WorldWideScience

Sample records for colorectal carcinogenesis biomarkers

  1. 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

  2. Inflammatory and redox reactions in colorectal carcinogenesis.

    Science.gov (United States)

    Guina, Tina; Biasi, Fiorella; Calfapietra, Simone; Nano, Mario; Poli, Giuseppe

    2015-03-01

    It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment. © 2015 New York Academy of Sciences.

  3. 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.

  4. Colorectal carcinogenesis-update and perspectives

    DEFF Research Database (Denmark)

    Raskov, Hans; Pommergaard, Hans-Christian; Burcharth, Jakob

    2014-01-01

    Colorectal cancer (CRC) is a very common malignancy in the Western World and despite advances in surgery, chemotherapy and screening, it is still the second leading cause of cancer deaths in this part of the world. Numerous factors are found important in the development of CRC including colonocyte....... To identify early cancers, screening programs have been initiated, and the leading strategy has been the use of faecal occult blood testing followed by colonoscopy in positive cases. Regarding the treatment of colorectal cancer, significant advances have been made in the recent decade. The molecular targets...

  5. Collagen mRNA levels changes during colorectal cancer carcinogenesis

    DEFF Research Database (Denmark)

    Skovbjerg, Hanne; Anthonsen, Dorit; Lothe, Inger M B

    2009-01-01

    BACKGROUND: Invasive growth of epithelial cancers is a complex multi-step process which involves dissolution of the basement membrane. Type IV collagen is a major component in most basement membranes. Type VII collagen is related to anchoring fibrils and is found primarily in the basement membrane...... zone of stratified epithelia. Immunohistochemical studies have previously reported changes in steady-state levels of different alpha(IV) chains in several epithelial cancer types. In the present study we aimed to quantitatively determine the mRNA levels of type IV collagen (alpha1/alpha 4/alpha 6......) and type VII collagen (alpha1) during colorectal cancer carcinogenesis. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for alpha1(IV), alpha 4(IV), alpha 6(IV), and alpha1(VII) in colorectal cancer tissue (n = 33), adenomas (n = 29) and in normal tissue from the same individuals...

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

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    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.

  7. 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.

  8. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; Gallon, Richard; Gebert, Johannes; Ballhausen, Alexej; Endris, Volker; Kirchner, Martina; Stenzinger, Albrecht; Burn, John; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2018-07-01

    Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. © 2018 UICC.

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

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    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.

  10. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis

    DEFF Research Database (Denmark)

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

    2011-01-01

    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......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...

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

    DEFF Research Database (Denmark)

    Lange, Jette Bornholdt; Friis, Stine; Godiksen, Sine

    2011-01-01

    -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....

  12. Proteomics for discovery of candidate colorectal cancer biomarkers

    Science.gov (United States)

    Álvarez-Chaver, Paula; Otero-Estévez, Olalla; Páez de la Cadena, María; Rodríguez-Berrocal, Francisco J; Martínez-Zorzano, Vicenta S

    2014-01-01

    Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in Europe and other Western countries, mainly due to the lack of well-validated clinically useful biomarkers with enough sensitivity and specificity to detect this disease at early stages. Although it is well known that the pathogenesis of CRC is a progressive accumulation of mutations in multiple genes, much less is known at the proteome level. Therefore, in the last years many proteomic studies have been conducted to find new candidate protein biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of colorectal carcinogenesis. An important advantage of the proteomic approaches is the capacity to look for multiple differentially expressed proteins in a single study. This review provides an overview of the recent reports describing the different proteomic tools used for the discovery of new protein markers for CRC such as two-dimensional electrophoresis methods, quantitative mass spectrometry-based techniques or protein microarrays. Additionally, we will also focus on the diverse biological samples used for CRC biomarker discovery such as tissue, serum and faeces, besides cell lines and murine models, discussing their advantages and disadvantages, and summarize the most frequently identified candidate CRC markers. PMID:24744574

  13. Molecular alterations and biomarkers in colorectal cancer

    Science.gov (United States)

    Grady, William M.; Pritchard, Colin C.

    2013-01-01

    The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer genetics is leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers). PMID:24178577

  14. 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.

  15. CBD: a biomarker database for colorectal cancer.

    Science.gov (United States)

    Zhang, Xueli; Sun, Xiao-Feng; Cao, Yang; Ye, Benchen; Peng, Qiliang; Liu, Xingyun; Shen, Bairong; Zhang, Hong

    2018-01-01

    Colorectal cancer (CRC) biomarker database (CBD) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data were collected, sorted, displayed and analysed. The CBD with the credible contents as a powerful and time-saving tool provide more comprehensive and accurate information for further CRC biomarker research. The CBD was constructed under MySQL server. HTML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD could provide to users the multiple individual biomarker information and categorized into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the average age of cohort, gender, race, the number of tumours, tumour location and stage. We only collect data from the articles with clear and credible results to prove the biomarkers are useful in the diagnosis, treatment or prognosis of CRC. The CBD can also provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high-quality research in CRC. They can submit their new findings to our database via the submission page and communicate with us in the CBD.Database URL: http://sysbio.suda.edu.cn/CBD/.

  16. Lactobacillus salivarius Ren prevent the early colorectal carcinogenesis in 1, 2-dimethylhydrazine-induced rat model.

    Science.gov (United States)

    Zhu, J; Zhu, C; Ge, S; Zhang, M; Jiang, L; Cui, J; Ren, F

    2014-07-01

    The objective of this study was to investigate the impact of Lactobacillus salivarius Ren (LS) on modulating colonic micro flora structure and influencing host colonic health in a rat model with colorectal precancerous lesions. Male F344 rats were injected with 1, 2-dimethylhydrazine (DMH) and treated with LS of two doses (5 × 10(8) and 1 × 10(10) CFU kg(-1) body weight) for 15 weeks. The colonic microflora profiles, luminal metabolites, epithelial proliferation and precancerous lesions [aberrant crypt foci (ACF)] were determined. A distinct segregation of colonic microflora structures was observed in LS-treated group. The abundance of one Prevotella-related strain was increased, and the abundance of one Bacillus-related strain was decreased by LS treatment. These changes were accompanied by increased short-chain fatty acid levels and decreased azoreductase activity. LS treatment also reduced the number of ACF by c. 40% and suppressed epithelial proliferation. Lactobacillus salivarius Ren improved the colonic microflora structures and the luminal metabolisms in addition preventing the early colorectal carcinogenesis in DMH-induced rat model. Colonic microflora is an important factor in colorectal carcinogenesis. Modulating the structural shifts of microflora may provide a novel option for preventing colorectal carcinogenesis. This study suggested a potential probiotic-based approach to modulate the intestinal microflora in the prevention of colorectal carcinogenesis. © 2014 The Society for Applied Microbiology.

  17. Cancer evolution and immunity in a rat colorectal carcinogenesis model

    Czech Academy of Sciences Publication Activity Database

    Vannucci, Luca; Fišerová, Anna; Horváth, Ondřej; Rossmann, Pavel; Mosca, F.; Pospíšil, Miloslav

    2004-01-01

    Roč. 25, - (2004), s. 973-981 ISSN 1019-6439 R&D Projects: GA ČR GV312/98/K034; GA AV ČR IAA7020006 Institutional research plan: CEZ:AV0Z5020903 Keywords : cancer * cancer model * colorectal adenocarcinoma Subject RIV: EE - Microbiology, Virology Impact factor: 3.056, year: 2004

  18. Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis

    International Nuclear Information System (INIS)

    Selzer-Plon, Joanna; Bornholdt, Jette; Friis, Stine; Bisgaard, Hanne C; Lothe, Inger MB; Tveit, Kjell M; Kure, Elin H; Vogel, Ulla; Vogel, Lotte K

    2009-01-01

    Clinical trials where cancer patients were treated with protease inhibitors have suggested that the serine protease, prostasin, may act as a tumour suppressor. Prostasin is proteolytically activated by the serine protease, matriptase, which has a very high oncogenic potential. Prostasin is inhibited by protease nexin-1 (PN-1) and the two isoforms encoded by the mRNA splice variants of hepatocyte growth factor activator inhibitor-1 (HAI-1), HAI-1A, and HAI-1B. Using quantitative RT-PCR, we have determined the mRNA levels for prostasin and PN-1 in colorectal cancer tissue (n = 116), severe dysplasia (n = 13), mild/moderate dysplasia (n = 93), and in normal tissue from the same individuals. In addition, corresponding tissues were examined from healthy volunteers (n = 23). A part of the cohort was further analysed for the mRNA levels of the two variants of HAI-1, here denoted HAI-1A and HAI-1B. mRNA levels were normalised to β-actin. Immunohistochemical analysis of prostasin and HAI-1 was performed on normal and cancer tissue. The mRNA level of prostasin was slightly but significantly decreased in both mild/moderate dysplasia (p < 0.001) and severe dysplasia (p < 0.01) and in carcinomas (p < 0.05) compared to normal tissue from the same individual. The mRNA level of PN-1 was more that two-fold elevated in colorectal cancer tissue as compared to healthy individuals (p < 0.001) and elevated in both mild/moderate dysplasia (p < 0.01), severe dysplasia (p < 0.05) and in colorectal cancer tissue (p < 0.001) as compared to normal tissue from the same individual. The mRNA levels of HAI-1A and HAI-1B mRNAs showed the same patterns of expression. Immunohistochemistry showed that prostasin is located mainly on the apical plasma membrane in normal colorectal tissue. A large variation was found in the degree of polarization of prostasin in colorectal cancer tissue. These results show that the mRNA level of PN-1 is significantly elevated in colorectal cancer tissue. Future studies

  19. Carcinogenesis

    International Nuclear Information System (INIS)

    Anon.

    1976-01-01

    Progress is reported on studies at the molecular, biochemical, and immunological level of carcinogenesis induced in mice by viruses, radiation, or environmental chemicals alone or in combinations. Emphasis was placed on the identification and assessments of cocarcinogens and studies on their mechanisms of action. Data are included on mechanisms of carcinogenesis in the liver, thyroid, Harderian glands, skin, and lungs. The effects of the food additive butylated hydroxytoluene (BHT), phenobarbitol, DDT, uv irradiation, the herbicide 3-amino-1,2,4-triazole(AT), the pituitary hormone prolactin, topically applied 8-methoxypsoralen (8-MOP), and benzo(a) pyrene(BaP) on tumor induction or enhancement were studied

  20. Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression

    International Nuclear Information System (INIS)

    Simiantonaki, Nektaria; Taxeidis, Marios; Jayasinghe, Caren; Kurzik-Dumke, Ursula; Kirkpatrick, Charles James

    2008-01-01

    Hypoxia-inducible factor 1 alpha (HIF-1α) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1α during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas. Immunohistochemistry and Western blot is used to analyse HIF-1α expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1α inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry. In normal mucosa, HPP and TA-LGD HIF-1α was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1α were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1α overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1α expression was strongly accumulated in perinecrotic regions. In these cases HIF-1α activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1α was also seen in periiflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1α expression and nuclear translocation. We conclude that HIF-1α expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic

  1. Oral Bacterial and Fungal Microbiome Impacts Colorectal Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Klara Klimesova

    2018-04-01

    Full Text Available Host’s physiology is significantly influenced by microbiota colonizing the epithelial surfaces. Complex microbial communities contribute to proper mucosal barrier function, immune response, and prevention of pathogen invasion and have many other crucial functions. The oral cavity and large intestine are distant parts of the digestive tract, both heavily colonized by commensal microbiota. Nevertheless, they feature different proportions of major bacterial and fungal phyla, mostly due to distinct epithelial layers organization and different oxygen levels. A few obligate anaerobic strains inhabiting the oral cavity are involved in the pathogenesis of oral diseases. Interestingly, these microbiota components are also enriched in gut inflammatory and tumor tissue. An altered microbiota composition – dysbiosis – and formation of polymicrobial biofilms seem to play important roles in the development of oral diseases and colorectal cancer. In this review, we describe the differences in composition of commensal microbiota in the oral cavity and large intestine and the mechanisms by which microbiota affect the inflammatory and carcinogenic response of the host.

  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. [Curcumin inhibited rat colorectal carcinogenesis by activating PPAR-γ: an experimental study].

    Science.gov (United States)

    Liu, Liu-bin; Duan, Chang-nong; Ma, Zeng-yi; Xu, Gang

    2015-04-01

    To explore the chemopreventive effect of curcumin on DMH induced colorectal carcinogenesis and the underlining mechanism. Totally 40 Wistar rats were divided into the model group and the curcumin group by random digit table, 20 in each group. Meanwhile, a normal control group was set up (n =10). A colorectal cancer model was induced by subcutaneously injecting 20 mg/kg DMH. The tumor incidence and the inhibition rate were calculated. The effect of curcumin on the expression of peroxisome proliferator-activated receptor gamma (PPARγ) in rat colon mucosal tissues was observed using immunohistochemistry and Western blot. HT 29 cell line were cultured and divided into a control group, the curcumin + GW9662 (2-chloro-5-nitro-N-4-phenylbenzamide) intervention group, and the curcumin group. The inhibition of different concentrations curcumin on HT29 cell line was detected using MTT. The expression of curcumin on PPARy was also detected using Western blot. The tumor incidence was 80. 00% (12/15 cases) in the model group, obviously higher than that of the curcumin group (58. 82%, 10/17 cases, P manners. The expression of PPARy protein was significantly increased in the GW9662 group and the curcumin group, showing statistical difference when compared with the normal control group (P <0. 01). Compared with the GW9662 group, the expression of PPARγ protein was significantly increased in the curcumin group (P <0. 01). Curcumin could inhibit DMH-induced rat colorectal carcinogenesis and the growth of in vitro cultured HT 29 cell line, which might be achieved by activating PPARy signal transduction pathway.

  4. Prognostic and predictive biomarkers in colorectal cancer. Towards precision medicine

    NARCIS (Netherlands)

    Reimers, Marlies Suzanne

    2015-01-01

    The aim of this thesis was to define prognostic and predictive biomarkers in colorectal cancer for improved risk stratification and treatment benefit in the individual patient, with the introduction of precision medicine in the near future as the ultimate goal. By definition, precision medicine is

  5. Genetic biomarkers for neoplastic colorectal cancer in peripheral lymphocytes.

    Science.gov (United States)

    Ionescu, Mirela; Ciocirlan, Mihai; Ionescu, Cristina; Becheanu, Gabriel; Gologan, Serban; Teiusanu, Adriana; Arbanas, Tudor; Mircea, Diculescu

    2011-04-01

    Loss of genomic stability appears as a key step in colorectal carcinogenesis. Micronucleus (MN) designates a chromosome fragment or an entire chromosme which lags behind mitosis. MN may be noticed as an additional nucleus within the cytoplasm cell during the intermediate mitosis phases. We tested the hypothesis that MN and its related anomalies may be associated with the presence of neoplastic colorectal lesions. Peripheral blood lymphocytes were cultured and microscopically examined. The frequency of micronuclei (FMN) and the presence of nucleoplasmic bridges (NPB) in binucleated cells were compared in patients with of without colorectal neoplastic lesions. We included 45 patients undergoing colonoscopy, 23 males and 22 females, with a median age of 59. 17 patients had polyps, 11 colorectal cancer (CRC) and 17 had a normal colonoscopy. The FMN was significantly higher in women than in men (8.14 vs 4.17, p=0.008); NPB were significantly less frequent in patients with advanced adenomas (>10mm or vilous) or CRC (p=0.044) when compared with patients with normal colonoscopy, hiperplastic polyps or non-advanced adenomas. Micronuclei are more frequent in women, but its frequency was not significantly different in patients with advanced adenomas or CRC. Null or low frequency values for nucleoplasmic bridges presence in peripheral lymphocyte may be predictive for advanced adenomas and colorectal cancer.

  6. 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.

  7. Carcinogenesis

    International Nuclear Information System (INIS)

    Fry, R.J.M.

    1975-01-01

    The long-term aims are concerned with various aspects of the natural history and biology of cancer, the mechanism of induction and of the advancement of time of appearance of tumors, the development of systems suitable for the assay of oncogenesis and cocarcinogenesis, and the elucidation of some of the factors important to the problem of extrapolation of estimates of risk made in experimental systems to the estimate of risk in man. It is necessary to have a number of test systems in order to study the various factors related to cocarcinogenesis; some of these are clearly tissue specific. The liver tumor system is clearly useful for certain compounds, and the liver is an excellent tissue for the study of the mechanisms of cocarcinogenesis. This year we report on the relatively rapid induction of what appears histologically to be carcinoma of the thyroid by aminotriazole. In a collaborative study with the Neutron and Gamma-Ray Toxicity Group, we have established a new example of synergism in carcinogenesis, namely between radiation and pituitary hormone(s) in the production of Harderian gland tumors. Not only does a synergistic effect on incidence occur, but also on the degree of malignancy of the tumor induced. We thus have three different model systems for the study of various aspects of cocarcinogenesis: various chemicals, including nononcogenic polycyclic hydrocarbons, in liver tumorigenesis; ionizing radiation and aminotriazole in thyroid tumorigenesis; and in conjunction with the JANUS Program, the interaction of radiation and hormones in the production of Harderian gland, mammary gland, and other tumors

  8. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances

    Science.gov (United States)

    Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

    2016-01-01

    Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments. PMID:26855534

  9. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances.

    Science.gov (United States)

    Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

    2016-02-07

    Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.

  10. Serum Adipocytokines (Visfatin and Resistin: New Biomarkers of Breast Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Sanaa A. El-Benhawy

    2015-10-01

    Full Text Available Background: Recent epidemiological studies demonstrate that obesity is associated with an increased risk for breast cancer in women. Increased estrogen levels are suggested as one possible explanation, but this does not fully explain the relationship between obesity and breast cancer. One alternative explanation is secretion by adipocytes of metabolites, hormones and cytokines, collectively known as adipocytokines, which regulate physiological and pathological processes. Among these adipokines are visfatin and resistin. This study investigates whether visfatin or resistin in serum of breast cancer patients can be used as potential diagnostic and prognostic tools for breast cancer, taking into account clinicopathological features and anthropometric parameters. Methods: Blood samples were collected from 70 breast cancer patients (35 obese and 35 non-obese and 20 healthy females matched for age and body mass index as the control group. Serum visfatin levels were measured by enzyme linked immunosorbent assay and serum resistin levels were measured by radioimmunoassay. Inflammatory status was assessed by measuring C-reactive protein levels by an automated turbidimetric analyzer. Results: We observed highly elevated serum resistin and visfatin levels in breast cancer patients compared to controls, independent of body mass index. Serum resistin and visfatin levels were likely to be associated with increased breast cancer risk and correlated with the inflammatory marker C-reactive protein. Conclusion: Targeting resistin and visfatin inhibition can be an effective therapeutic strategy in breast cancer by downregulating the inflammatory microenvironment in breast tissue. Serum visfatin promises to be a novel biomarker of diagnostic and prognostic value. Larger prospective studies are required to confirm our findings.

  11. Epigenetic prognostic biomarkers in colorectal cancer

    NARCIS (Netherlands)

    Benard, Anne

    2015-01-01

    Colorectal cancer is one of the most common diagnosed cancers worldwide, and is the second most important cause of cancer mortality in Europe. The current TNM staging system used at the time of diagnosis is insufficient, as patients with the same tumor stage show wide variations in survival and

  12. Independent Induction of Caspase-8 and cFLIP Expression during Colorectal Carcinogenesis in Sporadic and HNPCC Adenomas and Carcinomas

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    D. M. Heijink

    2007-01-01

    Full Text Available Background: TNF-Related Apoptosis Inducing Ligand (TRAIL is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase-8 and its anti-apoptotic competitor cellular Flice-Like Inhibitory Protein (cFLIP. Methods: The aim of this study was to investigate basic expression of caspase-8 and cFLIP in normal colorectal epithelium (n = 20, colorectal adenomas (n = 66 and colorectal carcinomas (n = 44 using immunohistochemistry performed on both sporadic and Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome-associated adenomas and carcinomas. Results: Expression of both caspase-8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase-8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P = 0.02. Nuclear, paranuclear as well as cytoplasmic localizations of caspase-8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P < 0.001. A large variation in the caspase-8/cFLIP ratio was observed between the individual adenomas and carcinomas. Conclusion: Caspase-8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase-8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.

  13. Biomarkers related to one-carbon metabolism as potential risk factors for distal colorectal adenomas

    NARCIS (Netherlands)

    Vogel, S. de; Schneede, J.; Ueland, P.M.; Vollset, S.E.; Meyer, K.; Fredriksen, A.; Midttun, O.; Bjorge, T.; Kampman, E.; Bretthauer, M.; Hoff, G.

    2011-01-01

    BACKGROUND: Efficient one-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may protect against colorectal carcinogenesis. However, plasma folate and vitamins B2 and B12 have inconsistently been associated with colorectal cancer risk, and there have been no

  14. Biomarkers Related to One-Carbon Metabolism as Potential Risk Factors for Distal Colorectal Adenomas

    NARCIS (Netherlands)

    Vogel, de S.; Schneede, J.; Ueland, P.M.; Vollset, S.E.; Meyer, K.; Fredriksen, A.; Midttun, O.; Bjorge, T.; Kampman, E.; Bretthauer, M.; Hoff, G.

    2011-01-01

    Background: Efficient one-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may protect against colorectal carcinogenesis. However, plasma folate and vitamins B2 and B12 have inconsistently been associated with colorectal cancer risk, and there have been no

  15. End-Binding Protein 1 (EB1) Up-regulation is an Early Event in Colorectal Carcinogenesis

    Science.gov (United States)

    Stypula-Cyrus, Yolanda; Mutyal, Nikhil N.; Cruz, Mart Angelo Dela; Kunte, Dhananjay P.; Radosevich, Andrew J.; Wali, Ramesh; Roy, Hemant K.; Backman, Vadim

    2014-01-01

    End-binding protein (EB1) is a microtubule protein that binds to the tumor suppressor adenomatous polyposis coli (APC). While EB1 is implicated as a potential oncogene, its role in cancer progression is unknown. Therefore, we analyzed EB1/APC expression at the earliest stages of colorectal carcinogenesis and in the uninvolved mucosa ("field effect") of human and animal tissue. We also performed siRNA-knockdown in colon cancer cell lines. EB1 is up-regulated in early and field carcinogenesis in the colon, and the cellular/nano-architectural effect of EB1 knockdown depended on the genetic context. Thus, dysregulation of EB1 is an important early event in colon carcinogenesis. PMID:24492008

  16. Predictive cytogenetic biomarkers for colorectal neoplasia in medium risk patients.

    Science.gov (United States)

    Ionescu, E M; Nicolaie, T; Ionescu, M A; Becheanu, G; Andrei, F; Diculescu, M; Ciocirlan, M

    2015-01-01

    DNA damage and chromosomal alterations in peripheral lymphocytes parallels DNA mutations in tumor tissues. The aim of our study was to predict the presence of neoplastic colorectal lesions by specific biomarkers in "medium risk" individuals (age 50 to 75, with no personal or family of any colorectal neoplasia). We designed a prospective cohort observational study including patients undergoing diagnostic or opportunistic screening colonoscopy. Specific biomarkers were analyzed for each patient in peripheral lymphocytes - presence of micronuclei (MN), nucleoplasmic bridges (NPB) and the Nuclear Division Index (NDI) by the cytokinesis-blocked micronucleus assay (CBMN). Of 98 patients included, 57 were "medium risk" individuals. MN frequency and NPB presence were not significantly different in patients with neoplastic lesions compared to controls. In "medium risk" individuals, mean NDI was significantly lower for patients with any neoplastic lesions (adenomas and adenocarcinomas, AUROC 0.668, p 00.5), for patients with advanced neoplasia (advanced adenoma and adenocarcinoma, AUROC 0.636 p 0.029) as well as for patients with adenocarcinoma (AUROC 0.650, p 0.048), for each comparison with the rest of the population. For a cut-off of 1.8, in "medium risk" individuals, an NDI inferior to that value may predict any neoplastic lesion with a sensitivity of 97.7%, an advanced neoplastic lesion with a sensitivity of 97% and adenocarcinoma with a sensitivity of 94.4%. NDI score may have a role as a colorectal cancer-screening test in "medium risk" individuals. DNA = deoxyribonucleic acid; CRC = colorectal cancer; EU = European Union; WHO = World Health Organization; FOBT = fecal occult blood test; CBMN = cytokinesis-blocked micronucleus assay; MN = micronuclei; NPB = nucleoplasmic bridges; NDI = Nuclear Division Index; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polypoid colorectal cancer; IBD = inflammatory bowel diseases; ROC = receiver operating

  17. Molecular markers of carcinogenesis for risk stratification of individuals with colorectal polyps: a case-control study.

    Science.gov (United States)

    Gupta, Samir; Sun, Han; Yi, Sang; Storm, Joy; Xiao, Guanghua; Balasubramanian, Bijal A; Zhang, Song; Ashfaq, Raheela; Rockey, Don C

    2014-10-01

    Risk stratification using number, size, and histology of colorectal adenomas is currently suboptimal for identifying patients at increased risk for future colorectal cancer. We hypothesized that molecular markers of carcinogenesis in adenomas, measured via immunohistochemistry, may help identify high-risk patients. To test this hypothesis, we conducted a retrospective, 1:1 matched case-control study (n = 216; 46% female) in which cases were patients with colorectal cancer and synchronous adenoma and controls were patients with adenoma but no colorectal cancer at baseline or within 5 years of follow-up. In phase I of analyses, we compared expression of molecular markers of carcinogenesis in case and control adenomas, blind to case status. In phase II of analyses, patients were randomly divided into independent training and validation groups to develop a model for predicting case status. We found that seven markers [p53, p21, Cox-2, β-catenin (BCAT), DNA-dependent protein kinase (DNApkcs), survivin, and O6-methylguanine-DNA methyltransferase (MGMT)] were significantly associated with case status on unadjusted analyses, as well as analyses adjusted for age and advanced adenoma status (P marker component). When applied to the validation set, a predictive model using these seven markers showed substantial accuracy for identifying cases [area under the receiver operation characteristic curve (AUC), 0.83; 95% confidence interval (CI), 0.74-0.92]. A parsimonious model using three markers performed similarly to the seven-marker model (AUC, 0.84). In summary, we found that molecular markers of carcinogenesis distinguished adenomas from patients with and without colorectal cancer. Furthermore, we speculate that prospective studies using molecular markers to identify individuals with polyps at risk for future neoplasia are warranted. ©2014 American Association for Cancer Research.

  18. A new dietary model to study colorectal carcinogenesis: experimental design, food preparation, and experimental findings.

    Science.gov (United States)

    Rozen, P; Liberman, V; Lubin, F; Angel, S; Owen, R; Trostler, N; Shkolnik, T; Kritchevsky, D

    1996-01-01

    Experimental dietary studies of human colorectal carcinogenesis are usually based on the AIN-76A diet, which is dissimilar to human food in source, preparation, and content. The aims of this study were to examine the feasibility of preparing and feeding rats the diet of a specific human population at risk for colorectal neoplasia and to determine whether changes in the colonic morphology and metabolic contents would differ from those resulting from a standard rat diet. The mean daily food intake composition of a previously evaluated adenoma patient case-control study was used for the "human adenoma" (HA) experimental diet. Foods were prepared as for usual human consumption and processed by dehydration to the physical characteristics of an animal diet. Sixty-four female Sprague-Dawley rats were randomized and fed ad libitum the HA or the AIN-76A diet. Every eight weeks, eight rats from each group were sacrificed, and the colons and contents were examined. Analysis of the prepared food showed no significant deleterious changes; food intake and weight gain were similar in both groups. Compared with the controls, the colonic contents of rats fed the HA diet contained significantly less calcium, concentrations of neutral sterols, total lipids, and cholic and deoxycholic acids were increased, and there were no colonic histological changes other than significant epithelial hyperproliferation. This initial study demonstrated that the HA diet can be successfully processed for feeding to experimental animals and is acceptable and adequate for growth but induces significant metabolic and hyperproliferative changes in the rat colon. This dietary model may be useful for studies of human food, narrowing the gap between animal experimentation and human nutritional research.

