoid of COX-inhibitory activity yet displays much more potent tumor cell growth-inhibitory activity in vitro compared with sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the transgenic adenocarcinoma of mouse prostate model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G(1) arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression through repressing cell proliferation in the transgenic adenocarcinoma of mouse prostate mice, whereas it did not significantly affect neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis.

  19. Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis.

    Science.gov (United States)

    Tai, Mei-Hui; Chang, Chia-Cheng; Kiupel, Matti; Webster, Joshua D; Olson, L Karl; Trosko, James E

    2005-02-01

    The Oct3/4 gene, a POU family transcription factor, has been noted as being specifically expressed in embryonic stem cells and in tumor cells but not in cells of differentiated tissues. With the ability to isolate adult human stem cells it became possible to test for the expression of Oct3/4 gene in adult stem cells and to test the stem cell theory of carcinogenesis. Using antibodies and PCR primers we tested human breast, liver, pancreas, kidney, mesenchyme and gastric stem cells, the cancer cell lines HeLa and MCF-7 and human, dog and rat tumors for Oct4 expression. The results indicate that adult human stem cells, immortalized non-tumorigenic cells and tumor cells and cell lines, but not differentiated cells, express Oct4. Oct4 is expressed in a few cells found in the basal layer of human skin epidermis. The data demonstrate that adult stem cells maintain expression of Oct4, consistent with the stem cell hypothesis of carcinogenesis.

  20. Preventive effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats.

    Science.gov (United States)

    Tsukamoto, Hironobu; Mizoshita, Tsutomu; Katano, Takahito; Hayashi, Noriyuki; Ozeki, Keiji; Ebi, Masahide; Shimura, Takaya; Mori, Yoshinori; Tanida, Satoshi; Kataoka, Hiromi; Tsukamoto, Tetsuya; Tatematsu, Masae; Joh, Takashi

    2015-03-01

    Chemoprevention strategies against gastric cancer (GC) need to be explored in light of the fact that stomach cancer still occurs in the absence of Helicobacter pylori (HP) infection and following HP eradication. We evaluated the effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in SD rats. Thirty-nine male rats were divided into four groups based on whether or not they were treated with rebamipide and/or MNNG: Control, Rebamipide, Control-M, and Rebamipide-M groups. From 8 weeks of age, rats in the Control-M and Rebamipide-M groups received MNNG in drinking water for 30 weeks. The Rebamipide and Rebamipide-M groups were administered 5mg/kg/day of rebamipide. At 50 weeks, cancerous lesions were not observed in either the Control or Rebamipide groups. Nine rats in the Control-M group had developed GC, while four rats in the Rebamipide-M group had developed GC. The incidence of cancer in the Rebamipide-M group was significantly less than in the Control-M group (pRebamipide-M group. Carcinomatous invasion into the muscularis propria was not observed in the Rebamipide-M group. In conclusion, the present study demonstrates that rebamipide suppresses. MNNG-induced carcinogenesis and may also inhibit progression of cancer in rats. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. Radiation-induced carcinogenesis: mechanistically based differences between gamma-rays and neutrons, and interactions with DMBA.

    Directory of Open Access Journals (Sweden)

    Igor Shuryak

    Full Text Available Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect. Densely ionizing radiation (e.g. neutrons often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect. These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA. The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis.

  2. Common cancer in a wild animal: the California sea lion (Zalophus californianus) as an emerging model for carcinogenesis.

    Science.gov (United States)

    Browning, Helen M; Gulland, Frances M D; Hammond, John A; Colegrove, Kathleen M; Hall, Ailsa J

    2015-07-19

    Naturally occurring cancers in non-laboratory species have great potential in helping to decipher the often complex causes of neoplasia. Wild animal models could add substantially to our understanding of carcinogenesis, particularly of genetic and environmental interactions, but they are currently underutilized. Studying neoplasia in wild animals is difficult and especially challenging in marine mammals owing to their inaccessibility, lack of exposure history, and ethical, logistical and legal limits on experimentation. Despite this, California sea lions (Zalophus californianus) offer an opportunity to investigate risk factors for neoplasia development that have implications for terrestrial mammals and humans who share much of their environment and diet. A relatively accessible California sea lion population on the west coast of the USA has a high prevalence of urogenital carcinoma and is regularly sampled during veterinary care in wildlife rehabilitation centres. Collaborative studies have revealed that genotype, persistent organic pollutants and a herpesvirus are all associated with this cancer. This paper reviews research to date on the epidemiology and pathoge