  19. Immunohistochemistry of colorectal cancer biomarker phosphorylation requires controlled tissue fixation.

    Directory of Open Access Journals (Sweden)

    Abbey P Theiss

    Full Text Available Phosphorylated signaling molecules are biomarkers of cancer pathophysiology and resistance to therapy, but because phosphoprotein analytes are often labile, poorly controlled clinical laboratory practices could prevent translation of research findings in this area from the bench to the bedside. We therefore compared multiple biomarker and phosphoprotein immunohistochemistry (IHC results in 23 clinical colorectal carcinoma samples after either a novel, rapid tissue fixation protocol or a standard tissue fixation protocol employed by clinical laboratories, and we also investigated the effect of a defined post-operative "cold" ischemia period on these IHC results. We found that a one-hour cold ischemia interval, allowed by ASCO/CAP guidelines for certain cancer biomarker assays, is highly deleterious to certain phosphoprotein analytes, specifically the phosphorylated epidermal growth factor receptor (pEGFR, but shorter ischemic intervals (less than 17 minutes facilitate preservation of phosphoproteins. Second, we found that a rapid 4-hour, two temperature, formalin fixation yielded superior staining in several cases with select markers (pEGFR, pBAD, pAKT compared to a standard overnight room temperature fixation protocol, despite taking less time. These findings indicate that the future research and clinical utilities of phosphoprotein IHC for assessing colorectal carcinoma pathophysiology absolutely depend upon attention to preanalytical factors and rigorously controlled tissue fixation protocols.

  20. Modulation of expression of Programmed Death-1 by administration of probiotic Dahi in DMH-induced colorectal carcinogenesis in rats.

    Science.gov (United States)

    Mohania, Dheeraj; Kansal, Vinod K; Kumar, Manoj; Nagpal, Ravinder; Yamashiro, Yuichiro; Marotta, Francesco

    2013-09-01

    Interaction of probiotic bacteria with the host immune system elicits beneficial immune modulating effects. Although, there are many published studies on interaction of probiotics with immune system focusing on activation of immune system by bacterial cell wall through the engagement of Toll-like receptor family; very few studies have focused on molecules involved in the T-cell activation, and not much work has been executed to study the correlation of probiotics and programmed death-1 in colorectal carcinogenesis in animal models. Hence, the present study was carried out to assess the effect of probiotic Dahi on expression of programmed death (PD-1) in colorectum of 1, 2-dimethylhydrazine treated Wistar rats. DMH was injected subcutaneously at the rate of 40 mg/kg body weight per animal twice a week for 2 weeks. A total of 168 male Wistar rats were randomly allocated to seven groups, each group having twenty-four animals. The rats were euthanized at the 8th, 16th and 32nd week of the experiment and examined for the expression of PD-1 in colorectal tissues by immunohistochemical staining. Expression of PD-1 was observed in colorectal tissues of normal and DMH-treated rats. Feeding rats with probiotic Dahi or the treatment with piroxicam decreased the expression of PD-1 in DMH-induced colorectal mucosa, and the combined treatment with probiotic Dahi and piroxicam was significantly more effective in reducing the expression of PD-1. PD-1 expressed independent of carcinogen administration in normal colonic mucosa and may play a role in modulation of immune response in DMH-induced colorectal carcinogenesis. The present study suggests that probiotic Dahi can be used as an effective chemopreventive agent in the management of colorectal cancer.

  1. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Identification of a biomarker panel for colorectal cancer diagnosis

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    García-Bilbao Amaia

    2012-01-01

    Full Text Available Abstract Background Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries. Methods A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60-mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables. Results After an exhaustive process of pre-processing to ensure data quality--lost values imputation, probes quality, data smoothing and intraclass variability filtering--the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples. Conclusions We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955.

  3. Interactive effects between dietary fat and a vegetables-fruit mixture on colorectal carcinogenesis

    NARCIS (Netherlands)

    Rijnkels, J.M.

    1998-01-01

    Several dietary compounds are associated with colorectal cancer risk. These include the amount of dietary fat, which is positively associated with colorectal cancer, and a variety of vegetables and fruit, which are suggested to possess anticarcinogenic potential. Because diet is complex and

  4. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

    International Nuclear Information System (INIS)

    Velho, Sérgia; Moutinho, Cátia; Cirnes, Luís; Albuquerque, Cristina; Hamelin, Richard; Schmitt, Fernando; Carneiro, Fátima; Oliveira, Carla; Seruca, Raquel

    2008-01-01

    BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC). In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP), MLH1 methylation and microsatellite instability (MSI). We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS) lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112), but statistically different from what is found in microsatellite stable (MSS) tumours (P = 0.0191). Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal serrated polyps and verified that colorectal serrated

  5. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

    Directory of Open Access Journals (Sweden)

    Schmitt Fernando

    2008-09-01

    Full Text Available Abstract Background BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC. In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP, MLH1 methylation and microsatellite instability (MSI. We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Methods Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. Results KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112, but statistically different from what is found in microsatellite stable (MSS tumours (P = 0.0191. Conclusion Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal

  6. Polymeric black tea polyphenols inhibit 1,2-dimethylhydrazine induced colorectal carcinogenesis by inhibiting cell proliferation via Wnt/β-catenin pathway

    International Nuclear Information System (INIS)

    Patel, Rachana; Ingle, Arvind; Maru, Girish B.

    2008-01-01

    Tea polyphenols like epigallocatechin gallate and theaflavins are established chemopreventive agents for colorectal carcinogenesis. However, studies on evaluating similar chemopreventive properties of thearubigins or polymeric black tea polyphenols (PBPs), the most abundant polyphenols in black tea, are limited. Hence, in the present study we aim to investigate chemopreventive effects along with probable mechanisms of action of PBP extract employing 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in Sprague-Dawley rats as experimental model. The present study suggests that PBPs, like other tea polyphenols, also inhibit DMH-induced colorectal tumorigenesis by decreasing tumor volume and multiplicity. This study also shows that although the pretreatment with PBP extract could induce detoxifying enzymes in hepatic and colorectal tissue, it did not show any additional chemopreventive effects when compared to treatments with PBP extract after initiation with DMH. Mechanistically, PBP extract may inhibit colorectal carcinogenesis by decreasing DMH-induced cell proliferation via Wnt/β-catenin pathway. Treatments with PBP extract showed decreased levels of COX-2, c-MYC and cyclin D1 proteins which aid cell proliferation probably by regulating β-catenin by maintaining expression of APC and decreasing inactivation of GSK3β. DMH-induced activation of MAP kinases such as ERK and JNK was also found to be inhibited by treatments with PBP extract. In conclusion, the protective effects of PBP extract could be attributed to inhibition of DMH-induced cellular proliferation probably through β-catenin regulation

  7. Proteomic profiling of a mouse model of acute intestinal Apc deletion leads to identification of potential novel biomarkers of human colorectal cancer (CRC).

    Science.gov (United States)

    Hammoudi, Abeer; Song, Fei; Reed, Karen R; Jenkins, Rosalind E; Meniel, Valerie S; Watson, Alastair J M; Pritchard, D Mark; Clarke, Alan R; Jenkins, John R

    2013-10-25

    Colorectal cancer (CRC) is the fourth most common cause of cancer-related death worldwide. Accurate non-invasive screening for CRC would greatly enhance a population's health. Adenomatous polyposis coli (Apc) gene mutations commonly occur in human colorectal adenomas and carcinomas, leading to Wnt signalling pathway activation. Acute conditional transgenic deletion of Apc in murine intestinal epithelium (AhCre(+)Apc(fl)(/)(fl)) causes phenotypic changes similar to those found during colorectal tumourigenesis. This study comprised a proteomic analysis of murine small intestinal epithelial cells following acute Apc deletion to identify proteins that show altered expression during human colorectal carcinogenesis, thus identifying proteins that may prove clinically useful as blood/serum biomarkers of colorectal neoplasia. Eighty-one proteins showed significantly increased expression following iTRAQ analysis, and validation of nine of these by Ingenuity Pathaway Analysis showed they could be detected in blood or serum. Expression was assessed in AhCre(+)Apc(fl)(/)(fl) small intestinal epithelium by immunohistochemistry, western blot and quantitative real-time PCR; increased nucelolin concentrations were also detected in the serum of AhCre(+)Apc(fl)(/)(fl) and Apc(Min)(/)(+) mice by ELISA. Six proteins; heat shock 60kDa protein 1, Nucleolin, Prohibitin, Cytokeratin 18, Ribosomal protein L6 and DEAD (Asp-Glu-Ala-Asp) box polypeptide 5,were selected for further investigation. Increased expression of 4 of these was confirmed in human CRC by qPCR. In conclusion, several novel candidate biomarkers have been identified from analysis of transgenic mice in which the Apc gene was deleted in the intestinal epithelium that also showed increased expression in human CRC. Some of these warrant further investigation as potential serum-based biomarkers of human CRC. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas

    Directory of Open Access Journals (Sweden)

    Lind Guro E

    2011-07-01

    Full Text Available Abstract Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94% and adenomas (35-91%, whereas normal mucosa samples were rarely (0-5% methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.

  9. Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human case?control epidemiological observations

    OpenAIRE

    Ingram, Nicola; Northwood, Emma L.; Perry, Sarah L.; Marston, Gemma; Snowden, Helen; Taylor, John C.; Scott, Nigel; Bishop, D. Timothy; Coletta, P. Louise; Hull, Mark A.

    2013-01-01

    We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a case-control genetic epidemiological study of IL-4Rα single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BALB/c mice, as well as in IL-4Rα (-) (/-) , IL-13 (-/-) and 'double-knockout' (DKO) animals. Colorectal cancer (CRC) cases (1502) and controls (584) ...

  10. Intestinal PTGS2 mRNA Levels, PTGS2 Gene Polymorphisms, and Colorectal Carcinogenesis

    DEFF Research Database (Denmark)

    Vogel, Lotte K.; Saebo, Mona; Hoyer, Helle

    2014-01-01

    Background & Aims: Inflammation is a major risk factor for development of colorectal cancer (CRC). Prostaglandin synthase cyclooxygenase-2 (COX-2) encoded by the PTGS2 gene is the rate limiting enzyme in prostaglandin synthesis and therefore plays a distinct role as regulator of inflammation...

  11. Lactobacillus rhamnosus ATCC 7469 exopolysaccharides synergizes with low level ionizing radiation to modulate signaling molecular targets in colorectal carcinogenesis in rats.

    Science.gov (United States)

    Zahran, Walid E; Elsonbaty, Sawsan M; Moawed, Fatma S M

    2017-08-01

    Combination therapy that targets cellular signaling pathway represents an alternative therapy for the treatment of colon cancer (CRC). The present study was therefore aimed to investigate the probable interaction of Lactobacillus rhamnosus ATCC 7469 exopolysaccharides (EPS) with low level ionizing γ radiation (γ-R) exposure against dimethylhydrazine (DMH)- induced colorectal carcinogenesis in rats. Colon cancer was induced with 20mg DMH/kg BW. Rats received daily by gastric gavage 100mg EPS/Kg BW concomitant with 1Gy γ-R over two months. Colonic oxidative and inflammatory stresses were assessed. The change in the expression of p-p38 MAPK, p-STAT3, β-catenin, NF-kB, COX-2 and iNOS was evaluated by western blotting and q-PCR. It was found that DMH treatment significantly induced colon oxidative injury accompanied by inflammatory disturbance along with increased protein expression of the targeted signaling factors p-p38 MAPK, p-STAT3 and β-catenin. The mRNA gene expression of NF-kB, COX-2 and iNOS was significantly higher in DMH-treated animals. It's worthy to note that colon tissues with DMH treatment showed significant dysplasia and anaplasia of the glandular mucosal lining epithelium with loses of goblet cells formation, pleomorphism in the cells and hyperchromachia in nuclei. Interestingly, EPS treatment with γ-R exposure showed statistically significant amelioration of the oxidative and inflammatory biomarkers with modulated signaling molecular factors accompanied by improved histological structure against DMH-induced CRC. In conclusion, our findings showed that Lactobacillus rhamnosus ATCC 7469 EPS with low level γ-R in synergistic interaction are efficacious control against CRC progression throughout the modulation of key signaling growth factors associated with inflammation via antioxidant mediated anti-inflammatory and anti-proliferative activities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Differential gene expression profile reveals deregulation of pregnancy specific β1 glycoprotein 9 early during colorectal carcinogenesis

    Directory of Open Access Journals (Sweden)

    Gallinger Steven

    2005-06-01

    Full Text Available Abstract Background APC (Adenomatous polyposis coli plays an important role in the pathogenesis of both familial and sporadic colorectal cancer. Patients carrying germline APC mutations develop multiple colonic adenomas at younger age and higher frequency than non-carrier cases which indicates that silencing of one APC allele may be sufficient to initiate the transformation process. Methods To elucidate the biological dysregulation underlying adenoma formation we examined global gene expression profiles of adenomas and corresponding normal mucosa from an FAP patient. Differential expression of the most significant gene identified in this study was further validated by mRNA in situ hybridization, reverse transcriptase PCR and Northern blotting in different sets of adenomas, tumours and cancer cell lines. Results Eighty four genes were differentially expressed between all adenomas and corresponding normal mucosa, while only seven genes showed differential expression within the adenomas. The first group included pregnancy specific β-1 glycoprotein 9 (PSG9 (p PSG9 is a member of the carcinoembryonic antigen (CEA/PSG family and is produced at high levels during pregnancy, mainly by syncytiotrophoblasts. Further analysis of sporadic and familial colorectal cancer confirmed that PSG9 is ectopically upregulated in vivo by cancer cells. In total, deregulation of PSG9 mRNA was detected in 78% (14/18 of FAP adenomas and 75% (45/60 of sporadic colorectal cancer cases tested. Conclusion Detection of PSG9 expression in adenomas, and at higher levels in FAP cases, indicates that germline APC mutations and defects in Wnt signalling modulate PSG9 expression. Since PSG9 is not found in the non-pregnant adult except in association with cancer, and it appears to be an early molecular event associated with colorectal cancer monitoring of its expression may be useful as a biomarker for the early detection of this disease.

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

    OpenAIRE

    Hisataka Moriwaki; Masaya Kubota; Masahito Shimizu; Takuji Tanaka

    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 a...

  14. Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and incidence of colorectal cancer

    NARCIS (Netherlands)

    Kyrø, Cecilie; Olsen, Anja; Landberg, Rikard; Skeie, Guri; Loft, Steffen; Åman, Per; Leenders, Max; Dik, Vincent K.; Siersema, Peter D.; Pischon, Tobias; Christensen, Jane; Overvad, Kim; Boutron-Ruault, Marie Christine; Fagherazzi, Guy; Cottet, Vanessa; Kühn, Tilman; Chang-Claude, Jenny; Boeing, Heiner; Trichopoulou, Antonia; Bamia, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Panico, Salvatore; Peeters, Petra H.; Weiderpass, Elisabete; Bakken, Toril; Åsli, Lene Angell; Argüelles, Marcial; Jakszyn, Paula; Sánchez, María José; Amiano, Pilar; Huerta, José María; Barricarte, Aurelio; Ljuslinder, Ingrid; Palmqvist, Richard; Khaw, Kay Tee; Wareham, Nick; Key, Timothy J.; Travis, Ruth C.; Ferrari, Pietro; Freisling, Heinz; Jenab, Mazda; Gunter, Marc J.; Murphy, Neil; Riboli, Eilo; Tjønneland, Anne; Bueno-De-Mesquita, H. B.

    2014-01-01

    BackgroundFew studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations.MethodsThe association

  15. Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang.

    Science.gov (United States)

    Amaro, Adriana; Chiara, Silvana; Pfeffer, Ulrich

    2016-03-01

    Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial-mesenchymal transition mediated by the TGF-β and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information.

  16. 65Zn kinetics as a biomarker of DMH induced colon carcinogenesis

    International Nuclear Information System (INIS)

    Chadha, Vijayta Dani

    2012-01-01

    Dietary factors are considered crucial for the prevention of initiating events in the multistep progression of colon carcinoma. There is substantial evidence that zinc may play a pivotal role in host defense against several malignancies, including colon cancer. The present study was conducted to evaluate the kinetics of zinc utilization following experimental colon carcinogenesis in rat model. The rats were segregated into two groups viz., untreated control and DMH treated. Colon carcinogenesis was established through weekly subcutaneous injections of DMH (30mg/Kg body weight) for 16 weeks. Whole body 65 Zn kinetics followed two compartment kinetics, with Tb1 representing the initial fast component of the biological half-life and Tb2, the slower component. The present study revealed a significant depression in the Tb1 and Tb2 components of 65 Zn in DMH treated rats. Further, DMH treatment caused a significant increase in the percent uptake values of 65 Zn in the colon, small intestine, kidney and blood, whereas a significant decrease was observed in the liver. Subcellular distribution revealed a significant increase in 65 Zn uptake in the mitochondrial and microsomal fractions following 16 weeks of DMH supplementation. The present study demonstrated a slow mobilization of zinc during promotion of experimentally induced colon carcinogenesis and provides a physiological basis for the role of zinc in colon tumorigenesis, a paradigm which may have clinical implications in the management of colon cancer. (author)

  17. Chemopreventive Effect of Aster glehni on Inflammation-Induced Colorectal Carcinogenesis in Mice

    Directory of Open Access Journals (Sweden)

    Kyung-Sook Chung

    2018-02-01

    Full Text Available Although Aster glehni is a common dietary herb that has various bioactivities, including anti-diabetic, anti-adipogenic, and anti-inflammatory effects, A. glehni has not been studied in colon cancer. Therefore, we hypothesized the chemopreventive effects of an ethanol extract of A. glehni (AG on azoxymethane/dextran sulfate sodium (AOM/DSS-induced colitis-associated cancer (CAC in mice. In this study, we found that treatment with AG significantly attenuated the AOM/DSS-induced enlargement of the spleen and shortening of the colon. In addition, colonic tumor formation, colonic damage, and increased muscle thickness were significantly reduced in AOM/DSS-induced mice fed AG. Treatment with AG also reduced intestinal interleukin (IL-1β, IL-6, and tumor necrosis factor (TNF-α production and decreased inducible nitric oxide synthase (iNOS and cyclooxygenase (COX-2 protein expression in mice with AOM/DSS-induced CAC. Furthermore, AG reduced nuclear factor (NF-κB activation via phosphorylation and degradation of inhibitor of kappa Bα (IκBα, leading to inhibition of NF-κB p65 nuclear translocation. It also downregulated the expression of NF-κB-related proteins, including the B-cell lymphoma 2 (Bcl-2 family and inhibitors of apoptosis proteins (IAPs, in mice with AOM/DSS-induced CAC. Taken together, these findings suggest that the treatment with AG inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly mediated by suppression of the NF-κB signaling pathway, indicating that AG could be a promising protective agent against CAC.

  18. Therapeutic effect of hydroxychloroquine on colorectal carcinogenesis in experimental murine colitis.

    Science.gov (United States)

    Yao, Junlin; Xie, Jiansheng; Xie, Binbin; Li, Yiran; Jiang, Liming; Sui, Xinbing; Zhou, Xiaoyun; Pan, Hongming; Han, Weidong

    2016-09-01

    Chronic inflammation in the intestine is a strong risk factor for colitis-associated colorectal cancer (CAC). Hydroxychloroquine (HCQ) is widely used as an anti-inflammatory drug in the treatment of immune-mediated inflammatory disorders and various tumors. However, little is known regarding the effects of HCQ on colitis-associated tumorigenesis. In this study, mice treated with HCQ showed a significant reduction in early-stage colitis following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration, as well as a remarkable inhibition of colonic tumorigenesis and tumor growth at late stages of CAC. Mechanistically, the therapeutic effects of HCQ were attributed to inhibition of inflammatory responses and production of mutagenic reactive oxygen species (ROS) in immune cells and subsequent promotion of apoptosis and cell cycle arrest in tumor cells. Furthermore, we found that HCQ inhibited the production of inflammatory cytokines and ROS in response to toll-like receptor 4 (TLR4) activation in macrophages. Our data presented herein may help guide the clinical use of HCQ as a prevention and treatment strategy for CAC. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The Differential Expression of Core Genes in Nucleotide Excision Repair Pathway Indicates Colorectal Carcinogenesis and Prognosis

    Directory of Open Access Journals (Sweden)

    Jingwei Liu

    2018-01-01

    Full Text Available Background. Nucleotide excision repair (NER plays a critical role in maintaining genome integrity. This study aimed to investigate the expression of NER genes and their associations with colorectal cancer (CRC development. Method. Expressions of NER genes in CRC and normal tissues were analysed by ONCOMINE. The Cancer Genome Atlas (TCGA data were downloaded to explore relationship of NER expression with clinicopathological parameters and survival of CRC. Results. ERCC1, ERCC2, ERCC5, and DDB2 were upregulated while ERCC4 was downregulated in CRC. For colon cancer, high ERCC3 expression was related to better T stage; ERCC5 expression indicated deeper T stage and distant metastasis; DDB2 expression suggested earlier TNM stage. For rectal cancer, ERCC2 expression correlated with favourable T stage; XPA expression predicted worse TNM stage. ERCC2 expression was associated with worse overall survival (OS in colon cancer (HR=1.53, P=0.043. Colon cancer patients with high ERCC4 expression showed favorable OS in males (HR=0.54, P=0.035. High XPC expression demonstrated decreased death hazards in rectal cancer (HR=0.40, P=0.026. Conclusion. ERCC1, ERCC2, ERCC4, ERCC5, and DDB2 were differently expressed in CRC and normal tissues; ERCC2, ERCC3, ERCC5, XPA, and DDB2 correlated with clinicopathological parameters of CRC, while ERCC2, ERCC4, and XPC might predict CRC prognosis.

  20. Mutator/hypermutable fetal/juvenile metakaryotic stem cells and human colorectal carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Lohith G. Kini

    2013-10-01

    Full Text Available Adult age-specific colorectal cancer incidence rates increase exponentially from maturity, reach a maximum, then decline in extreme old age. Armitage and Doll (1957 postulated that the exponential increase resulted from n mutations occurring throughout adult life in normal cells at risk that initiated the growth of a preneoplastic colony in which subsequent m mutations promoted one of the preneoplastic cells at risk to form a lethal neoplasia. We have reported cytologic evidence that these cells at risk are fetal/juvenile organogenic, then preneoplastic metakaryotic stem cells. Metakaryotic cells display stem-like behaviors of both symmetric and asymmetric nuclear divisions and peculiarities such as bell shaped nuclei and amitotic nuclear fission that distinguish them from embryonic, eukaryotic stem cells. Analyses of mutant colony sizes and numbers in adult lung epithelia supported the inferences that the metakaryotic organogenic stem cells are constitutively mutator/hypermutable and that their contributions to cancer initiation are limited to the fetal/juvenile period. We have amended the two-stage model of Armitage and Doll and incorporated these several inferences in a computer program CancerFit v.5.0. We compared the expectations of the amended model to adult (15-104 yr age-specific colon cancer rates for European American males born 1890-99 and observed remarkable concordance. When estimates of normal colonic fetal/juvenile APC and OAT gene mutation rates (~2-5 x 10-5 per stem cell doubling and preneoplastic colonic gene loss rates (~ 8 x 10-3 were applied, the model was in accordance only for the values of n = 2 and m = 4 or 5.

  1. Composite Biomarkers For Non-invasive Screening, Diagnosis And Prognosis Of Colorectal Cancer

    KAUST Repository

    Mansour, Hicham

    2014-09-11

    The present invention concerns particular biomarkers for diagnosing and/or prognosticating colorectal cancer, in particular in a non-invasive manner. The methods and compositions concern analysis of methylation patterns of one or more genes from a set of 29 genes identified as described herein. In certain embodiments, the gene set includes at least P15.INK4b, SST, GAS7, CNRIP1, and PIK3CG.

  2. Composite Biomarkers For Non-invasive Screening, Diagnosis And Prognosis Of Colorectal Cancer

    KAUST Repository

    Mansour, Hicham; Incitti, Roberto; Bajic, Vladimir B.

    2014-01-01

    The present invention concerns particular biomarkers for diagnosing and/or prognosticating colorectal cancer, in particular in a non-invasive manner. The methods and compositions concern analysis of methylation patterns of one or more genes from a set of 29 genes identified as described herein. In certain embodiments, the gene set includes at least P15.INK4b, SST, GAS7, CNRIP1, and PIK3CG.

  3. The role of Phosphatidylinositol 3 kinase (PI3K and Cycloxygenase-2 (COX2 in carcinogenesis of colorectal polyps

    Directory of Open Access Journals (Sweden)

    Raul Alberto Anselmi Júnior

    2018-01-01

    Full Text Available Objectives: Determine immunohistochemical expression of Phosphatase and tensin homolog (PTEN, Phosphatidylinositol 3 kinase (PI3K, Cycloxygenase-2 (COX2 and one proliferation marker (Ki67 in colorectal polyps and correlate with clinical and pathological data in search of carcinogenic pathways. Methods: The reports of 297 polyps diagnosed through endoscopy were reviewed for parameters including age, gender, prior colorectal cancer, the presence of multiple polyps, and polyps’ location, appearance and size. Was conducted a microscopic morphometric computerized analysis of immunohistochemical expression using, the selected antibodies and correlated with clinical and pathological variables. Results: The tissue immunohistochemical expression was higher in right colon polyps for the proliferation marker and Phosphatidylinositol 3 kinase (p ≤ 0.0001 and 0.057 respectively. Cycloxygenase-2 and Phosphatase and tensin homolog demonstrated higher tissue immunoexpression in pedunculated polyps (p = 0.009 and 0.002 respectively. Cycloxygenase-2 exhibited higher immunoexpression in larger polyps (p = 0.005. Phosphatidylinositol 3 kinase, Cycloxygenase-2, Phosphatase and tensin homolog and the proliferation marker exhibited higher immunoexpression in high-grade dysplastic polyps (p = 0.031, 0.013, 0.044 and <0.001 respectively. Phosphatase and tensin homolog labeling was higher in polyps with high-grade dysplasia and lower in some of serrated lesions (p = 0.044. Conclusions: The greater expression of the proliferation marker and Phosphatidylinositol 3 kinase in the right colon may be related to right-sided colorectal carcinogenesis. The proliferation marker, Cycloxygenase-2 and Phosphatidylinositol 3 kinase results can be associated with progression of polyps to colorectal cancer. The higher Phosphatase and tensin homolog expression suggests its attempt to control the cell cycle. Resumo: Objetivos: Determinar a expressão imuno-histoquímica de

  4. Physicochemical and nutraceutical properties of moringa (Moringa oleifera) leaves and their effects in an in vivo AOM/DSS-induced colorectal carcinogenesis model.

    Science.gov (United States)

    Cuellar-Nuñez, M L; Luzardo-Ocampo, I; Campos-Vega, R; Gallegos-Corona, M A; González de Mejía, E; Loarca-Piña, G

    2018-03-01

    Moringa (Moringa oleifera) is a plant that has generated great interest in recent years because of its attributed medicinal properties. The aim of this study was to characterize the bioactive compounds of moringa leaves (MO) and evaluate their effect on a colorectal carcinogenesis model. Twenty-four male CD-1 mice were divided into 4 groups: Group 1 fed with basal diet (negative control/NC); Group 2 received AOM/DSS (positive control); Groups 3 and 4 were fed with basal diet supplemented with moringa leaves (2.5% w/w and 5% w/w, respectively) for 12weeks. Moringa leaves exhibited a high content of dietary fiber (~18.75%) and insoluble dietary fiber (2.29%). There were identified 9 phenolic compounds whereas the chlorogenic and ρ-coumaric acid showed the higher contents (44.23-63.34μg/g and 180.45-707.42μg/g, respectively). Moringa leaves decreased the activity of harmful fecal enzymes (β-glucosidase, β-glucuronidase, tryptophanase and urease up to 40%, 43%, 103% and 266%, respectively) as well tumors incidence in male CD1-mice (~50% with 5% w/v of moringa dose). These findings suggest that the bioactive compounds of moringa such as total dietary fiber and phenolic compounds may have chemopreventive capacity. This is the first study of the suppressive effect of moringa leaves in an in vivo model of AOM/DSS-induced colorectal carcinogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment.

    Science.gov (United States)

    Kaiser, Jan Christian; Meckbach, Reinhard; Eidemüller, Markus; Selmansberger, Martin; Unger, Kristian; Shpak, Viktor; Blettner, Maria; Zitzelsberger, Horst; Jacob, Peter

    2016-12-01

    Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology. © The Author 2016. Published by Oxford University Press.

  6. Is Ep-CAM Expression a Diagnostic and Prognostic Biomarker for Colorectal Cancer? A Systematic Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Susu Han

    2017-06-01

    Conclusions: The present findings suggest that Ep-CAM expression may be associated with CRC carcinogenesis, while the loss of Ep-CAM expression is correlated with the progression, metastasis, and poor prognosis of CRC. Ep-CAM expression may be a useful biomarker for the clinical diagnosis of CRC.

  7. Biomarkers Discovery for Colorectal Cancer: A Review on Tumor Endothelial Markers as Perspective Candidates

    Directory of Open Access Journals (Sweden)

    Łukasz Pietrzyk

    2016-01-01

    Full Text Available Colorectal cancer (CRC is the third most common cancer in the world. The early detection of CRC, during the promotion/progression stages, is an enormous challenge for a successful outcome and remains a fundamental problem in clinical approach. Despite the continuous advancement in diagnostic and therapeutic methods, there is a need for discovery of sensitive and specific, noninvasive biomarkers. Tumor endothelial markers (TEMs are associated with tumor-specific angiogenesis and are potentially useful to discriminate between tumor and normal endothelium. The most promising TEMs for oncogenic signaling in CRC appeared to be the TEM1, TEM5, TEM7, and TEM8. Overexpression of TEMs especially TEM1, TEM7, and TEM8 in colorectal tumor tissue compared to healthy tissue suggests their role in tumor blood vessels formation. Thus TEMs appear to be perspective candidates for early detection, monitoring, and treatment of CRC patients. This review provides an update on recent data on tumor endothelial markers and their possible use as biomarkers for screening, diagnosis, and therapy of colorectal cancer patients.

  8. Biomarkers Discovery for Colorectal Cancer: A Review on Tumor Endothelial Markers as Perspective Candidates.

    Science.gov (United States)

    Pietrzyk, Łukasz

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer in the world. The early detection of CRC, during the promotion/progression stages, is an enormous challenge for a successful outcome and remains a fundamental problem in clinical approach. Despite the continuous advancement in diagnostic and therapeutic methods, there is a need for discovery of sensitive and specific, noninvasive biomarkers. Tumor endothelial markers (TEMs) are associated with tumor-specific angiogenesis and are potentially useful to discriminate between tumor and normal endothelium. The most promising TEMs for oncogenic signaling in CRC appeared to be the TEM1, TEM5, TEM7, and TEM8. Overexpression of TEMs especially TEM1, TEM7, and TEM8 in colorectal tumor tissue compared to healthy tissue suggests their role in tumor blood vessels formation. Thus TEMs appear to be perspective candidates for early detection, monitoring, and treatment of CRC patients. This review provides an update on recent data on tumor endothelial markers and their possible use as biomarkers for screening, diagnosis, and therapy of colorectal cancer patients.

  9. Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening: A Case-Control Study.

    Science.gov (United States)

    Bosch, Linda J W; de Wit, Meike; Pham, Thang V; Coupé, Veerle M H; Hiemstra, Annemieke C; Piersma, Sander R; Oudgenoeg, Gideon; Scheffer, George L; Mongera, Sandra; Sive Droste, Jochim Terhaar; Oort, Frank A; van Turenhout, Sietze T; Larbi, Ilhame Ben; Louwagie, Joost; van Criekinge, Wim; van der Hulst, Rene W M; Mulder, Chris J J; Carvalho, Beatriz; Fijneman, Remond J A; Jimenez, Connie R; Meijer, Gerrit A

    2017-12-19

    The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. Case-control study. Colonoscopy-controlled referral population from several centers. 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P control samples (P control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening. Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU

  10. Calcium and α-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers123

    Science.gov (United States)

    Martin, Océane CB; Santarelli, Raphaelle L; Taché, Sylviane; Naud, Nathalie; Guéraud, Françoise; Audebert, Marc; Dupuy, Jacques; Meunier, Nathalie; Attaix, Didier; Vendeuvre, Jean-Luc; Mirvish, Sidney S; Kuhnle, Gunter CG; Cano, Noel; Corpet, Denis E

    2013-01-01

    Background: Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and increases specific biomarkers in the colon of rats. Objectives: We investigated whether cured meat modulates biomarkers of cancer risk in human volunteers and whether specific agents can suppress cured meat–induced preneoplastic lesions in rats and associated biomarkers in rats and humans. Design: Six additives (calcium carbonate, inulin, rutin, carnosol, α-tocopherol, and trisodium pyrophosphate) were added to cured meat given to groups of rats for 14 d, and fecal biomarkers were measured. On the basis of these results, calcium and tocopherol were kept for the following additional experiments: cured meat, with or without calcium or tocopherol, was given to dimethylhydrazine-initiated rats (47% meat diet for 100 d) and to human volunteers in a crossover study (180 g/d for 4 d). Rat colons were scored for mucin-depleted foci, putative precancer lesions. Biomarkers of nitrosation, lipoperoxidation, and cytotoxicity were measured in the urine and feces of rats and volunteers. Results: Cured meat increased nitroso compounds and lipoperoxidation in human stools (both P meat (P = 0.01). Conclusion: Data suggest that the addition of calcium carbonate to the diet or α-tocopherol to cured meat may reduce colorectal cancer risk associated with cured-meat intake. This trial was registered at clinicaltrials.gov as NCT00994526. PMID:24025632

  11. MicroRNAs as growth regulators, their function and biomarker status in colorectal cancer

    Science.gov (United States)

    Cekaite, Lina; Eide, Peter W.; Lind, Guro E.; Skotheim, Rolf I.; Lothe, Ragnhild A.

    2016-01-01

    Gene expression is in part regulated by microRNAs (miRNAs). This review summarizes the current knowledge of miRNAs in colorectal cancer (CRC); their role as growth regulators, the mechanisms that regulate the miRNAs themselves and the potential of miRNAs as biomarkers. Although thousands of tissue samples and bodily fluids from CRC patients have been investigated for biomarker potential of miRNAs (>160 papers presented in a comprehensive tables), none single miRNA nor miRNA expression signatures are in clinical use for this disease. More than 500 miRNA-target pairs have been identified in CRC and we discuss how these regulatory nodes interconnect and affect signaling pathways in CRC progression. PMID:26623728

  12. Exosomal microRNA Biomarkers: Emerging Frontiers in Colorectal and Other Human Cancers

    Science.gov (United States)

    Goel, Ajay; Tovar-Camargo, Oscar A; Toden, Shusuke

    2016-01-01

    Diagnostic strategies, particularly non-invasive blood-based screening approaches, are gaining increased attention for the early detection and attenuation of mortality associated with colorectal cancer (CRC). However, the majority of current screening approaches are inadequate at replacing the conventional CRC diagnostic procedures. Yet, due to technological advances and a better understanding of molecular events underlying human cancer, a new category of biomarkers are on the horizon. Recent evidence indicates that cells release a distinct class of small vesicles called ‘exosomes’, which contain nucleic acids and proteins that reflect and typify host-cell molecular architecture. Intriguingly, exosomes released from cancer cells have a distinct genetic and epigenetic makeup, which allows them to undertake their tumorigenic function. From a clinical standpoint, these unique cancer-specific fingerprints present in exosomes appear to be detectable in a small amount of blood, making them very attractive substrates for developing cancer biomarkers, particularly noninvasive diagnostic approaches. PMID:26892862

  13. Cell-free nucleic acids as noninvasive biomarkers for colorectal cancer detection

    KAUST Repository

    Mansour, Hicham

    2014-08-27

    Cell-free nucleic acids (CFNA) have been reported by several authors in blood, stool, and urine of patients with colorectal cancer (CRC). These genetic biomarkers can be an indication of neoplastic colorectal epithelial cells, and can thus potentially be used as noninvasive tests for the detection of the disease in CRC patients and monitor their staging, without the need to use heavier and invasive tools. In a number of test-trials, these genetic tests have shown the advantage of non-invasiveness, making them well accepted by most of the patients, without major side effects. They have also shown a promising sensitivity and specificity in the detection of malignant and premalignant neoplasms. Moreover, costs for performing such tests are very low. Several studies reported and confirmed the proof of the principle for these genetic tests for screening, diagnosis, and prognosis; the main challenge of translating this approach from research to clinical laboratory is the validation from large and long-term randomized trials to prove sustainable high sensitivity and specificity. In this paper, we present a review on the noninvasive genetics biomarkers for CRC detection described in the literature and the challenges that can be encountered for validation processes.

  14. Cell-free nucleic acids as noninvasive biomarkers for colorectal cancer detection

    KAUST Repository

    Mansour, Hicham

    2014-01-01

    Cell-free nucleic acids (CFNA) have been reported by several authors in blood, stool, and urine of patients with colorectal cancer (CRC). These genetic biomarkers can be an indication of neoplastic colorectal epithelial cells, and can thus potentially be used as noninvasive tests for the detection of the disease in CRC patients and monitor their staging, without the need to use heavier and invasive tools. In a number of test-trials, these genetic tests have shown the advantage of non-invasiveness, making them well accepted by most of the patients, without major side effects. They have also shown a promising sensitivity and specificity in the detection of malignant and premalignant neoplasms. Moreover, costs for performing such tests are very low. Several studies reported and confirmed the proof of the principle for these genetic tests for screening, diagnosis, and prognosis; the main challenge of translating this approach from research to clinical laboratory is the validation from large and long-term randomized trials to prove sustainable high sensitivity and specificity. In this paper, we present a review on the noninvasive genetics biomarkers for CRC detection described in the literature and the challenges that can be encountered for validation processes.

  15. Long non-coding RNA PVT1 as a novel potential biomarker for predicting the prognosis of colorectal cancer.

    Science.gov (United States)

    Fan, Heng; Zhu, Jian-Hua; Yao, Xue-Qing

    2018-05-01

    Long non-coding RNA (lncRNA) plays a very important role in the occurrence and development of various tumors, and is a potential biomarker for cancer diagnosis and prognosis. The purpose of this study was to investigate the relationship between the expression of lncRNA plasmacytoma variant translocation 1 (PVT1) and the prognostic significance in patients with colorectal cancer. The expression of PVT1 was measured by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in cancerous and adjacent tissues of 210 colorectal cancer patients. The disease-free survival and overall survival of colorectal cancer patients were evaluated by Kaplan-Meier analysis, and univariate and multivariate analysis were performed by Cox proportional-hazards model. Our results revealed that PVT1 expression in cancer tissues of colorectal cancer was significantly higher than that of adjacent tissues ( Pcolorectal cancer patients, whether at TNM I/II stage or at TNM III/IV stage. A multivariate Cox regression analysis demonstrated that high PVT1 expression was an independent predictor of poor prognosis in colorectal cancer patients. Our results suggest that high PVT1 expression might be a potential biomarker for assessing tumor recurrence and prognosis in colorectal cancer patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Lucia Perez-Carbonell

    Full Text Available Aberrant hypermethylation of cancer-related genes has emerged as a promising strategy for the development of diagnostic, prognostic and predictive biomarkers in human cancer, including colorectal cancer (CRC. The aim of this study was to perform a systematic and comprehensive analysis of a panel of CRC-specific genes as potential diagnostic, prognostic and predictive biomarkers in a large, population-based CRC cohort.Methylation status of the SEPT9, TWIST1, IGFBP3, GAS7, ALX4 and miR137 genes was studied by quantitative bisulfite pyrosequencing in a population-based cohort of 425 CRC patients.Methylation levels of all genes analyzed were significantly higher in tumor tissues compared to normal mucosa (p<0.0001; however, cancer-associated hypermethylation was most frequently observed for miR137 (86.7% and IGFBP3 (83% in CRC patients. Methylation analysis using the combination of these two genes demonstrated greatest accuracy for the identification of colonic tumors (sensitivity 95.5%; specificity 90.5%. Low levels of IGFBP3 promoter methylation emerged as an independent risk factor for predicting poor disease free survival in stage II and III CRC patients (HR = 0.49, 95% CI: 0.28-0.85, p = 0.01. Our results also suggest that stage II & III CRC patients with high levels of IGFBP3 methylation do not benefit from adjuvant 5FU-based chemotherapy.By analyzing a large, population-based CRC cohort, we demonstrate the potential clinical significance of miR137 and IGFBP3 hypermethylation as promising diagnostic biomarkers in CRC. Our data also revealed that IGFBP3 hypermethylation may serve as an independent prognostic and predictive biomarker in stage II and III CRC patients.

  18. The RS4939827 polymorphism in the SMAD7 GENE and its association with Mediterranean diet in colorectal carcinogenesis.

    Science.gov (United States)

    Alonso-Molero, Jéssica; González-Donquiles, Carmen; Palazuelos, Camilo; Fernández-Villa, Tania; Ramos, Elena; Pollán, Marina; Aragonés, Nuria; Llorca, Javier; Henar Alonso, M; Tardón, Adonina; Amiano, Pilar; Moleon, José Juan Jiménez; Pérez, Rosana Peiró; Capelo, Rocío; Molina, Antonio J; Acebo, Inés Gómez; Guevara, Marcela; Perez-Gomez, Beatriz; Lope, Virginia; Huerta, José María; Castaño-Vinyals, Gemma; Kogevinas, Manolis; Moreno, Victor; Martín, Vicente

    2017-10-30

    The objective of our investigation is to study the relationship between the rs4939827 SNP in the SMAD7 gene, Mediterranean diet pattern and the risk of colorectal cancer. We examined 1087 cases of colorectal cancer and 2409 population controls with available DNA samples from the MCC-Spain study, 2008-2012. Descriptive statistical analyses, and multivariate logistic mixed models were performed. The potential synergistic effect of rs4939827 and the Mediterranean diet pattern was evaluated with logistic regression in different strata of of adherence to the Mediterranean diet and the genotype. High adherence to Mediterrenean diet was statistically significantly associated with colorectal cancer risk. A decreased risk for CRC cancer was observed for the CC compared to the TT genotype (OR = 0.65 and 95% CI = 0.51-0.81) of the rs4939827 SNP Also, we could show an association between the Mediterranean diet pattern (protective factor) and rs4939827. Although the decreased risk for the CC genotype was slightly more pronounced in subjects with high adherence to Mediterrenean diet, there was no statistically significant synergistic effect between genotype CC and adherence to the Mediterranean dietary pattern factors. The SMAD7 gene and specifically the allele C could be protective for colorectal cancer. An independent protective association was also observed between high adherence Mediterranean diet pattern and CRC risk. Findings form this study indicate that high adherence to Mediterranean diet pattern has a protective role for CRC cancer probably involving the Tumor Growth Factor- β pathway in this cancer.

  19. Molecular Genetic Changes Associated With Colorectal Carcinogenesis Are Not Prognostic for Tumor Regression Following Preoperative Chemoradiation of Rectal Carcinoma

    International Nuclear Information System (INIS)

    Zauber, N. Peter; Marotta, Steven P.; Berman, Errol; Grann, Alison; Rao, Maithili; Komati, Naga; Ribiero, Kezia; Bishop, D. Timothy

    2009-01-01

    Purpose: Preoperative chemotherapy and radiation has become the standard of care for many patients with rectal cancer. The therapy may have toxicity and delays definitive surgery. It would therefore be desirable to identify those cancers that will not regress with preoperative therapy. We assessed a series of rectal cancers for the molecular changes of loss of heterozygosity of the APC and DCC genes, K-ras mutations, and microsatellite instability, changes that have clearly been associated with rectal carcinogenesis. Methods and Materials: Diagnostic colonoscopic biopsies from 53 patients who received preoperative chemotherapy and radiation were assayed using polymerase chain reaction techniques followed by single-stranded conformation polymorphism and DNA sequencing. Regression of the primary tumor was evaluated using the surgically removed specimen. Results: Twenty-three lesions (45%) were found to have a high degree of regression. None of the molecular changes were useful as indicators of regression. Conclusions: Recognized molecular changes critical for rectal carcinogenesis including APC and DCC loss of heterozygosity, K-ras mutations, and microsatellite instability are not useful as indicators of tumor regression following chemoradiation for rectal carcinoma.

  20. Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Palshof, Jesper Andreas; Hogdall, Estrid Vilma Solyom; Poulsen, Tim Svenstrup

    2017-01-01

    Background No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients...... were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. Results In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5–9.5) and 2.......00 (range: 0.55–4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82–10.43) and 1.98 (range: 1.22–6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92–2.90) and 2.05 (range: 1.00–6.00), respectively. None...

  1. MicroRNA dysregulation as a prognostic biomarker in colorectal cancer

    International Nuclear Information System (INIS)

    Dong, Yujuan; Yu, Jun; Ng, Simon SM

    2014-01-01

    Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor–node–metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtypes and predict clinical outcomes. In this review, we summarize recent findings concerning the prognostic potential of microRNAs (miRNAs) in CRC. We first discuss the prognostic value of three tissue miRNAs (miR-21-5p, miR-29-3p, miR-148-3p) that have been examined in multiple studies. We also summarize the dysregulation of miRNA processing machinery DICER in CRC and its association with risk for mortality. We also reviewe the potential application of miRNA-associated single-nucleotide polymorphisms as prognostic biomarkers for CRC, especially the miRNA-associated polymorphism in the KRAS gene. Last but not least, we discuss the microsatellite instability-related miRNA candidates. Among all these candidates, miR-21-5p is the most promising prognostic marker, yet further prospective validation studies are required before it can go into clinical usage

  2. Exosomes As Potential Biomarkers and Targeted Therapy in Colorectal Cancer: A Mini-Review

    Directory of Open Access Journals (Sweden)

    Kha Wai Hon

    2017-08-01

    Full Text Available The number of colorectal cancer (CRC cases have increased gradually year by year. In fact, CRC is one of the most widely diagnosed cancer in men and women today. This disease is usually diagnosed at a later stage of the development, and by then, the chance of survival has declined significantly. Even though substantial progress has been made in understanding the basic molecular mechanism of CRC, there is still a lack of understanding in using the available information for diagnosing CRC effectively. Liquid biopsies are minimally invasive and have become the epitome of a good screening source for stage-specific diagnosis, measuring drug response and severity of the disease. There are various circulating entities that can be found in biological fluids, and among them, exosomes, have been gaining considerable attention. Exosomes can be found in almost all biological fluids including serum, urine, saliva, and breast milk. Furthermore, exosomes carry valuable molecular information such as proteins and nucleic acids that directly reflects the source of the cells. Nevertheless, the inconsistent yield and isolation process and the difficulty in obtaining pure exosomes have become major obstacles that need to be addressed. The potential usage of exosomes as biomarkers have not been fully validated and explored yet. This review attempts to uncover the potential molecules that can be derived from CRC-exosomes as promising biomarkers or molecular targets for effective diagnosing of CRC.

  3. Assessment of lipid peroxidation and p53 as a biomarker of carcinogenesis among workers exposed to formaldehyde in the cosmetic industry.

    Science.gov (United States)

    Attia, Dalia; Mansour, Neveen; Taha, Fatma; Seif El Dein, Aisha

    2016-06-01

    Despite the wide use of cosmetic products, they exert a number of health effects on tissues ranging from irritation to cancer. Our study aimed at assessing the effect of formaldehyde on lipid peroxidation and verifying the susceptibility to carcinogenesis using p53 as a biomarker among workers exposed to formaldehyde in cosmetic industry. Our entire exposed group (n = 40) and the controls (n = 20) were subjected to estimation of formate in urine, serum malondialdehyde (MDA), and p53. Also, complete blood picture, liver, and kidney function tests were carried out. The study revealed significant increase in the levels of formate, MDA, and p53 in the exposed group compared with their control group. Our results showed that workers in cosmetic industry had significant exposure to formaldehyde. Furthermore, the study pointed to the negative impact of formaldehyde as a cause of oxidative stress and suspicious carcinogen. © The Author(s) 2014.

  4. Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer.

    Science.gov (United States)

    Peng, Ke; Liu, Ruiqi; Yu, Yiyi; Liang, Li; Yu, Shan; Xu, Xiaojing; Liu, Tianshu

    2018-01-01

    Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling

    International Nuclear Information System (INIS)

    Petty, Russell D; Wang, Weiguang; Gilbert, Fiona; Semple, Scot; Collie-Duguid, Elaina SR; Samuel, Leslie M; Murray, Graeme I; MacDonald, Graham; O'Kelly, Terrence; Loudon, Malcolm; Binnie, Norman; Aly, Emad; McKinlay, Aileen

    2009-01-01

    5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets. Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified. APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent withAPRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set

  6. SATB2 is a Promising Biomarker for Identifying a Colorectal Origin for Liver Metastatic Adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Yi-Jun Zhang

    2018-02-01

    Full Text Available SATB2 (Special AT-rich sequence-binding protein 2 has recently been shown to be a specific biomarker of colorectal cancer (CRC. The aim of this study was to investigate the diagnostic potential of SATB2 as a means of detecting a CRC origin for liver metastases. SATB2 expression was examined in a resection cohort of 101 CRC and 273 non-CRC adenocarcinoma samples using immunohistochemistry (IHC. The diagnostic accuracy of CRC origins of liver metastases based on SATB2 and a three marker panel of SATB2, CK20 and CDX2 was evaluated using an independent cohort of 192 liver biopsies. IHC showed 97 of the 101 (96.0% primary CRC samples were SATB2 positive, compared to only 6 of the 273 (2.1% samples of other cancer types. The sensitivity, specificity and AUC values of SATB2 expression in resection samples were 97%, 97.1% and 0.977, respectively. Meanwhile, for the liver biopsy samples, the sensitivity, specificity and AUC values of a CRC liver metastases was 92.2%, 97.8% and 0.948 for SATB2, 95.1%, 91.0% and 0.959 for CK20, and 100%, 85.4% and 0.976 for CDX2, respectively. Further analysis demonstrated that all three-marker positivity was detected in 92/103 (89.3% CRC and 2/89 (2.2% non-CRC liver metastases sampled by biopsy. Our findings suggest that SATB2, as measured by IHC, could serve as a promising diagnostic biomarker of CRC metastases. Combining evaluation of SATB2 with CK20 and CDX2 to form a three marker panel further improved the detection of metastatic CRCs in liver biopsy tissues.

  7. Biomarkers for the early detection of relapses in metastatic colorectal cancers.

    Science.gov (United States)

    Chereches, Gabriela; Barbos, Otilia; Buiga, Rares; Balacescu, Ovidiu; Iancu, Dana; Todor, Nicolae; Balacescu, Loredana; Miron, Nicu; Bejinariu, Nona; Ciuleanu, Tudor-Eliade

    2017-01-01

    To assess prognostic/predictive value of carcinoembryonic antigen (CEA), transthyretin (TRT), αenolase (NNE), β2-microglobulin (β2-micro), B-cell activating factor (BAFF) and circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) patients treated with chemotherapy with or without bevacizumab. 72 histologically confirmed mCRC patients treated at Oncology Institute Cluj were included. Biomarker levels were measured through validated methods. A manual method was used for CTCs, involving hemolysis, cytospin centrifugation and immunocytochemical staining for pan-cytokeratin. Statistical endpoints were response, progression- free survival (PFS) and overall survival (OS). Initial chemotherapy was fluoropyrimidine/oxaliplatin-based in 93.1%; bevacizumab was added in 58.3% of the patients. Median PFS and OS were 16.4 and 24.4 months. Two-year OS for CR & PR vs SD vs PD were 90% vs 48% vs 12%, respectively (p<0.01). Two-year OS for chemo/ bevacizumab vs chemotherapy: 65% vs 42% (p=0.09). Baseline CEA ≥5 ng/ml had a negative prognostic impact on OS and PFS (p<0.01). High baseline CEA was predictive of improved OS when adding bevacizumab (2-year OS chemo/bevacizumab vs chemo: 60% vs 17%, p<0.01); adding bevacizumab in patients with normal CEA did not improve OS (p=0.29). Higher than cut-off values for TRT had a positive OS prognostic value (p<0.01); higher levels for NNE, β2-microglobulin and BAFF had a negative impact (p<0.01). Two-year OS for baseline <1 CTC/ml vs ≥1 CTC/ ml was 74% vs 64% respectively (p=0.15). The evaluated biomarkers could be useful prognostic factors for survival. Baseline CEA also has predictive value, suggesting that patients with low levels do not benefit from bevacizumab. A non-statistically significant correlation was observed between the number of CTCs and outcome.

  8. Ensemble of gene signatures identifies novel biomarkers in colorectal cancer activated through PPARγ and TNFα signaling.

    Directory of Open Access Journals (Sweden)

    Stefano Maria Pagnotta

    Full Text Available We describe a novel bioinformatic and translational pathology approach, gene Signature Finder Algorithm (gSFA to identify biomarkers associated with Colorectal Cancer (CRC survival. Here a robust set of CRC markers is selected by an ensemble method. By using a dataset of 232 gene expression profiles, gSFA discovers 16 highly significant small gene signatures. Analysis of dichotomies generated by the signatures results in a set of 133 samples stably classified in good prognosis group and 56 samples in poor prognosis group, whereas 43 remain unreliably classified. AKAP12, DCBLD2, NT5E and SPON1 are particularly represented in the signatures and selected for validation in vivo on two independent patients cohorts comprising 140 tumor tissues and 60 matched normal tissues. Their expression and regulatory programs are investigated in vitro. We show that the coupled expression of NT5E and DCBLD2 robustly stratifies our patients in two groups (one of which with 100% survival at five years. We show that NT5E is a target of the TNF-α signaling in vitro; the tumor suppressor PPARγ acts as a novel NT5E antagonist that positively and concomitantly regulates DCBLD2 in a cancer cell context-dependent manner.

  9. Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin.

    Science.gov (United States)

    Cohen, Stacey A; Wu, Chen; Yu, Ming; Gourgioti, Georgia; Wirtz, Ralph; Raptou, Georgia; Gkakou, Chryssa; Kotoula, Vassiliki; Pentheroudakis, George; Papaxoinis, George; Karavasilis, Vasilios; Pectasides, Dimitrios; Kalogeras, Konstantine T; Fountzilas, George; Grady, William M

    2016-06-01

    The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy. The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvant XELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival. Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

    International Nuclear Information System (INIS)

    Lim, Yoojoo; Lee, Kyung-Hun; Bang, Ji-In; Paeng, Jin Chul; Han, Sae-Won; Kim, Jee Hyun; Kang, Gyeong Hoon; Jeong, Seung-Yong; Park, Kyu Joo; Kim, Tae-You

    2017-01-01

    This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC). Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome. A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG 40 % ). Further analysis using TLG 40 % showed significantly longer overall survival (OS) in patients with lower baseline TLG 40 % (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG 40 % after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in % ΔTLG 40 % < -9.6 % and ≥ -9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in % ΔTLG 40 % < -9.6 % and ≥ -9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049). Measurement of TLG can predict treatment outcome of regorafenib in mCRC. (orig.)

  11. Impact of Novel Prebiotic Galacto-Oligosaccharides on Various Biomarkers of Colorectal Cancer in Wister Rats

    Directory of Open Access Journals (Sweden)

    Tahir Rasool Qamar

    2017-08-01

    Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer deaths around the globe. Bioactive food ingredients such as prebiotics have protective potential in colon cancer. Data on galacto-oligosaccharides (GalOS against CRC are very limited and GalOS used in this study have β-1,6 and β-1,3 as major glycosidic linkages and, to our best knowledge, were never used before against any cancer treatment. This study aims to investigate the protective role of novel GalOS against various biomarkers of CRC including aberrant crypt foci (ACF, bacterial enzymes and short chain fatty acids (SCFA in a rodent model induced with 1,2-dimethylhydrazine dihydrochloride (DMH. Inulin group was taken as positive control in present study to compare novel GalOS protective effects. GalOS doses of 76–151 mg and inulin doses of 114 mg were given to different groups treated with DMH. Results showed that ACF formation was significantly (p ≤ 0.05 less in high dose GalOS group (27.3%. GalOS also had protective effects against DMH-induced body weight loss and showed higher level of cecal and fecal SCFA (acetate, propionate and butyrate. High doses of GalOS also resulted in significant (p ≤ 0.05 reduction of bacterial enzymatic activities. Increased populations of beneficial bacteria (bifidobacteria and lactobacilli and decreased concentrations of harmful bacteria were observed in all prebiotics treatment groups. It can be concluded that novel GalOS exhibit robust protective activity against ACF formation in vivo.

  12. 14C glucose uptake and turnover, a biomarker in benzo(a)pyrene induced lung carcinogenesis: role of curcumin and resveratrol

    International Nuclear Information System (INIS)

    Malhotra, Anshoo; Nair, P.; Dhawan, D.K.

    2010-01-01

    in the BP treated mice. Supplementation with curcumin alone to BP treated mice resulted in a significant decrease in the tumor incidence as well as tumor multicity which were observed to be 77% and 1.42 respectively. Also, resveratrol significantly decreased tumor incidence and tumor multiplicity to 75% and 1.33 respectively. However, upon combined supplementation with phytochemicals, an appreciable decrease in the tumor incidence and multiplicity was observed which was found to be 66% and 1.16 respectively. Further, Supplementation with curcumin alone to BP treated mice resulted in statistically significant moderation in 14 C glucose uptake. Interestingly, individual treatment with resveratrol as well as combined treatment of both phytochemicals brought statistically significant moderation in 14 C glucose uptake as well as 14 C glucose turnover in the BP treated mice. Also, phytochemicals supplementation individually as well as in combination appreciably improved ultra histoarchitecture of lungs. The present study concludes that combined supplementation with curcumin and resveratrol modulates glucose metabolism and improves ultra-histoarchitectural changes during lung carcinogenesis and 14 C uptake and turnover can be used as biomarker for the assessment of carcinogenesis

  13. Radiation carcinogenesis

    International Nuclear Information System (INIS)

    1978-01-01

    The Cancergram deals with all aspects of radiation carcinogenesis. The term radiation here includes U-V radiation and the entire electromagnetic spectrum, electron and other charged particle beams, neutrons, and alpha and beta radiation from radioactive substances. Abstracts included concern relationships between radiation and carcinogenesis in humans, experimental induction of tumors in animals by irradiation, studies on the mechanism of radiation carcinogenesis at the cellular level, studies of RBE, dose response or dose threshold in relation to radiation carcinogenesis, and methods and policies for control of radiation exposure in the general population. In general, this Cancergram excludes abstracts on radio-therapy, radiologic diagnosis, radiation pathology, and radiation biology, where these articles have no bearing on radiation carcinogenesis

  14. Monitoring carcinogenesis in a case of oral squamous cell carcinoma using a panel of new metabolic blood biomarkers as liquid biopsies.

    Science.gov (United States)

    Grimm, Martin; Hoefert, Sebastian; Krimmel, Michael; Biegner, Thorsten; Feyen, Oliver; Teriete, Peter; Reinert, Siegmar

    2016-09-01

    One of the common malignant tumors of the head and neck worldwide with generally unfavorable prognosis is squamous cell carcinoma (OSCC) of the oral cavity. Early detection of primary, secondary, or recurrent OSCC by liquid biopsy tools is much needed. Twelve blood biomarkers were used for monitoring a case of OSCC suffering from precancerous oral lichen ruber planus mucosae (OLP). After curative R0 tumor resection of primary OSCC (buccal mucosa), elevated epitope detection in monocytes (EDIM)-Apo10, EDIM-transketolase-like-1 (TKTL1), squamous cell carcinoma antigen (SCC-Ag), total serum lactate dehydrogenase (LDH), and its anaerobic isoforms (LDH-4, LDH-5) decreased to normal levels. Three and six months after surgery, transformation of suspicious mucosal lesions has been accompanied with an increase of EDIM scores, total serum LDH values, and a metabolic shift from aerobic (decrease of LDH-1, LDH-2) to anaerobic (increase of LDH-4, LDH-5) conditions. Two months later, secondary OSCC was histopathologically analyzed after tissue biopsy. Cytokeratin fraction 21-1 (CYFRA 21-1), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were not affected during the clinical course of carcinogenesis. A combination strategy using a standardized panel of established (metabolic) blood biomarkers (TKTL1, LDH, LDH isoenzymes) is worth and can be recommended among others (apoptosis resistance-related Apo10, SCC-Ag) for early detection and diagnosis of primary, secondary, and recurrent OSCC. A tandem strategy utilizing (metabolic pronounced) routine liquid biopsies with imaging techniques may enhance diagnosis of OSCC in the future. Although we demonstrated the diagnostic utility of separated liquid biopsies in our previous study cohorts, further investigations in a larger patient cohort are necessary to recommend this combination strategy (EDIM blood test, LDH value, metabolic shift of LDH isoenzymes, and others, e.g., SCC-Ag or immunophenotyping) as a

  15. DEK over expression as an independent biomarker for poor prognosis in colorectal cancer

    International Nuclear Information System (INIS)

    Lin, Lijuan; Piao, Junjie; Gao, Wenbin; Piao, Yingshi; Jin, Guang; Ma, Yue; Li, Jinzi; Lin, Zhenhua

    2013-01-01

    The DEK protein is related to chromatin reconstruction and gene transcription, and plays an important role in cell apoptosis. High expression levels of the human DEK gene have been correlated with numerous human malignancies. This study explores the roles of DEK in tumor progression and as a prognostic determinant of colorectal cancer. Colorectal cancer specimens from 109 patients with strict follow-up, and colorectal adenomas from 52 patients were selected for analysis of DEK protein by immunohistochemistry. The correlations between DEK over expression and the clinicopathological features of colorectal cancers were evaluated by Chi-square test and Fisher’s exact tests. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. DEK protein showed a nuclear immunohistochemical staining pattern in colorectal cancers. The strongly positive rate of DEK protein was 48.62% (53/109) in colorectal cancers, which was significantly higher than that in either adjacent normal colon mucosa (9.17%, 10/109) or colorectal adenomas (13.46%, 7/52). DEK over expression in colorectal cancers was positively correlated with tumor size, grade, lymph node metastasis, serosal invasion, late stage, and disease-free survival- and 5-year survival rates. Further analysis showed that patients with late stage colorectal cancer and high DEK expression had worse survival rates than those with low DEK expression. Moreover, multivariate analysis showed high DEK expression, serosal invasion, and late stage are significant independent risk factors for mortality in colorectal cancer. DEK plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor of colorectal cancers

  16. Detection of serological biomarkers by proximity extension assay for detection of colorectal neoplasias in symptomatic individuals

    DEFF Research Database (Denmark)

    Buch Thorsen, Stine; Lundberg, Martin; Villablanca, Andrea

    2013-01-01

    of biomarkers from the bench to clinical practice we initiated a biomarker study focusing on a novel technique, the proximity extension assay, with multiplexing capability and the possible additive effect obtained from biomarker panels. We performed a screening of 74 different biomarkers in plasma derived from...

  17. Meat and cancer: haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats

    Science.gov (United States)

    Pierre, Fabrice; Taché, Sylviane; Petit, Claude R; Van Der Meer, Roelof; Corpet, Denis E

    2003-01-01

    High intake of red meat, but not of white meat, is associated with an increased risk of colon cancer. However, red meat does not promote cancer in rodents. Haemin, added to low-calcium diets, increases colonic proliferation, and haemoglobin, added to high-fat diets, increases the colon tumour incidence in rats, an effect possibly due to peroxyl radicals. We thus speculated that haem might be the promoting agent in meat, and that prevention strategies could use calcium and antioxidants. These hypotheses were tested in rats at the aberrant crypt foci (ACF) stage at 100 days. F344 rats (n=124) were given an injection of azoxymethane and were then randomised to 11 groups fed with low-calcium (20μmol/g) AIN76-based diets, containing 5% safflower oil. Haemin (0.25, 0.5 and 1.5μmol/g) or haemoglobin (1.5 and 3 μmol haem/g) was added to five experimental diets, compared to a control diet without haem. Three other high-haemin diets (1.5μmol/g) were supplemented with calcium (250μmol/g), antioxidant butylated hydroxyanisole and rutin (0.05% each), and olive oil, which replaced safflower oil. Faecal water was assayed for lipid peroxidation by thiobarbituric acid reactive substances (TBARs) test, and for cytolytic activity. Haemin strikingly increased the ACF size, dose-dependently, from 2.6 to 11.4 crypts/ACF (all p<0.001). The high-haemin diet also increased the number of ACF per colon (p<0.001). Promotion was associated with increased faecal water TBARs and cytotoxicity. Calcium, olive oil, and antioxidants each inhibited the haemin-induced ACF promotion, and normalised the faecal TBARs and cytotoxicity. The haemoglobin diets increased the number of ACF and faecal TBARs, but not the ACF size or the faecal cytotoxicity. In conclusion, dietary haemin is the most potent known ACF promoter. Haemoglobin is also a potent promoter of colorectal carcinogenesis. The results suggest that myoglobin in red meat could promote colon cancer. Diets high in calcium, or in oxidation

  18. Biological variations in plasma VEGF and VEGFR-1 may compromise their biomarker value in colorectal cancer

    DEFF Research Database (Denmark)

    Svendsen, Mads N.; Brunner, Nils; Christensen, Ib Jarle

    2010-01-01

    Vascular Endothelial Growth Factor (VEGF) plays a prominent role in tumor angiogenesis and plasma VEGF concentration may carry prognostic information in colorectal cancer. The VEGF receptor 1 (VEGFR-1) is a regulatory receptor which is shredded into plasma of patients with colorectal cancer. For ....... For both molecules, large biological variation and lack of standardization of assay procedures are major challenges....

  19. Up-regulated EMMPRIN/CD147 protein expression might play a role in colorectal carcinogenesis and its subsequent progression without an alteration of its glycosylation and mRNA level.

    Science.gov (United States)

    Zheng, Hua-chuan; Wang, Wei; Xu, Xiao-yan; Xia, Pu; Yu, Miao; Sugiyama, Toshiro; Takano, Yasuo

    2011-04-01

    Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of colorectal carcinomas (CRC). EMMPRIN expression was examined on tissue microarray containing colorectal carcinomas, adenoma and non-neoplastic mucosa (NNM) by immunohistochemistry and in situ hybridization (ISH). Colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) and tissues were studied for EMMPRIN expression by Western blot or RT-PCR, followed by sequencing. All carcinoma cell lines showed EMMPRIN expression at both mRNA and protein levels. Two synonymous mutations were found in carcinoma cell lines at codon109 (GCT → GCC: Ala) or 179 (GAT → GAC: Asp). Frozen CRC tissues displayed higher EMMPRIN expression than paired NNM (P EMMPRIN expression was immunohistochemically stronger in colorectal high-grade adenoma, adenocarcinoma and metastatic carcinoma than non-neoplastic superficial epithelium and low-grade adenoma (P 0.05). Immunohistochemically, EMMPRIN expression was positively correlated with tumor size, depth of invasion, vascular or lymphatic invasion, grade of infiltration (INF), ki-67 and VEGF expression of CRCs (P EMMPRIN expression in CRCs (P EMMPRIN protein expression might contribute to colorectal carcinogenesis without the alteration of its glycosylation and mRNA level. Aberrant EMMPRIN protein expression might promote growth or invasion of CRCs possibly through increased ki-67 expression and inducible angiogenesis via up-regulating VEGF expression.

  20. Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer

    International Nuclear Information System (INIS)

    Larsson, Anna; Fridberg, Marie; Gaber, Alexander; Nodin, Björn; Levéen, Per; Jönsson, Göran; Uhlén, Mathias; Birgisson, Helgi; Jirström, Karin

    2012-01-01

    Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and adverse outcome in several cancer types. We recently demonstrated that overexpression of PODXL is an independent factor of poor prognosis in colorectal cancer (CRC). The aim of this study was to validate these results in two additional independent patient cohorts and to examine the correlation between PODXL mRNA and protein levels in a subset of tumours. PODXL protein expression was analyzed by immunohistochemistry in tissue microarrays with tumour samples from a consecutive, retrospective cohort of 270 CRC patients (cohort 1) and a prospective cohort of 337 CRC patients (cohort 2). The expression of PODXL mRNA was measured by real-time quantitative PCR in a subgroup of 62 patients from cohort 2. Spearman´;s Rho and Chi-Square tests were used for analysis of correlations between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between PODXL expression and time to recurrence (TTR), disease free survival (DFS) and overall survival (OS). High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. In cohort 1, high PODXL expression was associated with a significantly shorter 5-year OS in both univariable (HR = 2.28; 95% CI 1.43-3.63, p = 0.001) and multivariable analysis (HR = 2.07; 95% CI 1.25-3.43, p = 0.005). In cohort 2, high PODXL expression was associated with a shorter TTR (HR = 2.93; 95% CI 1.26-6.82, p = 0.013) and DFS (HR = 2.44; 95% CI 1.32-4.54, p = 0.005), remaining significant in multivariable analysis, HR = 2.50; 95% CI 1.05-5.96, p = 0.038 for TTR and HR = 2.11; 95% CI 1.13-3.94, p = 0.019 for DFS. No significant correlation could be found between mRNA levels and protein expression of PODXL and there was no association between mRNA levels

  1. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Yoojoo; Lee, Kyung-Hun [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Bang, Ji-In; Paeng, Jin Chul [Seoul National University Hospital, Department of Nuclear Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Han, Sae-Won [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Kim, Jee Hyun [Seoul National University Bundang Hospital, Department of Internal Medicine, Geyonggi-do (Korea, Republic of); Kang, Gyeong Hoon [Seoul National University Hospital, Department of Pathology, Seoul (Korea, Republic of); Jeong, Seung-Yong; Park, Kyu Joo [Seoul National University Hospital, Department of Surgery, Seoul (Korea, Republic of); Kim, Tae-You [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of)

    2017-05-15

    This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC). Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome. A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG{sub 40} {sub %}). Further analysis using TLG{sub 40} {sub %} showed significantly longer overall survival (OS) in patients with lower baseline TLG{sub 40} {sub %} (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG{sub 40} {sub %} after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in % ΔTLG{sub 40} {sub %} < -9.6 % and ≥ -9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in % ΔTLG{sub 40} {sub %} < -9.6 % and ≥ -9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049). Measurement of TLG can predict treatment outcome of regorafenib in mCRC. (orig.)

  2. Gastric, pancreatic, and colorectal carcinogenesis following remote peptic ulcer surgery. Review of the literature with the emphasis on risk assessment and underlying mechanism

    NARCIS (Netherlands)

    Offerhaus, G. J.; Tersmette, A. C.; Tersmette, K. W.; Tytgat, G. N.; Hoedemaeker, P. J.; Vandenbroucke, J. P.

    1988-01-01

    Based upon literature data, a 2-fold risk for gastric and colorectal cancer and a 2- to 5-fold risk for pancreatic cancer are predicted after remote peptic ulcer surgery. The association between previous ulcer surgery and subsequent gastric cancer appears firm; the linkage between colorectal and

  3. Pathway activation strength is a novel independent prognostic biomarker for cetuximab sensitivity in colorectal cancer patients

    OpenAIRE

    Zhu, Qingsong; Izumchenko, Evgeny; Aliper, Alexander M; Makarev, Evgeny; Paz, Keren; Buzdin, Anton A; Zhavoronkov, Alex A; Sidransky, David

    2015-01-01

    Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), was shown to be active in colorectal cancer. Although some patients who harbor K-ras wild-type tumors benefit from cetuximab treatment, 40 to 60% of patients with wild-type K-ras tumors do not respond to cetuximab. Currently, there is no universal marker or method of clinical utility that could guide the treatment of cetuximab in colorectal cancer. Here, we demonstrate a method to predict response to cetuximab i...

  4. Changes in cytokine and biomarker blood levels in patients with colorectal cancer during dendritic cell-based vaccination

    DEFF Research Database (Denmark)

    Burgdorf, Stefan K; Claesson, Mogens Helweg; Nielsen, Hans J

    2009-01-01

    Introduction. Immunotherapy based on dendritic cell vaccination has exciting perspectives for treatment of cancer. In order to clarify immunological mechanisms during vaccination it is essential with intensive monitoring of the responses. This may lead to optimization of treatment and prediction...... of responding patients. The aim of this study was to evaluate cytokine and biomarker responses in patients with colorectal cancer treated with a cancer vaccine based on dendritic cells pulsed with an allogeneic melanoma cell lysate. Material and methods. Plasma and serum samples were collected prior...... disease showed increasing levels of plasma GM-CSF, TNF-alpha, IFN-gamma, IL-2, and IL-5. Patients with progressive disease showed significant increase in CEA and TIMP-1 levels, while patients with stable disease showed relatively unaltered levels. Conclusion. The increased levels of key pro...

  5. Changes in cytokine and biomarker blood levels in patients with colorectal cancer during dendritic cell-based vaccination

    DEFF Research Database (Denmark)

    Burgdorf, Stefan; Claesson, Mogens; Nielsen, Hans

    2009-01-01

    Introduction. Immunotherapy based on dendritic cell vaccination has exciting perspectives for treatment of cancer. In order to clarify immunological mechanisms during vaccination it is essential with intensive monitoring of the responses. This may lead to optimization of treatment and prediction......-inflammatory cytokines in serum of patients who achieved stable disease following vaccination suggest the occurrence of vaccine-induced Th1 responses. Since Th1 responses seem to be essential in cancer immunotherapy this may indicate a therapeutic potential of the vaccine....... of responding patients. The aim of this study was to evaluate cytokine and biomarker responses in patients with colorectal cancer treated with a cancer vaccine based on dendritic cells pulsed with an allogeneic melanoma cell lysate. Material and methods. Plasma and serum samples were collected prior...

  6. Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.

    Science.gov (United States)

    Vilar, Eduardo; Mork, Maureen E; Cuddy, Amanda; Borras, Ester; Bannon, Sarah A; Taggart, Melissa W; Ying, Jun; Broaddus, Russell R; Luthra, Rajyalakshmi; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; You, Yi-Qian Nancy

    2014-01-01

    Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats.

    Science.gov (United States)

    Martin, O C B; Lin, C; Naud, N; Tache, S; Raymond-Letron, I; Corpet, D E; Pierre, F H

    2015-01-01

    Epidemiological studies show that heme iron from red meat is associated with increased colorectal cancer risk. In carcinogen-induced-rats, a heme iron-rich diet increases the number of precancerous lesions and raises associated fecal biomarkers. Heme-induced lipoperoxidation measured by fecal thiobarbituric acid reagents (TBARs) could explain the promotion of colon carcinogenesis by heme. Using a factorial design we studied if microbiota could be involved in heme-induced carcinogenesis, by modulating peroxidation. Rats treated or not with an antibiotic cocktail were given a control or a hemoglobin-diet. Fecal bacteria were counted on agar and TBARs concentration assayed in fecal water. The suppression of microbiota by antibiotics was associated with a reduction of crypt height and proliferation and with a cecum enlargement, which are characteristics of germ-free rats. Rats given hemoglobin diets had increased fecal TBARs, which were suppressed by the antibiotic treatment. A duplicate experiment in rats given dietary hemin yielded similar results. These data show that the intestinal microbiota is involved in enhancement of lipoperoxidation by heme iron. We thus suggest that microbiota could play a role in the heme-induced promotion of colorectal carcinogenesis.

  8. Radiation carcinogenesis

    International Nuclear Information System (INIS)

    Adams, G.E.

    1987-01-01

    In this contribution about carcinogenesis induced by ionizing radiation some radiation dose-response relationships are discussed. Curves are shown of the relation between cell survival and resp. low and high LET radiation. The difference between both curves can be ascribed to endogenous repair mechanisms in the cell. The relation between single-gen mutation frequency and the surviving fractions of irradiated cells indicates that these repairing mechanisms are not error free. Some examples of reverse dose-response relationships are presented in which decreasing values of dose-rate (LET) correspond with increasing radiation induced cell transformation. Finally some molecular aspects of radiation carcinogenesis are discussed. (H.W.). 22 refs.; 4 figs

  9. The Influence of Tissue Ischemia on Biomarker Expression in Colorectal Cancer

    DEFF Research Database (Denmark)

    Havelund, Birgitte M; Aalund Olsen, Dorte; Andersen, Rikke F

    2013-01-01

    The aim of the present study was to investigate the influence of fixation delay and the perioperative ischemia on hypoxia inducible factor (HIF)-1α gene expression, HIF-1α protein expression, and immunohistochemical (IHC) expression of HIF-1α, GLUT-1, Bcl-2, and Ki-67 in colorectal cancer....... The study included 25 surgically removed colorectal tumors. Three sets of samples were collected readily after removal and exposed to 0, 30, and 60 minutes of delay of fixation or freezing. The perioperative ischemia time was registered. In each set of the samples, HIF-1α gene expression was analyzed...... by IHC. We found that the HIF-1α gene expression, HIF-1α protein concentration, and IHC expression of HIF-1α, GLUT-1, Ki-67, and Bcl-2 were not systematically affected by either the fixation or freezing delay of the tissue, the perioperative ischemia time, or the total ischemia time (perioperative...

  10. Gender and plasma iron biomarkers, but not HFE gene mutations, increase the risk of colorectal cancer and polyps.

    Science.gov (United States)

    Castiella, Agustin; Múgica, Fernando; Zapata, Eva; Zubiaurre, Leire; Iribarren, Arantxa; de Juan, M Dolores; Alzate, Luis; Gil, Ines; Urdapilleta, Gregorio; Otazua, Pedro; Emparanza, José Ignacio

    2015-09-01

    A cohort study of patients included in the Basque Country colorectal cancer (CRC) screening programme was carried out to assess the risk of adenomatous polyps and CRC (P-CRC) associated with HFE gene mutations, with gender and with iron biomarkers (serum ferritin (SF), iron (Fe) and transferrin saturation index (TSI)). Among 432 included patients (mean age 59.8 years), 263 were men (60.9 %) and 169 women (39.1 %). P-CRC were identified in 221 patients (51.2 %) and no polyps (NP) in 211 patients (48.8 %). HFE mutations were identified in 43.8 % of the patients. C282Y/wt genotypic frequency was 6.8 % in the P-CRC group and 1.4 % in the NP group (p < 0.05). The allelic frequency was 3.8 versus 1.2 % (p < 0.05). For laboratory, all three iron biomarkers showed a statistically significant difference: mean Fe, 91.29 ± 34 for P-CRC and 80.81 ± 30.59 for NP group. Mean TSI for P-CRC was 24.95 ± 8.90 and 22.74 ± 8.79 for NP group. Mean SF 308.09 ± 536.32 for P-CRC and 177.55 ± 159.95 for NP group. In a multivariate logistic regression analysis, only male gender (odds ratio (OR) = 2.04, 1.29-3.22), SF (OR = 1.001, 1.0004-1.003) and Fe (OR = 1.01, 1.004-1.02) were related with the presence of CRC and adenoma. Men gender and raised serum iron biomarkers increase the risk of P-CRC.

  11. Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8

    Directory of Open Access Journals (Sweden)

    Abdulamir Ahmed S

    2010-09-01

    Full Text Available Abstract Background Colorectal cancer (CRC has long been associated with bacteremia and/or endocarditis by Streptococcus gallolyticus member bacteria (SGMB but the direct colonization of SGMB along with its molecular carcinogenic role, if any, has not been investigated. We assessed the colonization of SGMB in CRC patients with history of bacteremia (CRC-w/bac and without history of bacteremia (CRC-wo/bac by isolating SGMB from feces, mucosal surfaces of colorectum, and colorectal tissues and detecting SGMB DNA, via PCR and in situ hybridization (ISH assays targeting SodA gene in colorectal tissues. Moreover, mRNA of IL1, IL-8, COX-2, IFN-γ, c-Myc, and Bcl-2 in colorectal tissues of studied groups was assessed via ISH and RT-PCR. Results SGMB were found to be remarkably isolated in tumorous (TU and non-tumorous (NTU tissues of CRC-w/bac, 20.5% and 17.3%, and CRC-wo/bac, 12.8% and 11.5%, respectively while only 2% of control tissues revealed SGMB (P 10 CN/g respectively, showed higher colonization in TU than in NTU and in CRC-w/bac than in CRC-wo/bac (P Conclusions The current study indicated that colorectal cancer is remarkably associated with SGMB; moreover, molecular detection of SGMB in CRC was superior to link SGMB with CRC tumors highlighting a possible direct and active role of SGMB in CRC development through most probably inflammation-based sequel of tumor development or propagation via, but not limited to, IL-1, COX-2, and IL-8.

  12. Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and incidence of colorectal cancer

    DEFF Research Database (Denmark)

    Kyrø, Cecilie; Olsen, Anja; Landberg, Rikard

    2014-01-01

    differences (Scandinavia, the Mediterranean, Central Europe) were also explored. RESULTS: High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total...... alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were...... not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher). CONCLUSIONS: High concentrations of plasma...

  13. Predictive Biomarkers in Colorectal Cancer: From the Single Therapeutic Target to a Plethora of Options

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2016-01-01

    Full Text Available Colorectal cancer (CRC is one of the most frequent cancers and is a leading cause of cancer death worldwide. Treatments used for CRC may include some combination of surgery, radiation therapy, chemotherapy, and targeted therapy. The current standard drugs used in chemotherapy are 5-fluorouracil and leucovorin in combination with irinotecan and/or oxaliplatin. Most recently, biologic agents have been proven to have therapeutic benefits in metastatic CRC alone or in association with standard chemotherapy. However, patients present different treatment responses, in terms of efficacy and toxicity; therefore, it is important to identify biological markers that can predict the response to therapy and help select patients that would benefit from specific regimens. In this paper, authors review CRC genetic markers that could be useful in predicting the sensitivity/resistance to chemotherapy.

  14. Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan

    International Nuclear Information System (INIS)

    Kim, Seung Tae; Ahn, Tae Jin; Lee, Eunjin; Do, In-Gu; Lee, Su Jin; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Kim, Suk Hyeong; Lee, Jeeyun; Kim, Hee Cheol

    2015-01-01

    More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC. We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes. BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS. The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC

  15. Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for pancreatic and colorectal adenocarcinoma

    DEFF Research Database (Denmark)

    Baraniskin, Alexander; Nöpel-Dünnebacke, Stefanie; Ahrens, Maike

    2013-01-01

    Improved non-invasive strategies for early cancer detection are urgently needed to reduce morbidity and mortality. Non-coding RNAs, such as microRNAs and small nucleolar RNAs, have been proposed as biomarkers for non-invasive cancer diagnosis. Analyzing serum derived from nude mice implanted...... with primary human pancreatic ductal adenocarcinoma (PDAC), we identified 15 diagnostic microRNA candidates. Of those miR-1246 was selected based on its high abundance in serum of tumor carrying mice. Subsequently, we noted a cross reactivity of the established miR-1246 assays with RNA fragments derived from U...... that hsa-miR-1246 is likely a pseudo microRNA. In a next step, RNU2-1f was measured by qRT-PCR and normalized to cel-54 in 191 serum/plasma samples from PDAC and colorectal carcinoma (CRC) patients. In comparison to 129 controls, we were able to classify samples as cancerous with a sensitivity...

  16. Understanding Carcinogenesis for Fighting Oral Cancer

    OpenAIRE

    Tanaka, Takuji; Ishigamori, Rikako

    2011-01-01

    Oral cancer is one of the major global threats to public health. Oral cancer development 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 able to measure the cancer risk of oral premalignancies. Understanding of the biology of oral carcinogenesis will give us important advances for...

  17. Cadmium carcinogenesis

    International Nuclear Information System (INIS)

    Waalkes, Michael P.

    2003-01-01

    Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis

  18. Cadmium carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Waalkes, Michael P

    2003-12-10

    Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis.

  19. MicroRNA-92a as a potential biomarker in diagnosis of colorectal cancer: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Xin Yang

    Full Text Available INTRODUCTION: Previous studies demonstrated that MicroRNA-92a (miR-92a was significantly differential expressed between colorectal cancer (CRC patients and control cohorts, which provide timely relevant evidence for miR-92a as a novel promising biomarker in the colorectal cancer patients. This meta-analysis aimed to evaluate potential diagnostic value of plasma miR-92a. METHODS: Relevant literatures were collected in PubMed, Embase, Chinese Biomedical Literature Database (CBM, Chinese National Knowledge Infrastructure (CNKI and Technology of Chongqing (VIP, and Wan Fang Data. Sensitivity, specificity and diagnostic odds ratio (DOR for miR-92a in the diagnosis of CRC were pooled using random effects models. Summary receiver operating characteristic (SROC curve analysis and the area under the curve (AUC were used to estimate the overall test performance. RESULTS: This Meta-analysis included six studies with a total of 521 CRC patients and 379 healthy controls. For miR-92a, the pooled sensitivity, specificity and DOR to predict CRC patients were 76% (95% confidence interval [CI]: 72%-79%, 64% (95% confidence interval [CI]: 59%-69% and 8.05 (95% CI: 3.50-18.56, respectively. In addition, the AUC of miR-92a in diagnosis CRC is 0.7720. CONCLUSIONS: MicroRNA-92a might be a novel potential biomarker in the diagnosis of colorectal cancer, and more studies are needed to highlight the theoretical strengths.

  20. Adiponectin, Leptin, IGF-1, and Tumor Necrosis Factor Alpha As Potential Serum Biomarkers for Non-Invasive Diagnosis of Colorectal Adenoma in African Americans.

    Science.gov (United States)

    Ashktorab, Hassan; Soleimani, Akbar; Nichols, Alexandra; Sodhi, Komal; Laiyemo, Adeyinka O; Nunlee-Bland, Gail; Nouraie, Seyed Mehdi; Brim, Hassan

    2018-01-01

    The potential role of adiponectin, leptin, IGF-1, and tumor necrosis factor alpha (TNF-α) as biomarkers in colorectal adenoma is not clear. Therefore, we aimed to investigate the blood serum levels of these biomarkers in colorectal adenoma. The case-control study consisted of serum from 180 African American patients with colon adenoma (cases) and 198 healthy African Americans (controls) at Howard University Hospital. We used ELISA for adiponectin, leptin, IGF-1, and TNF-α detection and quantification. Statistical analysis was performed by t -test and multivariate logistic regression. The respective differences in median leptin, adiponectin, IGF-1, and TNF-α levels between control and case groups (13.9 vs. 16.4), (11.3 vs. 46.0), (4.5 vs. 12.9), and (71.4 vs. 130.8) were statistically significant ( P  IGF-1 were 2.0 (95% CI = 1.6-2.5; P  IGF-1 concentrations with age ( r  = 0.17, P  IGF-1, and leptin concentration with body mass index (BMI) ( r  = 0.44, P  IGF-1, and TNF-α high levels correlate with higher risk of colon adenoma and can thus be used for colorectal adenomas risk assessment.

  1. Detection of colorectal neoplasia

    DEFF Research Database (Denmark)

    Wilhelmsen, Michael; Christensen, Ib J; Rasmussen, Louise

    2017-01-01

    Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA...... value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC....

  2. The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Ding X

    2016-03-01

    Full Text Available Xiaojie Ding,1,2,* Lijuan Qiu,1,2,* Lijuan Zhang,3 Juemin Xi,1,2 Duo Li,1,2 Xinwei Huang,1,2 Yujiao Zhao,1,2 Xiaodang Wang,1,2 Qiangming Sun1,2 1Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 2Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, 3Department of Pathology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Provincial Tumor Hospital, Kunming, People’s Republic of China*These authors contributed equally to this workBackground: Semaphorin 4D (Sema4D belongs to the class IV semaphorins, and accumulating evidence has indicated that its elevated level may be one strategy by which tumors evade current antiangiogenic therapies. The biological roles of Sema4D in colorectal cancer (CRC, however, remain largely undefined. This study was designed to investigate the effects of Sema4D on tumor angiogenesis and growth in CRC, especially in different vascular endothelial growth factor (VEGF backgrounds.Methods: The expression of Sema4D in human CRC was evaluated by immunohistochemical analysis of tumors and their matching normal control tissues. The expression level of Sema4D and VEGF was investigated in different CRC cell lines. To evaluate the contributions of Sema4D to tumor-induced angiogenesis, two CRC cell lines with opposite VEGF backgrounds were infected with lentiviruses expressing Sema4D or Sema4D short hairpin RNA, followed by in vitro migration and in vivo tumor angiogenic assays.Results: Immunohistochemical analysis of human CRC revealed high levels of Sema4D in a cell surface pattern. In all, 84.85% of CRC samples analyzed exhibited moderate to strong Sema4D expression. The positive ratios of Sema4D staining for well, moderately, and poorly differentiated cancers were 71.43%, 96.67%, and 77.27%, respectively. Sema4D is highly expressed in five different CRC cell lines, while VEGF

  3. Epigenetic silencing of ADAMTS5 is associated with increased invasiveness and poor survival in patients with colorectal cancer.

    Science.gov (United States)

    Li, Jizhen; Liao, Yi; Huang, Jintuan; Sun, Yi; Chen, Hao; Chen, Chunyu; Li, Senmao; Yang, Zuli

    2018-02-01

    A disintegrin and metalloprotease with motif 5(ADAMTS5) has been involved in colorectal cancer (CRC) with hypermethylation in the promoter. However, its role in CRC remains unclear. The aim of this study was to explore the clinical significance and biological effect of ADAMTS5 on colorectal carcinogenesis. Through MSP, qRT-PCR, WB and IHC analysis, followed by a variety of in vitro assays, we report the function of ADAMTS5 in CRC. ADAMTS5 was markedly hypermethylaed and downregulated in tumor tissues compared with non-tumor tissues (p colorectal cancer, and correlates with OS and DFS, indicating that ADAMTS5 might be a useful biomarker in colorectal cancer therapy.

  4. KRAS biomarker testing disparities in colorectal cancer patients in New Mexico

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    Alissa Greenbaum

    2017-11-01

    Full Text Available Introduction: American Society of Clinical Oncology (ASCO guidelines recommend that all patients with metastatic colorectal cancer (mCRC receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. The aim of this study was to assess for disparities in KRAS testing and mutational status. Methods: The New Mexico Tumor Registry (NMTR, a population-based cancer registry participating in the National Cancer Institute’s Surveillance, Epidemiology and End Results program, was queried to identify all incident cases of CRC diagnosed among New Mexico residents from 2010 to 2013. Results: Six hundred thirty-seven patients were diagnosed with mCRC from 2010–2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%, though testing in stage 3 (8.5%, stage 2 (3.4% and stage 1 (1.2% was also observed. In those with metastatic disease, younger patients (≤ 64 years were more likely to have had testing than patients 65 years and older (p < 0.0001. Patients residing in urban areas received KRAS testing more often than patients living in rural areas (p = 0.019. No significant racial/ethnic disparities were observed (p = 0.66. No significant differences were seen by year of testing. Conclusion: Age and geographic disparities exist in the rates of KRAS testing, while sex, race/ethnicity and the year tested were not significantly associated with testing. Further study is required to assess the reasons for these disparities and continued suboptimal adherence to current ASCO KRAS testing guidelines. Keywords: Oncology, Health sciences, Clinical genetics

  5. Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

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    Andrea Botticelli

    Full Text Available 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC. Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR and genetic polymorphisms (MTHFR, TSER, DPYD on survival.Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome.133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts; normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts; ultra-rapid metabolizer (UM with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts. PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029. A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019. No significant associations between genes polymorphisms and outcomes or toxicities were observed.5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.

  6. Molecular Classification and Correlates in Colorectal Cancer

    OpenAIRE

    Ogino, Shuji; Goel, Ajay

    2008-01-01

    Molecular classification of colorectal cancer is evolving. As our understanding of colorectal carcinogenesis improves, we are incorporating new knowledge into the classification system. In particular, global genomic status [microsatellite instability (MSI) status and chromosomal instability (CIN) status] and epigenomic status [CpG island methylator phenotype (CIMP) status] play a significant role in determining clinical, pathological and biological characteristics of colorectal cancer. In thi...

  7. TIMP-1 and CEA as biomarkers in third-line treatment with irinotecan and cetuximab for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2015-01-01

    in colorectal cancer (CRC). The aim of the present study was to investigate the clinical value of TIMP-1 in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan. Patients with chemotherapy-resistant mCRC referred to third-line treatment with cetuximab (initial 400 mg/m(2...

  8. Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Pool-Zobel, Beatrice [Department of Nutritional Toxicology, Institute for Nutrition, Friedrich Schiller University Jena, 07743 Jena (Germany)]. E-mail: b8pobe@uni-jena.de; Veeriah, Selvaraju [Department of Nutritional Toxicology, Institute for Nutrition, Friedrich Schiller University Jena, 07743 Jena (Germany); Boehmer, Frank-D. [Institute of Molecular Cell Biology, University Hospital, Friedrich Schiller University Jena, 07743 Jena (Germany)

    2005-12-11

    There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the

  9. Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis

    International Nuclear Information System (INIS)

    Pool-Zobel, Beatrice; Veeriah, Selvaraju; Boehmer, Frank-D.

    2005-01-01

    There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the

  10. {sup 18}F-FDG PET as novel imaging biomarker for disease progression after ablation therapy in colorectal liver metastases

    Energy Technology Data Exchange (ETDEWEB)

    Samim, M. [University Medical Centre Utrecht, Department Surgery, Utrecht (Netherlands); University Medical Centre Utrecht, Department Radiology and Nuclear Medicine, Utrecht (Netherlands); Prevoo, W.; Wit-van der Veen, B.J. de; Stokkel, M.P.M. [Antoni van Leeuwenhoek Hospital, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Kuhlmann, K.F.; Ruers, T. [Antoni van Leeuwenhoek Hospital, Department Surgical Oncology, Amsterdam (Netherlands); Hillegersberg, R. van [University Medical Centre Utrecht, Department Surgery, Utrecht (Netherlands); Bosch, M.A.A.J. van den; Verkooijen, H.M.; Lam, M.G.E.H. [University Medical Centre Utrecht, Department Radiology and Nuclear Medicine, Utrecht (Netherlands)

    2017-07-15

    Recurrent disease following thermal ablation therapy is a frequently reported problem. Preoperative identification of patients with high risk of recurrent disease might enable individualized treatment based on patients' risk profile. The aim of the present work was to investigate the role of metabolic parameters derived from the pre-ablation {sup 18}F-FDG PET/CT as imaging biomarkers for recurrent disease in patients with colorectal liver metastases (CLM). Included in this retrospective study were all consecutive patients with CLM treated with percutaneous or open thermal ablation therapy who had a pre-treatment baseline {sup 18}F-FDG PET/CT available. Multivariable cox regression for survival analysis was performed using different models for the metabolic parameters (SUL{sub peak}, SUL{sub mean}, SUL{sub max}, partial volume corrected SUL{sub mean} (cSUL{sub mean}), and total lesion glycolysis (TLG)) corrected for tumour and procedure characteristics. The study endpoints were defined as local tumour progression free survival (LTP-FS), new intrahepatic recurrence free survival (NHR-FS) and extrahepatic recurrence free survival (EHR-FS). Clinical and imaging follow-up data was used as the reference standard. Fifty-four patients with 90 lesions were selected. Univariable cox regression analysis resulted in eight models. Multivariable analysis revealed that after adjusting for lesion size and the approach of the procedure, none of the metabolic parameters were associated with LTP-FS or EHR-FS. Percutaneous approach was significantly associated with a shorter LTP-FS. It was demonstrated that lower values of SUL{sub peak}, SUL{sub max}, SUL{sub mean}, and cSUL{sub mean} are associated with a significant better NHR-FS, independent of the lesion size and number and prior chemotherapy. We found no association between the metabolic parameters on pre-ablation {sup 18}F-FDG PET/CT and the LTP-FS. However, low values of the metabolic parameters were significantly

  11. Discovery and validation of plasma-protein biomarker panels for the detection of colorectal cancer and advanced adenoma in a Danish collection of samples from patients referred for diagnostic colonoscopy

    DEFF Research Database (Denmark)

    Blume, John E.; Wilhelmsen, Michael; Benz, Ryan W.

    2016-01-01

    and utilization of such a resource is an important step in the development of blood-based biomarker tests for colorectal cancer.Methods: We have created a subject data and biological sample resource, Endoscopy II, which is based on 4698 individuals referred for diagnostic colonoscopy in Denmark between May 2010...

  12. Bone Marrow Stromal Antigen 2 Is a Novel Plasma Biomarker and Prognosticator for Colorectal Carcinoma: A Secretome-Based Verification Study

    Directory of Open Access Journals (Sweden)

    Sum-Fu Chiang

    2015-01-01

    Full Text Available Background. The cancer cell secretome has been recognized as a valuable reservoir for identifying novel serum/plasma biomarkers for different cancers, including colorectal cancer (CRC. This study aimed to verify four CRC cell-secreted proteins (tumor-associated calcium signal transducer 2/trophoblast cell surface antigen 2 (TACSTD2/TROP2, tetraspanin-6 (TSPAN6, bone marrow stromal antigen 2 (BST2, and tumor necrosis factor receptor superfamily member 16 (NGFR as potential plasma CRC biomarkers. Methods. The study population comprises 152 CRC patients and 152 controls. Target protein levels in plasma and tissue samples were assessed by ELISA and immunohistochemistry, respectively. Results. Among the four candidate proteins examined by ELISA in a small sample set, only BST2 showed significantly elevated plasma levels in CRC patients versus controls. Immunohistochemical analysis revealed the overexpression of BST2 in CRC tissues, and higher BST2 expression levels correlated with poorer 5-year survival (46.47% versus 65.57%; p=0.044. Further verification confirmed the elevated plasma BST2 levels in CRC patients (2.35 ± 0.13 ng/mL versus controls (1.04 ± 0.03 ng/mL (p<0.01, with an area under the ROC curve (AUC being 0.858 comparable to that of CEA (0.867. Conclusion. BST2, a membrane protein selectively detected in CRC cell secretome, may be a novel plasma biomarker and prognosticator for CRC.

  13. Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification

    Directory of Open Access Journals (Sweden)

    Smolich Beverly D

    2003-02-01

    Full Text Available Abstract Background Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. Methods Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF receptor tyrosine kinase (RTK inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. Results Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9 as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. Conclusions These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

  14. Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification

    International Nuclear Information System (INIS)

    DePrimo, Samuel E; Wong, Lily M; Khatry, Deepak B; Nicholas, Susan L; Manning, William C; Smolich, Beverly D; O'Farrell, Anne-Marie; Cherrington, Julie M

    2003-01-01

    Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies

  15. The clinical role of microRNA-21 as a promising biomarker in the diagnosis and prognosis of colorectal cancer: a systematic review and meta-analysis.

    Science.gov (United States)

    Peng, Qiliang; Zhang, Xueli; Min, Ming; Zou, Li; Shen, Peipei; Zhu, Yaqun

    2017-07-04

    This systematic analysis aimed to investigate the value of microRNA-21 (miR-21) in colorectal cancer for multiple purposes, including diagnosis and prognosis, as well as its predictive power in combination biomarkers. Fifty-seven eligible studies were included in our meta-analysis, including 25 studies for diagnostic meta-analysis and 32 for prognostic meta-analysis. For the diagnostic meta-analysis of miR-21 alone, the overall pooled results for sensitivity, specificity, and area under the curve (AUC) were 0.64 (95% CI: 0.53-0.74), 0.85 (0.79-0.90), and 0.85 (0.81-0.87), respectively. Circulating samples presented corresponding values of 0.72 (0.63-0.79), 0.84 (0.78-0.89), and 0.86 (0.83-0.89), respectively. For the diagnostic meta-analysis of miR-21-related combination biomarkers, the above three parameters were 0.79 (0.69-0.86), 0.79 (0.68-0.87), and 0.86 (0.83-0.89), respectively. Notably, subgroup analysis suggested that miRNA combination markers in circulation exhibited high predictive power, with sensitivity of 0.85 (0.70-0.93), specificity of 0.86 (0.77-0.92), and AUC of 0.92 (0.89-0.94). For the prognostic meta-analysis, patients with higher expression of miR-21 had significant shorter disease-free survival [DFS; pooled hazard ratio (HR): 1.60; 95% CI: 1.20-2.15] and overall survival (OS; 1.54; 1.27-1.86). The combined HR in tissues for DFS and OS were 1.76 (1.31-2.36) and 1.58 (1.30-1.93), respectively. Our comprehensive systematic review revealed that circulating miR-21 may be suitable as a diagnostic biomarker, while tissue miR-21 could be a prognostic marker for colorectal cancer. In addition, miRNA combination biomarkers may provide a new approach for clinical application.

  16. miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer.

    Science.gov (United States)

    Tanaka, Hironori; Hazama, Shoichi; Iida, Michihisa; Tsunedomi, Ryouichi; Takenouchi, Hiroko; Nakajima, Masao; Tokumitsu, Yukio; Kanekiyo, Shinsuke; Shindo, Yoshitaro; Tomochika, Shinobu; Tokuhisa, Yoshihiro; Sakamoto, Kazuhiko; Suzuki, Nobuaki; Takeda, Shigeru; Yamamoto, Shigeru; Yoshino, Shigefumi; Ueno, Tomio; Hamamoto, Yoshihiko; Fujita, Yusuke; Tanaka, Hiroaki; Tahara, Ko; Shimizu, Ryoichi; Okuno, Kiyotaka; Fujita, Koji; Kuroda, Masahiko; Nakamura, Yusuke; Nagano, Hiroaki

    2017-11-01

    Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse-transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR-125b-1 in cancer cells (P = 0.040), and miR-378a in both cancer cells (P = 0.009) and stromal cells (P colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  17. A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

    NARCIS (Netherlands)

    Heijink, D. M.; Fehrmann, R. S. N.; de Vries, E. G. E.; Koornstra, J. J.; Oosterhuis, D.; van der Zee, A. G. J.; Kleibeuker, J. H.; de Jong, S.

    Comparing normal colorectal mucosa and adenomas focusing on deregulated pathways obtains insight into the biological processes of early colorectal carcinogenesis. Publicly available microarray expression data from 26 normal mucosa and 47 adenoma samples were analyzed. Biological pathways enriched in

  18. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy.

    Science.gov (United States)

    Goede, V; Coutelle, O; Neuneier, J; Reinacher-Schick, A; Schnell, R; Koslowsky, T C; Weihrauch, M R; Cremer, B; Kashkar, H; Odenthal, M; Augustin, H G; Schmiegel, W; Hallek, M; Hacker, U T

    2010-10-26

    The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; Panti-angiogenic treatment.

  19. Systems approach for the selection of micro-RNAs as therapeutic biomarkers of anti-EGFR monoclonal antibody treatment in colorectal cancer

    Science.gov (United States)

    Deyati, Avisek; Bagewadi, Shweta; Senger, Philipp; Hofmann-Apitius, Martin; Novac, Natalia

    2015-01-01

    miRNA plays an important role in tumourgenesis by regulating expression of oncogenes and tumour suppressors. Thus affects cell proliferation and differentiation, apoptosis, invasion and angiogenesis. miRNAs are potential biomarkers for diagnosis, prognosis and therapies of different forms of cancer. However, relationship between response of cancer patients towards targeted therapy and the resulting modifications of the miRNA transcriptome in the context of pathway regulation is poorly understood. With ever-increasing pathways and miRNA-mRNA interaction databases, freely available mRNA and miRNA expression data in multiple cancer therapy have produced an unprecedented opportunity to decipher the role of miRNAs in early prediction of therapeutic efficacy in diseases. Efficient translation of -omics data and accumulated knowledge to clinical decision-making are of paramount scientific and public health interest. Well-structured translational algorithms are needed to bridge the gap from databases to decisions. Herein, we present a novel SMARTmiR algorithm to prospectively predict the role of miRNA as therapeutic biomarker for an anti-EGFR monoclonal antibody i.e. cetuximab treatment in colorectal cancer.

  20. The mRNA level of MLH1 in peripheral blood is a biomarker for the diagnosis of hereditary nonpolyposis colorectal cancer.

    Science.gov (United States)

    Yu, Hong; Li, Hui; Cui, Yongan; Xiao, Wei; Dai, Guihong; Huang, Junxing; Wang, Chaofu

    2016-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by functional defects in mismatch repair (MMR) genes, including mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2). This study aimed to assess whether the mRNA expression of MLH1 in peripheral blood could be used as a biomarkers for the diagnosis of HNPCC. The mRNA level of MLH1 was determined in 19 HNPCC families (46 members) using real-time quantitative polymerase chain reaction (qPCR). The mRNA levels of MLH1 in HNPCC were significantly lower than controls (P MLH1 for the diagnosis of HNPCC with the area under curve of 0.858. At an optimal cut-off value (0.511), the mRNA level of MLH1 had a sensitivity of 81.3% and a specificity of 86.7% for distinguishing HNPCC from controls. In conclusion, the mRNA expression of MLH1 in peripheral blood may serve as a biomarker for the diagnosis of HNPCC.

  1. Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF-1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue.

    Science.gov (United States)

    Zhang, Lirong; Hu, Yu; Xi, Ning; Song, Jie; Huang, Wenjing; Song, Shanshan; Liu, Yiting; Liu, Xianying; Xie, Yingjun

    2016-01-01

    Hypoxia is prognostically important in colorectal cancer (CRC) therapy. Partial oxygen pressure (pO 2 ) is an important parameter of hypoxia. The correlation between pO 2 levels and expression levels of prognostic biomarkers was measured in CRC tissues. Human CRC tissues were collected and pO 2 levels were measured by OxyLite. Three methods for tissue fixation were compared, including formalin, Finefix, and Finefix-plus-microwave. Immunohistochemistry (IHC) staining was conducted by using the avidin-biotin complex technique for detecting the antibodies to hypoxia inducible factor-1 (HIF-1) alpha, cytokeratin 20 (CK20), and cell proliferation factor Ki67. The levels of pO 2 were negatively associated with the size of CRC tissues. Finefix-plus-microwave fixation has the potential to replace formalin. Additionally, microwave treatment improved Finefix performance in tissue fixation and protein preservation. The percentage of positive cells and gray values of HIF-1 alpha, CK20, and Ki67 were associated with CRC development ( P < 0.05). The levels of pO 2 were positively related with the gray values of Ki67 and negatively related with the values of HIF-1 alpha and CK20 ( P < 0.05). Thus, the levels of microenvironmental pO 2 affect the expression of predictive biomarkers HIF-1 alpha, CK20, and Ki67 in the development of CRC tissues.

  2. Partial Oxygen Pressure Affects the Expression of Prognostic Biomarkers HIF-1 Alpha, Ki67, and CK20 in the Microenvironment of Colorectal Cancer Tissue

    Directory of Open Access Journals (Sweden)

    Lirong Zhang

    2016-01-01

    Full Text Available Hypoxia is prognostically important in colorectal cancer (CRC therapy. Partial oxygen pressure (pO2 is an important parameter of hypoxia. The correlation between pO2 levels and expression levels of prognostic biomarkers was measured in CRC tissues. Human CRC tissues were collected and pO2 levels were measured by OxyLite. Three methods for tissue fixation were compared, including formalin, Finefix, and Finefix-plus-microwave. Immunohistochemistry (IHC staining was conducted by using the avidin-biotin complex technique for detecting the antibodies to hypoxia inducible factor-1 (HIF-1 alpha, cytokeratin 20 (CK20, and cell proliferation factor Ki67. The levels of pO2 were negatively associated with the size of CRC tissues. Finefix-plus-microwave fixation has the potential to replace formalin. Additionally, microwave treatment improved Finefix performance in tissue fixation and protein preservation. The percentage of positive cells and gray values of HIF-1 alpha, CK20, and Ki67 were associated with CRC development (P<0.05. The levels of pO2 were positively related with the gray values of Ki67 and negatively related with the values of HIF-1 alpha and CK20 (P<0.05. Thus, the levels of microenvironmental pO2 affect the expression of predictive biomarkers HIF-1 alpha, CK20, and Ki67 in the development of CRC tissues.

  3. SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients.

    Science.gov (United States)

    Mei, Zhu; Shao, Yang W; Lin, Peinan; Cai, Xiaomin; Wang, Biao; Ding, Yan; Ma, Xiangyuan; Wu, Xue; Xia, Yewei; Zhu, Dongqin; Shu, Yongqian; Fu, Zan; Gu, Yanhong

    2018-04-27

    Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. Patients carrying SMAD4 mutations (SMAD4 mut , n = 8) or NF1 mutations (NF1 mut , n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4 wt , n = 25) (P = 0.0081) or wildtype NF1 (NF1 wt , n = 29) (P = 0.0028), respectively. None of the SMAD4 mut or NF1 mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4 mut and NF1 mut showed the shortest PFS among all the patients. Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

  4. Oral Carcinogenesis and Oral Cancer Chemoprevention: A Review

    OpenAIRE

    Tanaka, Takuji; Tanaka, Mayu; Tanaka, Takahiro

    2011-01-01

    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 adv...

  5. [Obesity and colorectal cancer].

    Science.gov (United States)

    Na, Soo-Young; Myung, Seung-Jae

    2012-01-01

    Obesity worldwide is constantly increasing. Obesity acts as an independent significant risk factor for malignant tumors of various organs including colorectal cancer. Visceral adipose tissue is physiologically more important than subcutaneous adipose tissue. The relative risk of colorectal cancer of obese patients is about 1.5 times higher than the normal-weight individuals, and obesity is also associated with premalignant colorectal adenoma. The colorectal cancer incidence of obese patients has gender-specific and site-specific characteristics that it is higher in men than women and in the colon than rectum. Obesity acts as a risk factor of colorectal carcinogenesis by several mechanisms. Isulin, insulin-like growth factor, leptin, adiponectin, microbiome, and cytokines of chronic inflammation etc. have been understood as its potential mechanisms. In addition, obesity in patients with colorectal cancer negatively affects the disease progression and response of chemotherapy. Although the evidence is not clear yet, there are some reports that weight loss as well as life-modification such as dietary change and physical activity can reduce the risk of colorectal cancer. It is very important knowledge in the point that obesity is a potentially modifiable risk factor that can alter the incidence and outcome of the colorectal cancer.

  6. miR-345 in metastatic colorectal cancer: a non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan

    DEFF Research Database (Denmark)

    Schou, Jakob V; Rossi, Simona; Jensen, Benny V

    2014-01-01

    for overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan. METHODS: From 138 patients with mCRC in 3rd line therapy with cetuximab and irinotecan in a prospective phase II study, 738 pretreatment miRNAs were isolated and profiled from whole blood...... to treatment with cetuximab and irinotecan. CONCLUSION: We identified miR-345 in whole blood as a potential biomarker for clinical outcome. MiR-345 was a single prognostic biomarker for both OS and PFS in all patients and also in the non-KRAS mutant population....

  7. 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.

  8. Microbiota, Inflammation and Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Cécily Lucas

    2017-06-01

    Full Text Available Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the intestinal microbiota composition in colorectal cancer patients compared to control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. This review will summarize the current knowledge about the potential links between the intestinal microbiota and colorectal cancer, with a focus on the pro-carcinogenic properties of bacterial microbiota such as induction of inflammation, the biosynthesis of genotoxins that interfere with cell cycle regulation and the production of toxic metabolites. Finally, we will describe the potential therapeutic strategies based on intestinal microbiota manipulation for colorectal cancer treatment.

  9. Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Jensen, Niels Frank; Smith, David Hersi; Nygård, Sune Boris

    2012-01-01

    Abstract The availability of systemic chemotherapy regimens for the treatment of patients with metastatic colorectal cancer (mCRC) is based on the results from large prospective, randomized studies. The main chemotherapeutic drugs used in treatment of mCRC are the fluoropyrimidines (5-fluorouracil......, a number of preclinical and clinical studies have indicated lack of full cross resistance between oxaliplatin based and irinotecan based treatment. Therefore, it is possible that certain mCRC patient subpopulations would benefit more from one drug combination rather than the other. To address this clinical...

  10. Environmental Factors and Colorectal Tumor Risk in Individuals With Hereditary Nonpolyposis Colorectal Cancer

    NARCIS (Netherlands)

    Diergaarde, B.; Braam, H.; Vasen, H.F.; Nagengast, F.M.; Muijen, van G.N.P.; Kok, F.J.; Kampman, E.

    2007-01-01

    Background & Aims: Individuals with hereditary nonpolyposis colorectal cancer (HNPCC) are at increased risk for colorectal cancer. Environmental factors might play a role in HNPCC-associated carcinogenesis. The aim of this study was to gain insight into the effects of environmental factors on

  11. Activation peptide of the coagulation factor XIII (AP-F13A1) as a new biomarker for the screening of colorectal cancer.

    Science.gov (United States)

    Peltier, Julien; Roperch, Jean-Pierre; Audebert, Stéphane; Borg, Jean-Paul; Camoin, Luc

    2018-01-01

    Colorectal cancer (CRC) remains a major cause of cancer fatalities in developed countries. The risk of death is correlated to the stage of CRC during the primary diagnosis. Early diagnosis is closely associated with enhanced survival rate. We therefore investigated the AP-F13A1 as a potential protein marker of CRC. The protein expression of FXIII in 40 serum samples was evaluated by enzyme-linked immunosorbent assays. Additionally, targeted proteomic assays (LC-PRM) were used to evaluate the expression of the activation peptide of F13A1 (AP-F13A1) in a further 113 serum samples. Results were analyzed by the Wilcoxon test and receiver operating characteristic curves generated to assess statistical differences and diagnostic factors between CRC patients and controls. AP-F13A1 was quantified in human serum samples using calibration curves with excellent linearity. AP-F13A1 was reduced in CRC patients using PRM assays from two distinct biobanks. The AUC for AP-F13A1 were 0.95 and 0.93. Sensitivity/specificity values for the two sets of patients were 75%/95% and 71%/95% respectively. We have presented the proof of principle that in vivo release of AP-F13A1 can be measured by PRM-based strategies in CRC serum samples. AP-F13A1 may be an effective serological biomarker as part of a screening program of CRC detection.

  12. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer

    DEFF Research Database (Denmark)

    Yu, Jun; Feng, Qiang; Wong, Sunny Hei

    2017-01-01

    known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with CRC, we found significant associations with several species, including Parvimonas micra and Solobacterium moorei. We identified 20 microbial gene markers that differentiated CRC and control microbiomes, and validated 4...... in the independent Chinese cohort with AUC=0.84 and OR of 23. These genes were enriched in early-stage (I-II) patient microbiomes, highlighting the potential for using faecal metagenomic biomarkers for early diagnosis of CRC. CONCLUSIONS: We present the first metagenomic profiling study of CRC faecal microbiomes...

  13. Epigenetics and Colorectal Cancer

    Science.gov (United States)

    Lao, Victoria Valinluck; Grady, William M.

    2012-01-01

    Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203

  14. Promoter Hypermethylation of the Eyes Absent 4 Gene is a Tumor-Specific Epigenetic Biomarker in Iranian Colorectal Cancer Patients

    Directory of Open Access Journals (Sweden)

    Matineh Barati Bagerabad

    2018-02-01

    Full Text Available The aim of this study was to investigate whether hypermethylation of Eyes Absent 4 (EYA4 is also implicated in Iranian Colorectal Cancer (CRC patients or not. From fresh frozen tissues, samples from 38 paired (cancer and normal CRC tissue specimens were used in this study, the DNA was isolated, sodium bisulfite treated and analyzed by methylation-specific polymerase (MSP chain reaction using primers specific for unmethylated or methylated promoter sequences of the EYA4 gene. We also analyzed EYA4 mRNA expression using real time RT-PCR. Demographic characteristics of these patients including age, sex, tumor grade, location, stage, and TNM classification were evaluated and the relationship between methylation status of the gene and clinicopathological features was analyzed. Current study indicated that EYA4 promoter hypermethylation has a sensitivity of 81.57% and specificity of 78.94%. Findings showed lower expression of EYA-4 in methylated samples in comparison with its normal adjacent tissue, although it was not significant (P>0.05. No significant associations were observed between EYA4 hypermethylation and the clinicopathological characteristics. Although the clinical patient outcome of our 38 CRC patients was not associated with EYA4 promoter hypermethylation, the high frequency of this methylation and its high sensitivity and specificity to neoplastic cells may qualify EYA4 promoter methylation as a potential candidate screening marker in Iranian population and may help to improve early detection of CRC.

  15. Mechanisms of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Bekkum, D.W. van

    1975-01-01

    This speculative review on radiation carcinogenesis deals mainly with its immunological aspects. It need not be emphasized that the role of immunology in carcinogenesis is not yet well understood. Immunological aspects of radiation carcinogenesis comprise a large number of different parameters on the part of the host as well as on the part of the tumor itself. Only two aspects, both related to radiation, will be discussed here. One is the way in which the carcinogenic exposure to ionizing radiation may affect the immune reactivity of the irradiated organism, thereby perhaps changing its responses against the malignant cells. The second aspect is the immunological properties of cells transformed by ionizing irradiation, which may provide the targets for a host-anti-tumor reaction

  16. Circulating exosomal miR-27a and miR-130a act as novel diagnostic and prognostic biomarkers of colorectal cancer.

    Science.gov (United States)

    Wang, Shukui; Liu, Xiangxiang; Pan, Bei; Sun, Li; Chen, Xiaoxiang; Zeng, Kaixuan; Hu, Xiuxiu; Xu, Tao; Xu, Mu

    2018-05-08

    Colorectal cancer (CRC) is one of the most common cancers worldwide usually with poor prognosis due to the advanced stage when diagnosed. This study aimed to investigate whether specific circulating exosomal miRNAs could act as biomarkers for early diagnosis of CRC. A total of 369 peripheral blood samples were included in this study. In the discovery phase, circulating exosomal miR-27a and miR-130a were selected after synthetical analysis of two GEO datasets and TCGA database. The differential expression and diagnostic utility of miR-27a and miR-130a panel were validated using quantitative reverse-transcriptase PCR (qRT-PCR) and Receiver operating characteristic (ROC) curve analysis in subsequent training phase, validation phase and external validation phase. The prognosis of circulating exosomal miR-27a and miR-130a were investigated using the Kaplan-Meier method. The expression of exosomal miR-27a and miR-130a in plasma significantly increased in CRC. The area under ROC curves (AUCs) of miR-27a (miR-130a) were 0.773 (0.742) in the training phase, 0.82 (0.787) in the validation phase, and 0.746 (0.697) in the external validation phase. The combination of two miRNAs presented higher diagnostic utility for CRC (AUCs = 0.846, 0.898 and 0.801 for the training, validation, and external validation phases, respectively). CRC patients with high expression of circulating exosomal miR-27a or miR-130a underwent poorer prognosis. We identified a circulating exosomal miRNAs panel for the detection of CRC. The exosomal miR-27a and miR-130a panel in plasma may act as a non-invasive biomarker for early detection and predicting prognosis of CRC. Copyright ©2018, American Association for Cancer Research.

  17. Can Vascular Endothelial Growth Factor and Microvessel Density Be Used as Prognostic Biomarkers for Colorectal Cancer? A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yibaina Wang

    2014-01-01

    Full Text Available Background. Vascular endothelial growth factor (VEGF and microvessel density (MVD are associated with greater incidence of metastases and decreased survival. Whether they can be used as prognostic indicators of colorectal cancer (CRC is still controversial. Methods. The authors performed a meta-analysis using the results of a literature search of databases of PubMed and EMBASE, and the references of articles included in the analysis. Meta-analysis was performed using random effects model and hazard ratios (HRs and 95% confidence intervals (CIs as effect measures. Results. Twenty studies contributed to the analysis of VEGF, of which 16 were used for overall survival (OS and 9 for disease-free survival (DFS. High VEGF levels has a relationship with unfavorable survival (OS: HR = 1.98, 95% CI: 1.30–3.02; DFS: HR = 2.10, 95% CI: 1.26–3.49 and a 4.22-fold increase in the rate of distant metastases. Analysis was performed on 18 studies for MVD; the results showed that patients with high MVD expression in tumors appeared to have poorer overall survival (HR = 1.39, 95% CI: 1.22–1.58 and were at a greater risk of having unfavorable clinical characteristics related to prognosis. Corresponding results were obtained from quantitative and/or qualitative analysis of clinicopathological. Conclusions. The meta-analysis demonstrates that VEGF and MVD can be used as prognostic biomarkers for CRC patients.

  18. Molecular biomarkers of resistance to anti-EGFR treatment in metastatic colorectal cancer, from classical to innovation.

    Science.gov (United States)

    Giampieri, Riccardo; Scartozzi, Mario; Del Prete, Michela; Maccaroni, Elena; Bittoni, Alessandro; Faloppi, Luca; Bianconi, Maristella; Cecchini, Luca; Cascinu, Stefano

    2013-11-01

    Systematic dissection of the EGFR pathway was considered as the best way to identify putative markers of resistance to anti-EGFR therapies. This kind of approach leaves other, less known but by no means less important, putative mechanisms of resistance. We tried to shed some light on these mechanisms of resistance. We performed a research through Pubmed database of all published articles highlighting mechanisms of resistance to Cetuximab and Panitumumab based therapies, published in 2000-2012 period. We reviewed the "classical" molecular factors, extensively analyzed as predictive factors for efficacy to anti-EGFR therapy, such as K-ras, B-raf, and PI3K-mTOR-Akt, focusing on their predictive or prognostic value and on the controversial aspects of the biomarker analysis for clinical practice. On the second part we will then move on to other less known molecular markers, for the future understanding of biological mechanisms underlying anti-EGFR therapy resistance, such as non-canonical heterodimer candidates, microRNA, IGF1-IGF1R, HGF-cMET and secondary mutations of EGFR. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study

    NARCIS (Netherlands)

    Botma, A.; Vasen, H.F.; Duijnhoven, F.J.B. van; Kleibeuker, J.H.; Nagengast, F.M.; Kampman, E.

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  20. Dietary Patterns and Colorectal Adenomas in Lynch Syndrome: The GEOLynch Cohort Study

    NARCIS (Netherlands)

    Botma, A.; Vasen, H.F.; Duijnhoven, van F.J.B.; Kleibeuker, J.H.; Nagengast, F.M.; Kampman, E.

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  1. Dietary Patterns and Colorectal Adenomas in Lynch Syndrome The GEOLynch Cohort Study

    NARCIS (Netherlands)

    Botma, Akke; Vasen, Hans F. A.; van Duijnhoven, Franzel J. B.; Kleibeuker, Jan H.; Nagengast, Fokko M.; Kampman, Ellen

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  2. Radiation carcinogenesis, laboratory studies

    International Nuclear Information System (INIS)

    Shellabarger, C.J.

    1974-01-01

    Laboratory studies on radioinduced carcinogenesis are reviewed. Some topics discussed are: radioinduced neoplasia in relation to life shortening; dose-response relationships; induction of skin tumors in rats by alpha particles and electrons; effects of hormones on tumor response; effects of low LET radiations delivered at low dose-rates; effects of fractionated neutron radiation; interaction of RBE and dose rate effects; and estimates of risks for humans from animal data. (U.S.)

  3. [Colorectal cancer (CCR): genetic and molecular alterations].

    Science.gov (United States)

    Juárez-Vázquez, Clara Ibet; Rosales-Reynoso, Mónica Alejandra

    2014-01-01

    The aim of this review is to present a genetic and molecular overview of colorectal carcinogenesis (sporadic and hereditary origin) as a multistage process, where there are a number of molecular mechanisms associated with the development of colorectal cancer and genomic instability that allows the accumulation of mutations in proto-oncogenes and tumor suppressor genes, chromosomal instability, and methylation and microsatellite instability, and the involvement of altered expression of microRNAs' prognosis factors.

  4. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Inés Mármol

    2017-01-01

    Full Text Available Colorectal cancer (CRC is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%; inherited (5% and familial (25%. The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN, microsatellite instability (MSI and CpG island methylator phenotype (CIMP. Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53, and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined

  5. Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

    Science.gov (United States)

    Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induce...

  6. Evaluation of promoter methylation status of MLH1 gene in Iranian patients with colorectal tumors and adenoma polyps.

    Science.gov (United States)

    Zarandi, Ashkan; Irani, Shiva; Savabkar, Sanaz; Chaleshi, Vahid; Ghavideldarestani, Maryam; Mirfakhraie, Reza; Khodadoostan, Mahsa; Nazemalhosseini-Mojarad, Ehsan; Asadzadeh Aghdaei, Hamid

    2017-01-01

    The aim of this study was to evaluate the methylation status of the promoter region of MLH1 gene in colorectal cancer (CRC) and its precursor lesions as well as elucidate its association with various clinicopathological characteristics among Iranian population. Epigenetic silencing of mismatch repair genes, such as MLH1 , by methylation of CpG islands of their promoter region has been proved to be an important mechanism in colorectal carcinogenesis. Fifty colorectal cancer and polyp tissue samples including 13 Primary colorectal tumor and 37 Adenoma polyp samples were enrolled in this study. Methylation-specific polymerase chain reaction (MSP) was performed to find the frequency of MLH1 Promoter Methylation. Promoter methylation of MLH1 gene was detected in 5 out of 13 tumor tissues and 4 out of 37 adenoma polyp. The frequency of MLH1 methylation in tumor samples was significantly higher compared to that in polyp tissues (P= 0.026). No significant association was observed between MLH1 promoter methylation and clinicopathological characteristics of the patients. The frequency of  MLH1  promoter methylation in CRC and colon polyp was 18%. Our findings indicated that methylation of MLH1 promoter region alone cannot be considered as a biomarker for early detection of CRC.

  7. Colorectal polyps

    Science.gov (United States)

    Intestinal polyps; Polyps - colorectal; Adenomatous polyps; Hyperplastic polyps; Villous adenomas; Serrated polyp; Serrated adenoma; Precancerous polyps; Colon cancer - polyps; Bleeding - colorectal polyps

  8. A randomized, placebo-controlled, preoperative trial of allopurinol in subjects with colorectal adenoma.

    Science.gov (United States)

    Puntoni, Matteo; Branchi, Daniela; Argusti, Alessandra; Zanardi, Silvia; Crosta, Cristiano; Meroni, Emanuele; Munizzi, Francesco; Michetti, Paolo; Coccia, Gianni; De Roberto, Giuseppe; Bandelloni, Roberto; Turbino, Laura; Minetti, Egle; Mori, Marco; Salvi, Sandra; Boccardo, Simona; Gatteschi, Beatrice; Benelli, Roberto; Sonzogni, Angelica; DeCensi, Andrea

    2013-02-01

    Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of -10.6%, 95% confidence interval (CI), -20.5 to -0.7, and -8.1%, 95% CI, -22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (-16.4%; 95% CI, -29.0 to -3.8). No dose-response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity.

  9. Carcinogenesis. Genetics and circumstances

    International Nuclear Information System (INIS)

    Hino, Okio

    2005-01-01

    Described are the author's study and aspect concerning carcinogenesis and radiation carcinogenesis, where he thinks cancer is not automatic, has a process and takes time. For radiation carcinogenic studies, he has used a model of the rat with genetically determined kidney cancer which is highly radiosensitive. That is, mutation by the so-called 2nd-hit of the causal gene (tumor suppressing gene Tsc2) is studied in the animal where the 1st-hit has been done by retrotransposon insertion, with and without exposure to radiations (X-ray, heavy particle beam and cosmic ray) for elucidating the mutation spectrum of the causal gene, the carcinogenic target, for the ultimate aim to prevent human cancer. He discusses the drama-type molecular mechanisms leading to cancer, gene abnormality and disease crisis, discontinuity in continuity in cancer formation, and importance of the timely diagnosis and appropriate therapy, and concludes the present age is becoming such one as that the nature of cancer even if genetic can be controlled by circumstances like timely and appropriate intervention. (S.I.)

  10. Radiation and multistage carcinogenesis

    International Nuclear Information System (INIS)

    Day, N.E.

    1984-01-01

    Epidemiological data are insufficient at present to define with much precision the shape of the dose-response curve for radiation carcinogenesis at low or moderate dose levels, for different organs. The available data have to be supplemented with theoretical models for the mode of action. These models, however, often seem not to take into account the complex nature of the process of carcinogenesis. They relate more to mutational events, rather than the long process of cancer induction. In addition, they ignore the fact that in the human situation radiation is one among a large number of exposures, and even the basic form of the dose response may be dependent on the presence or absence of other factors. Information on modes of action usually comes from experimental results, where the requisite combination of exposures can be chosen in advance. Epidemiology, however, also provides information on mechanisms. The purpose of this paper is to consider some of the information that epidemiology provides on the role of radiation in increasing cancer risk in humans

  11. Serum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancer.

    Science.gov (United States)

    Guertin, Kristin A; Loftfield, Erikka; Boca, Simina M; Sampson, Joshua N; Moore, Steven C; Xiao, Qian; Huang, Wen-Yi; Xiong, Xiaoqin; Freedman, Neal D; Cross, Amanda J; Sinha, Rashmi

    2015-05-01

    Coffee intake may be inversely associated with colorectal cancer; however, previous studies have been inconsistent. Serum coffee metabolites are integrated exposure measures that may clarify associations with cancer and elucidate underlying mechanisms. Our aims were 2-fold as follows: 1) to identify serum metabolites associated with coffee intake and 2) to examine these metabolites in relation to colorectal cancer. In a nested case-control study of 251 colorectal cancer cases and 247 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we conducted untargeted metabolomics analyses of baseline serum by using ultrahigh-performance liquid-phase chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Usual coffee intake was self-reported in a food-frequency questionnaire. We used partial Pearson correlations and linear regression to identify serum metabolites associated with coffee intake and conditional logistic regression to evaluate associations between coffee metabolites and colorectal cancer. After Bonferroni correction for multiple comparisons (P = 0.05 ÷ 657 metabolites), 29 serum metabolites were positively correlated with coffee intake (partial correlation coefficients: 0.18-0.61; P 0.40) included trigonelline (N'-methylnicotinate), quinate, and 7 unknown metabolites. Of 29 serum metabolites, 8 metabolites were directly related to caffeine metabolism, and 3 of these metabolites, theophylline (OR for 90th compared with 10th percentiles: 0.44; 95% CI: 0.25, 0.79; P-linear trend = 0.006), caffeine (OR for 90th compared with 10th percentiles: 0.56; 95% CI: 0.35, 0.89; P-linear trend = 0.015), and paraxanthine (OR for 90th compared with 10th percentiles: 0.58; 95% CI: 0.36, 0.94; P-linear trend = 0.027), were inversely associated with colorectal cancer. Serum metabolites can distinguish coffee drinkers from nondrinkers; some caffeine-related metabolites were inversely associated with colorectal

  12. Serum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancer12345

    Science.gov (United States)

    Guertin, Kristin A; Loftfield, Erikka; Boca, Simina M; Sampson, Joshua N; Moore, Steven C; Xiao, Qian; Huang, Wen-Yi; Xiong, Xiaoqin; Freedman, Neal D; Cross, Amanda J; Sinha, Rashmi

    2015-01-01

    Background: Coffee intake may be inversely associated with colorectal cancer; however, previous studies have been inconsistent. Serum coffee metabolites are integrated exposure measures that may clarify associations with cancer and elucidate underlying mechanisms. Objectives: Our aims were 2-fold as follows: 1) to identify serum metabolites associated with coffee intake and 2) to examine these metabolites in relation to colorectal cancer. Design: In a nested case-control study of 251 colorectal cancer cases and 247 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we conducted untargeted metabolomics analyses of baseline serum by using ultrahigh-performance liquid-phase chromatography–tandem mass spectrometry and gas chromatography–mass spectrometry. Usual coffee intake was self-reported in a food-frequency questionnaire. We used partial Pearson correlations and linear regression to identify serum metabolites associated with coffee intake and conditional logistic regression to evaluate associations between coffee metabolites and colorectal cancer. Results: After Bonferroni correction for multiple comparisons (P = 0.05 ÷ 657 metabolites), 29 serum metabolites were positively correlated with coffee intake (partial correlation coefficients: 0.18–0.61; P coffee intake (partial correlation coefficients >0.40) included trigonelline (N′-methylnicotinate), quinate, and 7 unknown metabolites. Of 29 serum metabolites, 8 metabolites were directly related to caffeine metabolism, and 3 of these metabolites, theophylline (OR for 90th compared with 10th percentiles: 0.44; 95% CI: 0.25, 0.79; P-linear trend = 0.006), caffeine (OR for 90th compared with 10th percentiles: 0.56; 95% CI: 0.35, 0.89; P-linear trend = 0.015), and paraxanthine (OR for 90th compared with 10th percentiles: 0.58; 95% CI: 0.36, 0.94; P-linear trend = 0.027), were inversely associated with colorectal cancer. Conclusions: Serum metabolites can

  13. Review of colorectal cancer and its metastases in rodent models: comparative aspects with those in humans

    DEFF Research Database (Denmark)

    Kobaek-Larsen, M; Thorup, I; Diederichsen, Axel Cosmus Pyndt

    2000-01-01

    BACKGROUND AND PURPOSE: Colorectal cancer (CRC) remains one of the most common cancer forms developing in industrialized countries, and its incidence appears to be rising. Studies of human population groups provide insufficient information about carcinogenesis, pathogenesis, and treatment of CRC...

  14. External radiation carcinogenesis

    International Nuclear Information System (INIS)

    Fry, R.J.M.; Storer, J.B.

    1987-01-01

    There have been many reviews of the subject of radiation carcinogenesis in general and of specific radiation-induced cancers. The aim of this article is not to give an exhaustive, and perhaps exhausting, review of all that has been published since the thorough treatise of Walburg in volume 4 of this series but rather to concentrate on the questions that still remain of importance and recent contributions to the answers. In the years since 1974 a vast amount of information has been reported, and the authors assess what gain there has been in knowledge. For example, it is in the 13 years since the last review that the great majority of data for the carcinogenic effects of neutrons has appeared. It is over 50 years since the discovery of the neutron, and yet knowledge of the carcinogenic effects of neutrons is far from adequate

  15. Linking Gut Microbiota to Colorectal Cancer

    DEFF Research Database (Denmark)

    Raskov, Hans; Burcharth, Jakob; Pommergaard, Hans-Christian

    2017-01-01

    Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion...... and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota...... and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health....

  16. Present status of theories and data analyses of mathematical models for carcinogenesis

    International Nuclear Information System (INIS)

    Kai, Michiaki; Kawaguchi, Isao

    2007-01-01

    Reviewed are the basic mathematical models (hazard functions), present trend of the model studies and that for radiation carcinogenesis. Hazard functions of carcinogenesis are described for multi-stage model and 2-event model related with cell dynamics. At present, the age distribution of cancer mortality is analyzed, relationship between mutation and carcinogenesis is discussed, and models for colorectal carcinogenesis are presented. As for radiation carcinogenesis, models of Armitage-Doll and of generalized MVK (Moolgavkar, Venson, Knudson, 1971-1990) by 2-stage clonal expansion have been applied to analysis of carcinogenesis in A-bomb survivors, workers in uranium mine (Rn exposure) and smoking doctors in UK and other cases, of which characteristics are discussed. In analyses of A-bomb survivors, models above are applied to solid tumors and leukemia to see the effect, if any, of stage, age of exposure, time progression etc. In miners and smokers, stages of the initiation, promotion and progression in carcinogenesis are discussed on the analyses. Others contain the analyses of workers in Canadian atomic power plant, and of patients who underwent the radiation therapy. Model analysis can help to understand the carcinogenic process in a quantitative aspect rather than to describe the process. (R.T.)

  17. Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival.

    Science.gov (United States)

    Lochhead, Paul; Nishihara, Reiko; Qian, Zhi Rong; Mima, Kosuke; Cao, Yin; Sukawa, Yasutaka; Kim, Sun A; Inamura, Kentaro; Zhang, Xuehong; Wu, Kana; Giovannucci, Edward; Meyerhardt, Jeffrey A; Chan, Andrew T; Fuchs, Charles S; Ogino, Shuji

    2015-11-01

    Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses' Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food-frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. In 1550 stage I-III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer-specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality (multivariate P-trend ≥ 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one-carbon nutrients or alcohol and any of the tumor molecular

  18. Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival123

    Science.gov (United States)

    Lochhead, Paul; Nishihara, Reiko; Qian, Zhi Rong; Mima, Kosuke; Cao, Yin; Sukawa, Yasutaka; Kim, Sun A; Inamura, Kentaro; Zhang, Xuehong; Wu, Kana; Giovannucci, Edward; Meyerhardt, Jeffrey A; Chan, Andrew T; Fuchs, Charles S; Ogino, Shuji

    2015-01-01

    Background: Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. Objective: We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. Design: We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses’ Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food-frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer–specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. Results: In 1550 stage I–III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer–specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer–specific mortality (multivariate P-trend ≥ 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one

  19. Meat processing and colon carcinogenesis: cooked, nitrite-treated, and oxidized high-heme cured meat promotes mucin-depleted foci in rats.

    Science.gov (United States)

    Santarelli, Raphaëlle L; Vendeuvre, Jean-Luc; Naud, Nathalie; Taché, Sylviane; Guéraud, Françoise; Viau, Michelle; Genot, Claude; Corpet, Denis E; Pierre, Fabrice H F

    2010-07-01

    Processed meat intake is associated with colorectal cancer risk, but no experimental study supports the epidemiologic evidence. To study the effect of meat processing on carcinogenesis promotion, we first did a 14-day study with 16 models of cured meat. Studied factors, in a 2 x 2 x 2 x 2 design, were muscle color (a proxy for heme level), processing temperature, added nitrite, and packaging. Fischer 344 rats were fed these 16 diets, and we evaluated fecal and urinary fat oxidation and cytotoxicity, three biomarkers of heme-induced carcinogenesis promotion. A principal component analysis allowed for selection of four cured meats for inclusion into a promotion study. These selected diets were given for 100 days to rats pretreated with 1,2-dimethylhydrazine. Colons were scored for preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF). Cured meat diets significantly increased the number of ACF/colon compared with a no-meat control diet (P = 0.002). Only the cooked nitrite-treated and oxidized high-heme meat significantly increased the fecal level of apparent total N-nitroso compounds (ATNC) and the number of MDF per colon compared with the no-meat control diet (P nitrite-treated and oxidized cured meat specifically increased the MDF number compared with similar nonnitrite-treated meat (P = 0.03) and with similar nonoxidized meat (P = 0.004). Thus, a model cured meat, similar to ham stored aerobically, increased the number of preneoplastic lesions, which suggests colon carcinogenesis promotion. Nitrite treatment and oxidation increased this promoting effect, which was linked with increased fecal ATNC level. This study could lead to process modifications to make nonpromoting processed meat. 2010 AACR.

  20. contribution to carcinogenesis

    Directory of Open Access Journals (Sweden)

    Aneta Białkowska

    2014-01-01

    Full Text Available The centrosomes are subcellular organelles composed of two centrioles surrounded by a pericentriolar material. In animal cells they are responsible for the organization of the interphase microtubule cytoskeleton including microtubule nucleation and elongation, their attachment and release. The centrosomes are also involved in the construction of the mitotic spindle and chromosome segregation. More than a century ago it was suggested that these structures might be involved in human diseases, including cancer. Cancer cells show a high frequency of centrosome aberrations, especially amplification. Centrosome defects may increase the incidence of multipolar mitoses that lead to chromosomal segregation abnormalities and aneuploidy, which is the predominant type of genomic instability found in human solid tumors. The number of these organelles in cells is strictly controlled and is dependent on the proper process of centrosome duplication. Multiple genes that are frequently found mutated in cancers encode proteins which participate in the regulation of centrosome duplication and the numeral integrity of centrosomes. In recent years there has been growing interest in the potential participation of centrosomes in the process of carcinogenesis, especially because centrosome abnormalities are observed in premalignant stages of cancer development. The common presence of abnormal centrosomes in cancer cells and the role these organelles play in the cells suggest that the factors controlling the number of centrosomes may be potential targets for cancer therapy.

  1. Gene amplification in carcinogenesis

    Directory of Open Access Journals (Sweden)

    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.

  2. Modeling Multiple Causes of Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Jones, T D

    1999-01-24

    An array of epidemiological results and databases on test animal indicate that risk of cancer and atherosclerosis can be up- or down-regulated by diet through a range of 200%. Other factors contribute incrementally and include the natural terrestrial environment and various human activities that jointly produce complex exposures to endotoxin-producing microorganisms, ionizing radiations, and chemicals. Ordinary personal habits and simple physical irritants have been demonstrated to affect the immune response and risk of disease. There tends to be poor statistical correlation of long-term risk with single agent exposures incurred throughout working careers. However, Agency recommendations for control of hazardous exposures to humans has been substance-specific instead of contextually realistic even though there is consistent evidence for common mechanisms of toxicological and carcinogenic action. That behavior seems to be best explained by molecular stresses from cellular oxygen metabolism and phagocytosis of antigenic invasion as well as breakdown of normal metabolic compounds associated with homeostatic- and injury-related renewal of cells. There is continually mounting evidence that marrow stroma, comprised largely of monocyte-macrophages and fibroblasts, is important to phagocytic and cytokinetic response, but the complex action of the immune process is difficult to infer from first-principle logic or biomarkers of toxic injury. The many diverse database studies all seem to implicate two important processes, i.e., the univalent reduction of molecular oxygen and breakdown of aginuine, an amino acid, by hydrolysis or digestion of protein which is attendant to normal antigen-antibody action. This behavior indicates that protection guidelines and risk coefficients should be context dependent to include reference considerations of the composite action of parameters that mediate oxygen metabolism. A logic of this type permits the realistic common-scale modeling of

  3. Colorectal Cancer

    Science.gov (United States)

    ... rectum are part of the large intestine. Colorectal cancer occurs when tumors form in the lining of ... men and women. The risk of developing colorectal cancer rises after age 50. You're also more ...

  4. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: Associations with promoter CpG island hypermethylation in colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Wouters, K.A.D.; Gottschalk, R.W.H.; Schooten, F.J. van; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Weijenberg, M.P.; Engeland, M. van

    2009-01-01

    Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of

  5. Apoptotic effects of inositol hexaphosphate on biomarker Itpr3 in induced colon rat carcinogenesis Efeito de apoptose do inositol hexafosfato no marcador biológico Itpr3 em carcinogênese induzida de colo em ratos

    Directory of Open Access Journals (Sweden)

    Marks Guido

    2008-04-01

    Full Text Available PURPOSE: To study the effect of the modulation of inositol hexaphosphate (IP6 in the biological immunohistochemistry expression of cellular signaling marker apoptosis, in model of carcinogenesis of colon induced by azoxymethane (AOM. METHODS: Wistar rats (N=112 distributed in 4 groups (n=28: Control; B, AOM (5 mg kg-1, 2x, to break week 3; C, IP6 (in water 1%, six weeks; D, IP6+AOM. Weekly euthanasia (n=7, from week three. Immunohistochemistry of ascendant colon with biological marker inositol 1,4,5 triphosphate receptor type III (Itpr3. Quantification of the immune-expression with use of computer-assisted image processing. Analysis statistics of the means between groups, weeks in groups, groups in weeks, and established significance when pOBJETIVO: Estudar os efeitos da modulação do inositol hexafosfato (IP6 na expressão imunoistoquímica de marcador biológico de sinalização celular de apoptose, em modelo de carcinogênese induzida pelo azoximetano (AOM. MÉTODOS: Ratos Wistar (N=112 distribuídos em 4 grupos (n=28: A, controle; B, AOM (5 mg Kg-1, 2x, a partir semana 3; C, IP6 (em água a 1%, seis semanas; D, IP6+AOM. Eutanásia semanal (n=7, a partir de semana três. Imunoistoquímica de colo ascendente com marcador biológico inositol 1,4,5 trisphosphate receptor type III (Itpr3. Quantificação da imunoexpressão com uso de processamento imagem assistida computador. Análise estatística da expressão média entre grupos, semanas em grupos e grupos em semanas, e estabelecido significância quando p<0.05. RESULTADOS: Evidenciou-se diferença significante entre grupos na expressão de Itpr3, p<0.0001; com diminuição Itpr3 de grupo BxD, p<0.001. CONCLUSÃO: O inositol hexafostato promove a modulação de marcador biológico com diminuição Itpr3 em carcinogênese de colo.

  6. Association between Fusobacterium nucleatum and colorectal cancer: Progress and future directions

    Science.gov (United States)

    Zhang, Sheng; Cai, Sanjun; Ma, Yanlei

    2018-01-01

    The initiation and progression of colorectal cancer (CRC) involves genetic and epigenetic alterations influenced by dietary and environmental factors. Increasing evidence has linked the intestinal microbiota and colorectal cancer. More recently, Fusobacterium nucleatum (Fn), an opportunistic commensal anaerobe in the oral cavity, has been associated with CRC. Several research teams have reported an overabundance of Fn in human CRC and have elucidated the possible mechanisms by which Fn is involved in colorectal carcinogenesis in vitro and in mouse models. However, the mechanisms by which Fn promotes colorectal carcinogenesis remain unclear. To provide new perspectives for early diagnosis, the identification of high risk populations and treatment for colorectal cancer, this review will summarize the relative research progresses regarding the relationship between Fn and colorectal cancer. PMID:29760804

  7. Meat and colo-rectal cancer.

    Science.gov (United States)

    Hill, M J

    1999-05-01

    In early epidemiological studies of diet and cancer the stress was on the search for causal factors. Population (ecological) studies tended to show a strong correlation between meat intake, particularly red meat, and the risk of colo-rectal cancer. They also tended to show meat to be strongly inversely correlated with cancers of the stomach and oesophagus and liver. Early case-control studies tended to support the postulated role for red meat in colo-rectal carcinogenesis, although more recent case-control studies, particularly those from Europe, have tended to show no relationship. The cohort studies in general failed to detect any relationship between meat intake and colo-rectal cancer risk. The available evidence points to the intake of protective factors such as vegetables and whole-grain cereals being the main determinants of colo-rectal cancer risk, with meat intake only coincidentally related.

  8. Predictive and prognostic value of circulating nucleosomes and serum biomarkers in patients with metastasized colorectal cancer undergoing Selective Internal Radiation Therapy

    International Nuclear Information System (INIS)

    Fahmueller, Yvonne Nadine; Nagel, Dorothea; Hoffmann, Ralf-Thorsten; Tatsch, Klaus; Jakobs, Tobias; Stieber, Petra; Holdenrieder, Stefan

    2012-01-01

    Selective Internal Radiation Therapy (SIRT) is a new and effective locoregional anticancer therapy for colorectal cancer patients with liver metastases. Markers for prediction of therapy response and prognosis are needed for the individual management of those patients undergoing SIRT. Blood samples were prospectively and consecutively taken from 49 colorectal cancer patients with extensive hepatic metastases before, three, six, 24 and 48 h after SIRT to analyze the concentrations of nucleosomes and further laboratory parameters, and to compare them with the response to therapy regularly determined 3 months after therapy and with overall survival. Circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), C-reactive protein (CRP) and various liver markers increased already 24 h after SIRT. Pretherapeutical levels of CYFRA 21-1, CEA, cancer antigen 19-9 (CA 19-9), asparate-aminotransferase (AST) and lactate dehydrogenase (LDH) as well as 24 h values of nucleosomes were significantly higher in patients suffering from disease progression (N = 35) than in non-progressive patients (N = 14). Concerning overall survival, CEA, CA 19-9, CYFRA 21-1, CRP, LDH, AST, choline esterase (CHE), gamma-glutamyl-transferase, alkaline phosphatase, and amylase (all 0 h, 24 h) and nucleosomes (24 h) were found to be prognostic relevant markers in univariate analyses. In multivariate Cox-Regression analysis, the best prognostic model was obtained for the combination of CRP and AST. When 24 h values were additionally included, nucleosomes (24 h) further improved the existing model. Panels of biochemical markers are helpful to stratify pretherapeutically colorectal cancer patients for SIR-therapy and to early estimate the response to SIR-therapy

  9. Epigenetic mechanism of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Niwa, Ohtsura

    1995-01-01

    Carcinogenic action of radiations has long been thought to be due to its mutagenic activity. Since DNA damage is induced and distributes in a stochastic fashion, radiation induction of cancers was also assumed to follow a stochastic kinetics. However, recent progress in radiation research has revealed that some features of radiation carcinogenesis are not explainable by the simple action of radiation as a DNA damaging and mutagenic agent. Firstly, frequencies of radiation-induced transformation in vitro and radiation-induced mammary cancers in rats are too high to be accounted for by the frequency of radiation-induced mutation. Secondly, trans-generation carcinogenesis among F1 mice born to irradiated parents occurs also much more frequently than to be predicted by the frequency of radiation induced germline mutation. Thirdly, multistage carcinogenesis theory predicts that carcinogens give hits to the target cells so as to shorten the latency of cancers. However, latencies of radiation induced solid cancers among atomic bomb survivors are similar to those of the control population. Fourthly, although radiation elevates the frequency of cancers, the induced cancers seem to share the same spectrum of cancer types as in the unirradiated control populations. This suggests that radiation induces cancer by enhancement of the spontaneous carcinogenesis process. These data suggest that the first step of radiation carcinogenesis may not be the direct induction of mutation. Radiation may induce genetic instability which increases the spontaneous mutation rate in the cells to produce carcinogenic mutations. Growth stimulatory effect of radiation may also contribute to the process. Thus, epigenetic, but not genetic effect of radiation might better contribute in the process of carcinogenesis. (author)

  10. Colorectal Cancer Screening

    Science.gov (United States)

    ... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Screening (PDQ®)–Patient Version What is screening? Go ... These are called diagnostic tests . General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

  11. Colorectal Cancer Prevention

    Science.gov (United States)

    ... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... to keep cancer from starting. General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

  12. 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.

  13. Experimental radiation carcinogenesis is studies at NIRS

    International Nuclear Information System (INIS)

    Sado, Toshihiko

    1992-01-01

    Experimental radiation carcinogenesis studies conducted during the past decade at NIRS are briefly reviewed. They include the following: 1) Age dependency of susceptibility to radiation carcinogenesis. 2) Radiation-induced myeloid leukemia. 3) Mechanism of fractionated X-irradiation (FX) induced thymic lymphomas. 4) Significance of radiation-induced immunosuppression in radiation carcinogenesis in vivo. 5) Other ongoing studies. (author)

  14. Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.

    Science.gov (United States)

    Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

    2015-03-01

    Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  15. Radiation carcinogenesis: radioprotectors and photosensitizers

    International Nuclear Information System (INIS)

    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

  16. 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.

  17. Downregulated Ku70 and ATM associated to poor prognosis in colorectal cancer among Chinese patients

    Directory of Open Access Journals (Sweden)

    Lu YF

    2014-10-01

    Full Text Available Yuanfang Lu,1,2 Jingyan Gao,1,3 Yuanming Lu,1 1Department of Toxicology, School of Public Health, Guilin Medical University, Guangxi, People's Republic of China; 2Department of Clinical Research Center, Affiliated 2nd Hospital of Nanjing Medical University, Nanjing, People's Republic of China; 3Department of Human Anatomy and Histo-Embryology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China Background: Double-strand DNA breaks (DSBs are a key factor in carcinogenesis. The necessary repair of DSBs is pivotal in maintaining normal cell division. To address the relationship between altered expression of DSB repair of proteins Ku70 and ataxia-telangiectasia mutated (ATM in colorectal cancer (CRC, we examined the expression levels and patterns of Ku70 and ATM in CRC samples. Methods: Expression and coexpression of Ku70 and ATM were investigated by using real-time quantitative polymerase chain reaction assays and confirmed further with fluorescent immunohistochemistry in CRC and pericancerous samples from 112 Chinese patients. Results: Downexpression patterns for both Ku70 and ATM were found in the CRC samples and were significantly associated with advanced tumor node metastasis stage and decreased 5-year overall survival rate. Conclusion: Downregulated Ku70 and ATM were associated with poor disease-free survival. Loss of Ku70 and ATM expression might act as a biomarker to predict poor prognosis in patients with CRC. Keywords: DNA double-strand breaks, ataxia-telangiectasia mutated, Ku70, colorectal cancer

  18. CCR 20th Anniversary Commentary: RAS as a Biomarker for EGFR--Targeted Therapy for Colorectal Cancer-From Concept to Practice.

    Science.gov (United States)

    Camp, E Ramsay; Ellis, Lee M

    2015-08-15

    Clinical data support the use of EGFR mAbs in patients with metastatic colorectal cancer (mCRC) with wild-type RAS status. This notion, hypothesized in the review article by Camp, Ellis, and colleagues in the January 1, 2005, issue of Clinical Cancer Research, serves as an example of the successful application of basic science principles to clinical practice. The exclusion of patients with mCRC with Ras-mutated tumors from therapy with EGFR mAbs has led to improved outcomes while sparing patients unnecessary and potentially harmful therapy. See related article by Camp et al., Clin Cancer Res 2005;11(1): January 1, 2005;397-405. ©2015 American Association for Cancer Research.

  19. Nutrients, foods, and colorectal cancer prevention.

    Science.gov (United States)

    Song, Mingyang; Garrett, Wendy S; Chan, Andrew T

    2015-05-01

    Diet has an important role in the development of colorectal cancer. In the past few decades, findings from extensive epidemiologic and experimental investigations have linked consumption of several foods and nutrients to the risk of colorectal neoplasia. Calcium, fiber, milk, and whole grains have been associated with a lower risk of colorectal cancer, and red meat and processed meat have been associated with an increased risk. There is substantial evidence for the potential chemopreventive effects of vitamin D, folate, fruits, and vegetables. Nutrients and foods also may interact, as a dietary pattern, to influence colorectal cancer risk. Diet likely influences colorectal carcinogenesis through several interacting mechanisms. These include the direct effects on immune responsiveness and inflammation, and the indirect effects of overnutrition and obesity-risk factors for colorectal cancer. Emerging evidence also implicates the gut microbiota as an important effector in the relationship between diet and cancer. Dietary modification therefore has the promise of reducing colorectal cancer incidence. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  20. Fas Ligand Expression in Lynch Syndrome-Associated Colorectal Tumours

    NARCIS (Netherlands)

    Koornstra, Jan J.; de Jong, Steven; Boersma-van Eck, Wietske; Zwart, Nynke; Hollema, Harry; de Vries, Elisabeth G. E.; Kleibeuker, Jan H.

    Fas Ligand (FasL) expression by cancer cells may contribute to tumour immune escape via the Fas counterattack against tumour-infiltrating lymphocytes (TILs). Whether this plays a role in colorectal carcinogenesis in Lynch syndrome was examined studying FasL expression, tumour cell apoptosis and

  1. Dietary factors and Truncating APC Mutations in Sporadic Colorectal Adenomas

    NARCIS (Netherlands)

    Diergaarde, B.; Tiemersma, E.W.; Braam, H.; Muijen, van G.N.P.; Nagengast, F.M.; Kok, F.J.; Kampman, E.

    2005-01-01

    Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control

  2. Dietary factors and truncating APC mutations in sporadic colorectal adenomas.

    NARCIS (Netherlands)

    Diergaarde, B.; Tiemersma, E.W.; Braam, H.; Muijen, G.N.P. van; Nagengast, F.M.; Kok, F.J.; Kampman, E.

    2005-01-01

    Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control

  3. Oral Bacterial and Fungal Microbiome Impacts Colorectal Carcinogenesis

    OpenAIRE

    Klara Klimesova; Zuzana Jiraskova Zakostelska; Helena Tlaskalova-Hogenova

    2018-01-01

    Host’s physiology is significantly influenced by microbiota colonizing the epithelial surfaces. Complex microbial communities contribute to proper mucosal barrier function, immune response, and prevention of pathogen invasion and have many other crucial functions. The oral cavity and large intestine are distant parts of the digestive tract, both heavily colonized by commensal microbiota. Nevertheless, they feature different proportions of major bacterial and fungal phyla, mostly due to distin...

  4. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each...... pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226...

  5. Expression of insulin-like growth factor system components in colorectal tissue and its relation with serum IGF levels

    NARCIS (Netherlands)

    Vrieling, A.; Voskuil, D.W.; Bosma, A.; Majoor, D.M.; Doorn, van J.; Cats, A.; Depla, A.; Timmer, R.; Witteman, B.J.M.; Wesseling, J.; Kampman, E.; van't Veer, L.J.

    2009-01-01

    Context: The insulin-like growth factor (IGF)-system has been implicated in colorectal tumor carcinogenesis. Although both tumor expression levels and serum concentrations of IGF-system components are related to colorectal cancer risk, it is unknown whether IGF levels in tissue and serum are

  6. Expression of insulin-like growth factor system components in colorectal tissue and its relation with serum IGF levels.

    NARCIS (Netherlands)

    Vrieling, A.; Voskuil, D.W.; Bosma, A.; Majoor, D.M.; Doorn, J. van; Cats, A.; Depla, A.C.; Timmer, R.; Witteman, B.J.; Wesseling, J.; Kampman, E.; Veer, L.J. van 't

    2009-01-01

    CONTEXT: The insulin-like growth factor (IGF)-system has been implicated in colorectal tumor carcinogenesis. Although both tumor expression levels and serum concentrations of IGF-system components are related to colorectal cancer risk, it is unknown whether IGF levels in tissue and serum are

  7. Radiation carcinogenesis in scid mice

    Energy Technology Data Exchange (ETDEWEB)

    Ishii, Hiroko; Nishimura, Mayumi; Kobayashi, Shigeru; Tsuji, Hideo; Shimada, Yoshiya; Ogiu, Toshiaki [National Inst. of Radiological Sciences, Chiba (Japan); Suzuki, Fumio; Sado, Toshihiko

    1999-06-01

    Scid mice which have the defect of DNA-dependent protein kinase catalitic subunit, exhibit the limited activities of repair from DNA double strand breaks, and are sensitive to ionizing radiation. In order to study the relationship between repair capacity for DNA double strand breaks and carcinogenesis, the effects of ionizing radiation were studied using scid homozygotes (scid/scid), scid heterozygotes (scid/+) and CB-17 (+/+) mice. Both the Scid bone marrow cells and fibroblast cell lines from Scid embryos were highly sensitivity to acute effects of ionizing radiation. Carcinogenesis experiments showed the high incidence of thymic lymphomas (80 to 90%) in 1 to 3 Gy {sup 137}Cs-{gamma}-ray-irradiated Scid mice. (author)

  8. Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer

    Science.gov (United States)

    Suenaga, Mitsukuni; Mashima, Tetsuo; Kawata, Naomi; Wakatsuki, Takeru; Horiike, Yuki; Matsusaka, Satoshi; Dan, Shingo; Shinozaki, Eiji; Seimiya, Hiroyuki; Mizunuma, Nobuyuki; Yamaguchi, Kensei; Yamaguchi, Toshiharu

    2016-01-01

    Regorafenib is an oral multi-kinase inhibitor used as salvage therapy for metastatic colorectal cancer (mCRC). We tested whether serum cytokine levels are associated with clinical outcome in the mCRC patients receiving regorafenib. Serum samples were collected before treatment start, day 21, and progressive disease, and eleven angiogenic and inflammatory cytokine serum levels were examined. Fifty-four patients of a total of 62 enrolled patients were eligible for the analyses. The chemokine ligand 5 (CCL5) levels ≤ cut-off value (59959 pg/ml) at baseline was associated with relative tumor shrinkage (P = 0.021), better progression-free survival (PFS) (P = 0.036) and overall survival (OS) (P = 0.019). Vascular endothelial growth factor A (VEGF-A) levels showing a decrease on day 21 were significantly associated with a better PFS (P = 0.021). CCL5 levels ≤ cut-off was associated with any grade hand-foot skin reaction (HFSR) (P = 0.025) and thrombocytopenia (P = 0.013). Low chemokine ligand 2 levels at baseline were associated with grade 2 ≤ HFSR. High angiopoietin-2 and basic fibroblast growth factor (bFGF) levels at baseline were associated with grade 3 ≤ total bilirubin increase and transaminases increase, respectively. Low bFGF levels at baseline were associated with grade 3 ≤ hypertension. No correlation with severe events was observed. Baseline serum CCL5 levels and decrease of the serum VEGF-A levels may serve as potential predictive markers for survival or treatment-specific toxicities in mCRC patients receiving regorafenib. PMID:27166185

  9. Subnuclear proteomics in colorectal cancer

    DEFF Research Database (Denmark)

    Albrethsen, Jakob; Knol, Jaco C; Piersma, Sander R

    2010-01-01

    for early cancer detection. Here we evaluate a proteomics work flow for profiling protein constituents in subnuclear domains in colorectal cancer tissues and apply this work flow to a comparative analysis of the nuclear matrix fraction in colorectal adenoma and carcinoma tissue samples. First, we......Abnormalities in nuclear phenotype and chromosome structure are key features of cancer cells. Investigation of the protein determinants of nuclear subfractions in cancer may yield molecular insights into aberrant chromosome function and chromatin organization and in addition may yield biomarkers...... with statistics, we identified proteins that are significantly enriched in the nuclear matrix fraction relative to two earlier fractions (the chromatin-binding and intermediate filament fractions) isolated from six colorectal tissue samples. The total data set contained 2,059 non-redundant proteins. Gene ontology...

  10. Colorectal tuberculosis

    International Nuclear Information System (INIS)

    Nagi, B.; Kochhar, R.; Bhasin, D.K.; Singh, K.

    2003-01-01

    Our objective was to evaluate the incidence of colorectal tuberculosis in our series and to study its radiological spectrum. A total of 684 cases of proven gastrointestinal tuberculosis with positive barium contrast findings seen over a period of more than one decade were evaluated. The study did not include cases where colon was involved in direct contiguity with ileo-caecal tuberculosis. Seventy-four patients (10.8%) had colorectal tuberculosis. Commonest site involved was transverse colon, closely followed by rectum and ascending colon. Radiological findings observed were in the form of strictures (54%), colitis (39%) and polypoid lesions (7%). Complications noted were in the form of perforations and fistulae in 18.9% of cases. Colorectal tuberculosis is a very common site for gastrointestinal tuberculosis. Typical findings of colorectal tuberculosis are strictures, signs of colitis and polypoid lesions. Common complications are perforation and fistulae. (orig.)

  11. Colorectal Cancer

    Science.gov (United States)

    ... possible. Research will help us better understand whether chemotherapy can benefit elderly colorectal cancer patients. Such patients often do not receive chemotherapy due to concerns about side effects. We will ...

  12. 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

  13. Carcinogenesis

    International Nuclear Information System (INIS)

    Reilly, C.A. Jr.

    1979-01-01

    This section contains summaries of research in the following areas: use of liver for mechanistic studies of multistage hepatocarcinogenesis and for screening of environmental contaminants for tumor initiating and promoting activity; molecular properties of rat liver ornithine aminotransferase; regulation of gene expression in rat liver; methods of tumor detection; mechanisms of radiation and viral oncogenesis; biphenyl metabolism by rat liver microsomes; and studies on aryl hydrocarbon hydroxylase activity

  14. Carcinogenesis

    International Nuclear Information System (INIS)

    Buess, E.M.; Cerny, E.A.; Chan, E.W.

    1977-01-01

    The first section deals with the assessment of carcinogens and cocarcinogens and the underlying mechanisms of their actions. The second concerns cancer induction by bone-seeking radionuclides and seeks to provide a firm foundation for estimating cancer risks to human populations in the event of accidental incorporation of radionuclides. The third is aimed at defining the role of oncornavirus activation in tumor induction by radiation and other environmental pollutants. The other two sections describe the new studies, one dealing with the development of an in vitro cell system (murine teratocarcinoma cells) to screen chemicals rapidly for carcinogenic and mutagenic capacity, and the other investigating the potential use of plasma isozymes as indicators of mutagenesis in mammals. Accomplishments and projections for each of these studies follow

  15. 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.

  16. Folate, colorectal cancer and the involvement of DNA methylation.

    Science.gov (United States)

    Williams, Elizabeth A

    2012-11-01

    Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a high-dose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.

  17. Mutagenesis and carcinogenesis resulting from environment pollution

    International Nuclear Information System (INIS)

    Dimitrov, B.

    2001-01-01

    The paper reviews different ways of environmental contamination with natural and artificial harmful substances (chemical and radioactive) and their role in the processes of mutagenesis and carcinogenesis. The recent studies of the mechanism of mutagenesis and carcinogenesis due to environmental pollution are discussed

  18. Mutiple simultaneous event model for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Baum, J.W.

    1979-01-01

    Theoretical Radiobiology and Risk Estimates includes reports on: Multiple Simultaneous Event Model for Radiation Carcinogenesis; Cancer Risk Estimates and Neutron RBE Based on Human Exposures; A Rationale for Nonlinear Dose Response Functions of Power Greater or Less Than One; and Rationale for One Double Event in Model for Radiation Carcinogenesis

  19. Dietary B vitamin and methionine intake and MTHFR C677T genotype on risk of colorectal tumors in Lynch syndrome: the GEOLynch cohort study

    NARCIS (Netherlands)

    Jung, A.Y.; van Duijnhoven, F.J.B.; Nagengast, F.M.; Botma, A.; Heine-Broring, R.C.; Kleibeuker, J.H.; Vasen, H.F.A.; Harryvan, J.L.; Winkels, R.M.; Kampman, E.

    2014-01-01

    Purpose: Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given

  20. Sugars, sucrose and colorectal cancer risk: the Fukuoka colorectal cancer study.

    Science.gov (United States)

    Wang, Zhenjie; Uchida, Kazuhiro; Ohnaka, Keizo; Morita, Makiko; Toyomura, Kengo; Kono, Suminori; Ueki, Takashi; Tanaka, Masao; Kakeji, Yoshihiro; Maehara, Yoshihiko; Okamura, Takeshi; Ikejiri, Koji; Futami, Kitaroh; Maekawa, Takafumi; Yasunami, Yohichi; Takenaka, Kenji; Ichimiya, Hitoshi; Terasaka, Reiji

    2014-05-01

    A diet high in sugars may promote colorectal carcinogenesis, but it remains uncertain whether high intake of sugars or sucrose confers increased risk of colorectal cancer. The authors investigated the associations of sugars and sucrose intake with colorectal cancer risk in a community-based case-control study in Japan. The study subjects comprised 816 incident cases of colorectal cancer and 815 community controls. Consumption frequencies and portion sizes of 148 food and beverage items were ascertained by a computer-assisted interview. The authors used the consumption of 29 food items to estimate sugars and sucrose intake. The odds ratios of colorectal cancer risk according to intake categories were obtained using a logistic regression model with adjustment for potential confounding variables. Overall, intakes of sugars and sucrose were not related to colorectal cancer risk either in men or women. The association between sugars intake and colorectal cancer risk differed by smoking status and alcohol use in men, but not in women. In men, sugars intake tended to be associated with colorectal cancer risk inversely among never-smokers and positively among male ever-smokers (interaction p=0.01). Sugars intake was associated with an increased risk among men with no alcohol consumption, but was unrelated to the risk among male alcohol drinkers (interaction p=0.02). Body mass index did not modify the association with sugars intake in either men or women. Sugars intake was associated with increased risk of colorectal cancer among smokers and non-alcohol drinkers in men selectively.

  1. The inflammatory microenvironment in colorectal neoplasia.

    Science.gov (United States)

    McLean, Mairi H; Murray, Graeme I; Stewart, Keith N; Norrie, Gillian; Mayer, Claus; Hold, Georgina L; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N Ashley G; Drew, Janice E; El-Omar, Emad M

    2011-01-07

    Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

  2. The Inflammatory Microenvironment in Colorectal Neoplasia

    Science.gov (United States)

    McLean, Mairi H.; Murray, Graeme I.; Stewart, Keith N.; Norrie, Gillian; Mayer, Claus; Hold, Georgina L.; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N. Ashley G.; Drew, Janice E.; El-Omar, Emad M.

    2011-01-01

    Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified. PMID:21249124

  3. The inflammatory microenvironment in colorectal neoplasia.

    Directory of Open Access Journals (Sweden)

    Mairi H McLean

    Full Text Available Colorectal cancer (CRC is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5 are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

  4. Identification of Kininogen 1 as a Serum Protein Marker of Colorectal Adenoma in Patients with a Family History of Colorectal Cancer

    Science.gov (United States)

    Yu, Jiekai; Huang, Yanqin; Lin, Chen; Li, Xiaofen; Fang, Xuefeng; Zhong, Chenhan; Yuan, Ying; Zheng, Shu

    2018-01-01

    The serum protein markers of colorectal adenoma in patients with a family history of colorectal cancer have been rarely reported. Serum samples from colorectal adenoma patients with or without a family history of colorectal cancer and healthy controls were profiled using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). The model to distinguish colorectal adenoma patients with a family history of colorectal cancer from atypical hereditary colorectal families (CRA-H) and sporadic colorectal adenoma patients without a family history of colorectal cancer (CRA-S) was established with 85.0% accuracy. The model distinguishing CRA-H from healthy individuals was established with 90.0% specificity and 86.7% sensitivity. Additionally, five peaks (2202, 5821, 3260, 2480, and 2218) showing differential expression in advanced colorectal adenoma patients with a family history of colorectal cancer were selected. The protein Kininogen 1 (KNG1) was identified in colorectal adenoma patients and validated using Western Blotting. KNG1 may be a biomarker for colorectal adenoma patients with a family history of colorectal cancer. PMID:29535795

  5. Environmental carcinogenesis and genetic variability

    International Nuclear Information System (INIS)

    Knudsen, A.G. Jr

    1977-01-01

    It was found that carcinogenesis in man may involve the interaction of genetic and environmental forces, and that mutation, whether germinal or somatic, seems to be involved in the origin of many, perhaps all cancers. The cancers of man may be visualized as occurring in four groups of individuals according to whether (1) neither genetic nor environmental factors are dominant, i.e. 'background' or 'spontaneous' cancer, (2) heredity alone is dominant, (3) environment alone is important, or (4) both are operating (Knudsen, 1977). The last two groups together are widely thought to contribute 70-80% of cancer cases in the United States; the relative contribution of each group is a major question to be answered

  6. Time factors in radiation carcinogenesis

    International Nuclear Information System (INIS)

    Sasaki, Shunsaku

    1995-01-01

    Results of experiments using B6C3F 1 female mice were made subject of analysis on the time factors in radiation carcinogenesis. In the experiment for examination of influence of age at irradiation on the lifetime risk and on distribution of ages at death, mice were irradiated at day 12, 14 or 17 of the prenatal period, or day 0, 7, 35, 105, 240 or 365 of the postnatal period with doses ranging from 0.48 to 5.7 Gy gamma-rays from 137 Cs. In the experiment to examine the reduction factor for carcinogenic effect by multiple fractionation of gamma-rays dose 1.9 or 3.8 Gy was divided into 10 fractions, which were delivered once a week during period from 5 to 15 weeks of age. All mice were allowed to live out their life spans under a specific pathogen free condition. The cumulative relative risk for mortality from all causes except lymphoma and leukemia was shown to decrease with age when mice were irradiated at the fetal, neonatal, suckling, adolescent or young adult period, whereas, the decrease in the cumulative relative risk was very little when gamma-rays were given at the intermediate adult period. The lifetime risk for the increase in mortality and for the induction of solid tumors was highest in mice irradiated during neonatal, suckling or adolescent period. Age-dependence of susceptibility to radiation carcinogenesis was different for each type of neoplasm. However, the most susceptible period for induction of each type of neoplasm concentrated in the age from neonatal to adolescent period. Radiation-induced late effects were apparently reduced by multiple fractionation of radiation dose, but the reduction factor for the increase in the long-term mortality did not exceed 2.0. (author)

  7. Risks of Colorectal Cancer Screening

    Science.gov (United States)

    ... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Screening (PDQ®)–Patient Version What is screening? Go ... These are called diagnostic tests . General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

  8. Helicobacter pylori and colorectal neoplasia: Is there a causal link?

    Science.gov (United States)

    Papastergiou, Vasilios; Karatapanis, Stylianos; Georgopoulos, Sotirios D

    2016-01-01

    Ever since Helicobacter pylori (H. pylori) was recognized as an infectious cause of gastric cancer, there has been increasing interest in examining its potential role in colorectal carcinogenesis. Data from case-control and cross-sectional studies, mostly relying on hospital-based samples, and several meta-analyses have shown a positive statistical relationship between H. pylori infection and colorectal neoplasia. However, the possibility exists that the results have been influenced by bias, including the improper selection of patients and disparities with respect to potential confounders. While the evidence falls short of a definitive causal link, it appears that infection with H. pylori/H. pylori-related gastritis is associated with an increased, although modest, risk of colorectal adenoma and cancer. The pathogenic mechanisms responsible for this association remain uncertain. H. pylori has been detected in colorectal malignant tissues; however, the possibility that H. pylori is a direct activator of colonic carcinogenesis remains purely hypothetical. On the other hand, experimental data have indicated a series of potential oncogenic interactions between these bacteria and colorectal mucosa, including induction and perpetuation of inflammatory responses, alteration of gut microflora and release of toxins and/or hormonal mediators, such as gastrin, which may contribute to tumor formation. PMID:26811614

  9. Gut microbiome development along the colorectal adenoma-carcinoma sequence

    DEFF Research Database (Denmark)

    Feng, Qiang; Liang, Suisha; Jia, Huijue

    2015-01-01

    factors indicates that high intake of red meat relative to fruits and vegetables appears to associate with outgrowth of bacteria that might contribute to a more hostile gut environment. These findings suggest that faecal microbiome-based strategies may be useful for early diagnosis and treatment......Colorectal cancer, a commonly diagnosed cancer in the elderly, often develops slowly from benign polyps called adenoma. The gut microbiota is believed to be directly involved in colorectal carcinogenesis. The identity and functional capacity of the adenoma- or carcinoma-related gut microbe...

  10. Diagnosing lynch syndrome in absence of colorectal cancer.

    Science.gov (United States)

    Lynch, Henry T; Knezetic, Joseph; Lanspa, Stephen

    2012-11-01

    There are many ways in which a diagnosis of Lynch syndrome can be made, most prominent of which is family history, presence of cancer, high microsatellite instability, immunohistochemistry, and a mismatch repair germline mutation. There are at least four molecular pathways for colorectal cancer carcinogenesis: 1) adenoma-carcinoma sequence; 2) hereditary microsatellite instability; 3) serrated pathway; 4) epidermal growth factor receptor. The answer to diagnosing Lynch syndrome in the absence of colorectal cancer may be partially based upon the phenotypic characteristics of the colonic polyps should they be identified at colonoscopy, specifically their phenotypic characteristics of location, size, histology, number, and age of polyp onset.

  11. Free radicals in chemical carcinogenesis.

    Science.gov (United States)

    Clemens, M R

    1991-12-15

    During the past decade, remarkable progress has been made in our understanding of cancer-causing agents, mechanisms of cancer formation and the behavior of cancer cells. Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). It has been estimated that about 75-80% of all human cancers are environmentally induced, 30-40% of them by diet. Only a small minority, possibly no more than 2% of all cases, result purely from inherent genetic changes. Several lines of evidence confirm that the fundamental molecular event or events that cause a cell to become malignant occur at the level of the DNA and a variety of studies indicate that the critical molecular event in chemical carcinogenesis is the interaction of the chemical agent with DNA. The demonstration that DNA isolated from tumor cells can transfect normal cells and render them neoplastic provides direct proof that an alteration of the DNA is responsible for cancer. The transforming genes, or oncogenes, have been identified by restriction endonuclease mapping. One of the characteristics of tumor cells generated by transformation with viruses, chemicals, or radiation is their reduced requirement for serum growth factors. A critical significance of electrophilic metabolites of carcinogenes in chemical carcinogenesis has been demonstrated. A number of "proximate" and "ultimate" metabolites, especially those of aromatic amines, were described. The "ultimate" forms of carcinogens actually interact with cellular constituents to cause neoplastic transformation and are the final metabolic products in most pathways. Recent evidence indicates that free radical derivatives of chemical carcinogens may be produced both metabolically and nonenzymatically during their metabolism. Free radicals carry no

  12. Statistical modeling and extrapolation of carcinogenesis data

    International Nuclear Information System (INIS)

    Krewski, D.; Murdoch, D.; Dewanji, A.

    1986-01-01

    Mathematical models of carcinogenesis are reviewed, including pharmacokinetic models for metabolic activation of carcinogenic substances. Maximum likelihood procedures for fitting these models to epidemiological data are discussed, including situations where the time to tumor occurrence is unobservable. The plausibility of different possible shapes of the dose response curve at low doses is examined, and a robust method for linear extrapolation to low doses is proposed and applied to epidemiological data on radiation carcinogenesis

  13. Potential targets for colorectal cancer prevention.

    Science.gov (United States)

    Temraz, Sally; Mukherji, Deborah; Shamseddine, Ali

    2013-08-22

    The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), survivin and insulin-like growth factor-I (IGF-I). Clinical trials of COX-2 inhibitors have provided the "proof of principle" that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.

  14. Potential Targets for Colorectal Cancer Prevention

    Directory of Open Access Journals (Sweden)

    Ali Shamseddine

    2013-08-01

    Full Text Available The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2, nuclear factor kappa B (NF-κB, survivin and insulin-like growth factor-I (IGF-I. Clinical trials of COX-2 inhibitors have provided the “proof of principle” that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.

  15. 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.

  16. Biological Complexities in Radiation Carcinogenesis and Cancer Radiotherapy: Impact of New Biological Paradigms

    Directory of Open Access Journals (Sweden)

    Hossein Mozdarani

    2012-01-01

    Full Text Available Although radiation carcinogenesis has been shown both experimentally and epidemiologically, the use of ionizing radiation is also one of the major modalities in cancer treatment. Various known cellular and molecular events are involved in carcinogenesis. Apart from the known phenomena, there could be implications for carcinogenesis and cancer prevention due to other biological processes such as the bystander effect, the abscopal effect, intrinsic radiosensitivity and radioadaptation. Bystander effects have consequences for mutation initiated cancer paradigms of radiation carcinogenesis, which provide the mechanistic justification for low-dose risk estimates. The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system (mainly cell-mediated immunity. It results from loss of growth and stimulatory and/or immunosuppressive factors from the tumor. Intrinsic radiosensitivity is a feature of some cancer prone chromosomal breakage syndromes such as ataxia telangectiasia. Radiosensitivity is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. However, it is not yet known whether this effect is good or bad for those receiving radiation or radiomimetic agents for treatment. Radiation hormesis is another major concern for carcinogenesis. This process which protects cells from higher doses of radiation or radio mimic chemicals, may lead to the escape of cells from mitotic death or apoptosis and put cells with a lower amount of damage into the process of cancer induction. Therefore, any of these biological phenomena could have impact on another process giving rise to genome instability of cells which are not in the field of radiation but still receiving a lower amount of radiation. For prevention of radiation induced carcinogenesis or risk assessment as well as for successful radiation

  17. Recent progress in nickel carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Sunderman, F.W. Jr.

    1984-01-01

    Positive bacterial mutagenesis tests have been obtained with Ni(II) in Corynybacterium, but not in E. coli, S. typhimurium, or B. subtilis. Transformation assays of several soluble and crystalline Ni compounds have been positive in Syrian hamster embryo cells. Ni(II) binds to DNA, RNA, and nucleoproteins, and becomes localized in nucleoli. Genotoxic effects of Ni include: (a) chromosomal aberrations, including sister-chromatid exchanges, (b) DNA strandbreaks and DNA-protein crosslinks, (c) inhibition of DNA and RNA synthesis, (d) infidelity of DNA transcription, and (e) mutations at the HGPRTase locus in Chinese hamster cells and the TK locus in mouse lymphoma cells. These findings are consistent with somatic mutation as the mechanism for initiation of nickel carcinogenesis. Ni compounds cause reversible transition of double-stranded poly(dG-dC) DNA from the right-handed B-helix to the left-handed Z-helix, suggesting a mechanism whereby nickel might modulate oncogene expression. 99 references, 4 tables.

  18. The Involvement of miR-23a/APAF1 Regulation Axis in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Fung Lin Yong

    2014-07-01

    Full Text Available Recent advances in microRNAome have made microRNAs (miRNAs a compelling novel class of biomarker in cancer biology. In the present study, the role of miR-23a in the carcinogenesis of colorectal cancer (CRC was investigated. Cell viability, apoptosis, and caspase 3/7 activation analyses were conducted to determine the potentiality of apoptosis resistance function of miR-23a in CRC. Luciferase assay was performed to verify a putative target site of miR-23a in the 3'-UTR of apoptosis protease activating factor 1 (APAF1 mRNA. The expression levels of miR-23a and APAF1 in CRC cell lines (SW480 and SW620 and clinical samples were assessed using reverse transcription-quantitative real-time PCR (RT-qPCR and Western blot. We found that the inhibition of miR-23a in SW480 and SW620 cell lines resulted in significant reduction of cell viability and promotion of cell apoptosis. Moreover, miR-23a up-regulation was coupled with APAF1 down-regulation in CRC tissue samples. Taken together, miR-23a was identified to regulate apoptosis in CRC. Our study highlights the potential application of miR-23a/APAF1 regulation axis in miRNA-based therapy and prognostication.

  19. A Randomized Controlled Trial to Increase Navy Bean or Rice Bran Consumption in Colorectal Cancer Survivors.

    Science.gov (United States)

    Borresen, Erica C; Brown, Dustin G; Harbison, Greg; Taylor, Lynn; Fairbanks, Amanda; O'Malia, Joanne; Bazan, Marlon; Rao, Sangeeta; Bailey, Susan M; Wdowik, Melissa; Weir, Tiffany L; Brown, Regina J; Ryan, Elizabeth P

    2016-01-01

    Consumption of navy beans (NB) and rice bran (RB) have been shown to inhibit colon carcinogenesis. Given the overall poor diet quality in colorectal cancer (CRC) survivors and low reported intake of whole grains and legumes, practical strategies to increase consumption merit attention. This study determined feasibility of increasing NB or RB intake in CRC survivors to increase dietary fiber and examined serum inflammatory biomarkers and telomere lengths. Twenty-nine subjects completed a randomized controlled trial with foods that included cooked NB powder (35 g/day), heat-stabilized RB (30 g/day), or no additional ingredient. Fasting blood, food logs, and gastrointestinal health questionnaires were collected. The amount of NB or RB consumed equated to 4-9% of subjects' daily caloric intake and no major gastrointestinal issues were reported with increased consumption. Dietary fiber amounts increased in NB and RB groups at Weeks 2 and 4 compared to baseline and to control (P ≤ 0.01). Telomere length correlated with age and HDL cholesterol at baseline, and with improved serum amyloid A (SAA) levels at Week 4 (P ≤ 0.05). This study concludes feasibility of increased dietary NB and RB consumption to levels associated with CRC chemoprevention and warrants longer-term investigations with both foods in high-risk populations that include cancer prevention and control outcomes.

  20. PPARγ Ligand as a Promising Candidate for Colorectal Cancer Chemoprevention: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Hirokazu Takahashi

    2010-01-01

    Full Text Available Activating synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARγ, such as pioglitazone, are commonly used to treat persons with diabetes mellitus with improvement of insulin resistance. Several reports have clearly demonstrated that PPARγ ligands could inhibit colorectal cancer cell growth and induce apoptosis. Meanwhile, aberrant crypt foci (ACF have come to be established as a biomarker of the risk of CRC in azoxymethane-treated mice and rats. In humans, ACF can be detected using magnifying colonoscopy. Previously, CRC and adenoma were used as a target for chemopreventive agents, but it needs a long time to evaluate, however, ACF can be a surrogate marker of CRC even for a brief period. In this clinical study, we investigated the chemopreventive effect of pioglitazone on the development of human ACF as a surrogate marker of CRC. Twenty-nine patients were divided into two groups, 20 were in the endoscopically normal control group and 9 were in the pioglitazone (15 mg/day group, and ACF and adenoma were examined before and after 1-month treatment. The number of ACF was significantly decreased (5.8±1.1 to 3.3±2.3 after 1 month of pioglitazone treatment, however, there was no significant change in the number of crypts/ACF or in the number and size of adenomas. Pioglitazone may have a clinical application as a cancer-preventive drug. This investigation is just a pilot study, therefore, further clinical studies are needed to show that the PPARγ ligand may be a promising candidate as a chemopreventive agent for colorectal carcinogenesis.

  1. Meta-analysis of the association between APC promoter methylation and colorectal cancer.

    Science.gov (United States)

    Ding, Zhenyu; Jiang, Tong; Piao, Ying; Han, Tao; Han, Yaling; Xie, Xiaodong

    2015-01-01

    Previous studies investigating the association between adenomatous polyposis coli (APC) gene promoter methylation and colorectal cancer (CRC) have yielded conflicting results. The aim of this study was to comprehensively evaluate the potential application of the detection of APC promoter methylation to the prevention and treatment of CRC. PubMed, Embase, and MEDLINE (results updated to October 2014) were searched for relevant studies. The effect size was defined as the weighted odds ratio (OR), which was calculated using either the fixed-effects or random-effects model. Prespecified subgroup and sensitivity analyses were conducted to evaluate potential heterogeneity among the included studies. Nineteen studies comprising 2,426 participants were selected for our meta-analysis. The pooled results of nine studies comprising a total of 740 subjects indicated that APC promoter methylation was significantly associated with CRC risk (pooled OR 5.53; 95% confidence interval [CI] 3.50-8.76; PAPC promoter methylation and the presence of CRC metastasis, and the pooled OR was 0.80 (95% CI 0.44-1.46; P=0.47). A meta-analysis conducted with four studies with a total of 467 patients found no significant correlation between APC promoter methylation and the presence of colorectal adenoma (pooled OR 1.85; 95% CI 0.67-5.10; P=0.23). No significant correlation between APC promoter methylation and patients' Dukes' stage, TNM stage, differentiation grade, age, or sex was identified. In conclusion, APC promoter methylation was found to be significantly associated with a higher risk of developing CRC. The findings indicate that APC promoter methylation may be a potential biomarker for the carcinogenesis of CRC.

  2. Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis

    International Nuclear Information System (INIS)

    Sakellariou, Stratigoula; Fragkou, Paraskevi; Levidou, Georgia; Gargalionis, Antonios N.; Piperi, Christina; Dalagiorgou, Georgia; Adamopoulos, Christos; Saetta, Angelica; Agrogiannis, George; Theohari, Irini; Sougioultzis, Stavros; Tsioli, Panagiota; Karavokyros, Ioannis; Tsavaris, Nikolaos; Kostakis, Ioannis D.; Zizi-Serbetzoglou, Adamantia; Vandoros, Gerasimos P.; Patsouris, Efstratios; Korkolopoulou, Penelope

    2016-01-01

    evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance

  3. Colorectal cancer

    International Nuclear Information System (INIS)

    Akiba, Suminori

    1992-01-01

    This paper describes colorectal cancer risk in relation to A-bomb radiation. The RERF Life Span Study has revealed the incidence of colorectal cancer to be significantly high in the group of A-bomb survivors than the control group. With regard to relative risk or excess relative risk, there is no definitive difference among sites in the colon. Risk for colon cancer is found to be linearly increased with increasing radiation doses, and in younger A-bomb survivors at the time of exposure. Risk associated with one Gy is estimated to be increased by double. There is no definitive variation between sex and between Hiroshima and Nagasaki. Excess relative risk would be increased rapidly with aging in the whole group of A-bomb survivors and with the cancer-prone age in younger A-bomb survivors at the time of exposure. (N.K.)

  4. 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.

  5. Prospective study of blood metabolites associated with colorectal cancer risk.

    Science.gov (United States)

    Shu, Xiang; Xiang, Yong-Bing; Rothman, Nathaniel; Yu, Danxia; Li, Hong-Lan; Yang, Gong; Cai, Hui; Ma, Xiao; Lan, Qing; Gao, Yu-Tang; Jia, Wei; Shu, Xiao-Ou; Zheng, Wei

    2018-02-26

    Few prospective studies, and none in Asians, have systematically evaluated the relationship between blood metabolites and colorectal cancer risk. We conducted a nested case-control study to search for risk-associated metabolite biomarkers for colorectal cancer in an Asian population using blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess associations of metabolites with cancer risk. In this study, we included 250 incident cases with colorectal cancer and individually matched controls nested within two prospective Shanghai cohorts. We found 35 metabolites associated with risk of colorectal cancer after adjusting for multiple comparisons. Among them, 12 metabolites were glycerophospholipids including nine associated with reduced risk of colorectal cancer and three with increased risk [odds ratios per standard deviation increase of transformed metabolites: 0.31-1.98; p values: 0.002-1.25 × 10 -10 ]. The other 23 metabolites associated with colorectal cancer risk included nine lipids other than glycerophospholipid, seven aromatic compounds, five organic acids and four other organic compounds. After mutual adjustment, nine metabolites remained statistically significant for colorectal cancer. Together, these independently associated metabolites can separate cancer cases from controls with an area under the curve of 0.76 for colorectal cancer. We have identified that dysregulation of glycerophospholipids may contribute to risk of colorectal cancer. © 2018 UICC.

  6. Transplacental arsenic carcinogenesis in mice

    International Nuclear Information System (INIS)

    Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

    2007-01-01

    Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans

  7. 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

  8. 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.

  9. Expression of Oct-4 is significantly associated with the development and prognosis of colorectal cancer

    Science.gov (United States)

    ZHOU, HUAN; HU, YU; WANG, WEIPENG; MAO, YONG; ZHU, JINGJIE; ZHOU, BIN; SUN, JING; ZHANG, XUEGUANG

    2015-01-01

    Octamer-binding transcription factor 4 (Oct-4), is an essential transcription factor, which is required for pluripotency and self-renewal in embryonic stem cells and germ cells. It is also involved in maintaining cancer stem-like properties in certain types of tumor, and is an important biomarker for cancer stem cells. The present study investigated whether Oct-4 expression was associated with colorectal cancer (CRC). In order to achieve this, primary CRC tissues, matched non-tumor tissues and benign polyp tissues, representing different stages of carcinogenesis, were obtained, and Oct-4 expression was analyzed using reverse transcription-quantitative polymerase chain reaction, flow cytometry analysis and immunohistochemistry. Furthermore, the medical records of patients with CRC were reviewed, and clinicopathological analysis was performed in order to assess the association between Oct-4 expression and certain clinicopathological parameters. It was shown that the transcription and translation of Oct-4 increased in a stepwise manner, from non-tumor to benign polyp tissues, and from benign polyps to CRC tissues. Oct-4 expression in CRC was significantly correlated with histological grade (P=0.007), lymph node metastasis (P=0.027), distant metastasis (P=0.017) and TNM stage (P=0.041). Kaplan-Meier survival curve analysis demonstrated that Oct-4+ cases had a shorter median survival time (37.0 months) compared with Oct-4− cases (76.0 months; P=0.001). These results indicated that aberrant expression of Oct-4 may be involved in the development of CRC. Thus, Oct-4 may be a biomarker for the prediction, diagnosis or assessment of prognosis in CRC, in addition to a potential target for the treatment of this disease. PMID:26622555

  10. 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

  11. Gut microbiome development along the colorectal adenoma-carcinoma sequence.

    Science.gov (United States)

    Feng, Qiang; Liang, Suisha; Jia, Huijue; Stadlmayr, Andreas; Tang, Longqing; Lan, Zhou; Zhang, Dongya; Xia, Huihua; Xu, Xiaoying; Jie, Zhuye; Su, Lili; Li, Xiaoping; Li, Xin; Li, Junhua; Xiao, Liang; Huber-Schönauer, Ursula; Niederseer, David; Xu, Xun; Al-Aama, Jumana Yousuf; Yang, Huanming; Wang, Jian; Kristiansen, Karsten; Arumugam, Manimozhiyan; Tilg, Herbert; Datz, Christian; Wang, Jun

    2015-03-11

    Colorectal cancer, a commonly diagnosed cancer in the elderly, often develops slowly from benign polyps called adenoma. The gut microbiota is believed to be directly involved in colorectal carcinogenesis. The identity and functional capacity of the adenoma- or carcinoma-related gut microbe(s), however, have not been surveyed in a comprehensive manner. Here we perform a metagenome-wide association study (MGWAS) on stools from advanced adenoma and carcinoma patients and from healthy subjects, revealing microbial genes, strains and functions enriched in each group. An analysis of potential risk factors indicates that high intake of red meat relative to fruits and vegetables appears to associate with outgrowth of bacteria that might contribute to a more hostile gut environment. These findings suggest that faecal microbiome-based strategies may be useful for early diagnosis and treatment of colorectal adenoma or carcinoma.

  12. Get Tested for Colorectal Cancer

    Science.gov (United States)

    ... Print This Topic En español Get Tested for Colorectal Cancer Browse Sections The Basics Overview What to Expect ... section Overview 2 of 6 sections The Basics: Colorectal Cancer What is colorectal cancer? Colorectal cancer is a ...

  13. Diagnostic and prognostic epigenetic biomarkers in cancer.

    Science.gov (United States)

    Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

    2015-01-01

    Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers.

  14. Circulating Serum miRNAs as Diagnostic Markers for Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Abdel-Rahman N Zekri

    Full Text Available The study was designed to assess the possibility of using circulating miRNAs (serum miRNAs as diagnostic biomarkers in colorectal cancer (CRC and to identify their possibility as candidates for targeted therapy.The study involved two sample sets: 1- a training set which included 90 patients with colorectal related disease (30 with CRC, 18 with inflammatory bowel disease (IBD, 18 with colonic polyps (CP and 24 with different colonic symptoms but without any colonoscopic abnormality who were enrolled as control group and 2- a validation set which included 100 CRC patients. Serum miRNAs were extracted from all subjects to assess the expression profiles for the following miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-146a, miR-223, miR-24, miR-454, miR-183, miR-135a, miR- 135b and miR- 92a using the custom miScript miRNA PCR-based sybergreen array. The area under the receiver operating characteristic curve (AUC was used to evaluate the diagnostic performance of the studied miRNAs for colorectal cancer diagnosis.Data analysis of miRNA from the training set showed that; compared to control group, only miR-19b was significantly up-regulated in patients with IBD group (fold change = 5.24, p = 0.016, whereas in patients with colonic polyps, miR-18a was significantly up-regulated (fold change = 3.49, p-value = 0.018. On the other hand, miR-17, miR-19a, miR-20a and miR-223 were significantly up-regulated (fold change = 2.35, 3.07, 2.38 and 10.35; respectively and p-value = 0.02, 0.015, 0.017 and 0.016; respectively in CRC patients. However, the validation set showed that only miR-223 was significantly up-regulated in CRC patients (fold change = 4.06, p-value = 0.04.Aberrant miRNA expressions are highly involved in the cascade of colorectal carcinogenesis. We have found that (miR-17, miR-19a, miR-20a and miR-223 could be used as diagnostic biomarkers for CRC. On the other hand, miR-19b and miR-18a could be used as diagnostic biomarkers for

  15. Meat processing and colon carcinogenesis: cooked, nitrite-treated, and oxidized high-heme cured meat promotes mucin-depleted foci in rats

    OpenAIRE

    Santarelli, Raphaëlle L; Vendeuvre, Jean-Luc; Naud, Nathalie; Taché, Sylviane; Guéraud, Françoise; Viau, Michelle; Genot, Claude; Corpet, Denis E; Pierre, Fabrice H F

    2010-01-01

    International audience; Processed meat intake is associated with colorectal cancer risk, but no experimental study supports the epidemiologic evidence. To study the effect of meat processing on carcinogenesis promotion, we first did a 14-day study with 16 models of cured meat. Studied factors, in a 2 x 2 x 2 x 2 design, were muscle color (a proxy for heme level), processing temperature, added nitrite, and packaging. Fischer 344 rats were fed these 16 diets, and we evaluated fecal and urinary ...

  16. Radiation carcinogenesis and related radiobiology. Special listing

    International Nuclear Information System (INIS)

    1980-01-01

    The special listing of Current Cancer Research Projects is a publication of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute. Each Listing contains descriptions of ongoing projects in one selected cancer research area. The research areas include: Human cancer and exposure to radiation; Experimental radiation carcinogenesis and radiation biology

  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. Experimental radiation carcinogenesis: what have we learned

    International Nuclear Information System (INIS)

    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

  19. Molecular mechanisms in radiation carcinogenesis: introduction

    International Nuclear Information System (INIS)

    Setlow, R.B.

    1975-01-01

    Molecular studies of radiation carcinogenesis are discussed in relation to theories for extrapolating from cellular and animal models to man. Skin cancer is emphasized because of sunlight-induced photochemical damage to DNA. It is emphasized that cellular and animal models are needed as well as molecular theories for quantitative evaluation of hazardous environmental agents. (U.S.)

  20. In vitro studies of human lung carcinogenesis.

    Science.gov (United States)

    Harris, C C; Lechner, J F; Yoakum, G H; Amstad, P; Korba, B E; Gabrielson, E; Grafstrom, R; Shamsuddin, A; Trump, B F

    1985-01-01

    Advances in the methodology to culture normal human lung cells have provided opportunities to investigate fundamental problems in biomedical research, including the mechanism(s) of carcinogenesis. Using the strategy schematically shown in Figure 1, we have initiated studies of the effects of carcinogens on the normal progenitor cells of the human cancers caused by these carcinogens. Extended lifespans and aneuploidy were found after exposure of mesothelial cells to asbestos and bronchial epithelial cells to nickel sulfate. These abnormal cells may be considered to be preneoplastic and at an intermediate position in the multistage process of carcinogenesis. Human bronchial epithelial cells can also be employed to investigate the role of specific oncogenes in carcinogenesis and tumor progression. Using the protoplast fusion method for high frequency gene transfection, vHa-ras oncogene initiates a cascade of events in the normal human bronchial cells leading to their apparent immortality, aneuploidy, and tumorigenicity in athymic nude mice. These results suggest that oncogenes may play an important role in human carcinogenesis.

  1. High Prevalence of Human Papillomavirus in Colorectal Cancer in Hispanics: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Raul D. Bernabe-Dones

    2016-01-01

    Full Text Available The role of Human Papillomavirus (HPV in colorectal carcinogenesis remains elusive. Based on the high incidence of HPV-associated malignancies among Puerto Rican Hispanics, this study aimed to assess the prevalence of HPV infection and viral integration in colorectal tissues in order to evaluate its putative role in colorectal cancer (CRC. In this case-control study, the prevalence of HPV infection in CRC (cases n = 45 and normal colon mucosa from cancer-free subjects (controls n = 36 was assessed by a nested PCR strategy. HPV-16 genotyping was performed in HPV-positive tissues and the physical status of the HPV-16 genome was determined by E2 detection. HPV was detected in 19 of 45 (42.2% CRC cases (mean age 61.1 ± 10.7 years, 24 males and in 1 of 36 (2.8% controls (mean age 60.9 ± 9.6 years, 24 males with an OR = 25.58 (95% CI 3.21 to 203.49. HPV-16 was detected in 63.2% of the HPV-positive colorectal tumors; genome integration was observed in all HPV-16 positive cases. This is the first report showing the high prevalence of HPV infections in Caribbean Hispanic colorectal tumors. Despite evidence of HPV integration into the host genome, further mechanistic analysis examining HPV oncoprotein expression and the putative role of these oncoproteins in colorectal carcinogenesis is warranted.

  2. Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status.

    Science.gov (United States)

    Hanyuda, Akiko; Cao, Yin; Hamada, Tsuyoshi; Nowak, Jonathan A; Qian, Zhi Rong; Masugi, Yohei; da Silva, Annacarolina; Liu, Li; Kosumi, Keisuke; Soong, Thing Rinda; Jhun, Iny; Wu, Kana; Zhang, Xuehong; Song, Mingyang; Meyerhardt, Jeffrey A; Chan, Andrew T; Fuchs, Charles S; Giovannucci, Edward L; Ogino, Shuji; Nishihara, Reiko

    2017-05-01

    Previous studies suggest that abnormal energy balance status may dysregulate intestinal epithelial homeostasis and promote colorectal carcinogenesis, yet little is known about how host energy balance and obesity influence enterocyte differentiation during carcinogenesis. We hypothesized that the association between high body mass index (BMI) and colorectal carcinoma incidence might differ according to tumor histopathologic differentiation status. Using databases of the Nurses' Health Study and Health Professionals Follow-up Study, and duplication-method Cox proportional hazards models, we prospectively examined an association between BMI and the incidence of colorectal carcinoma subtypes classified by differentiation features. 120,813 participants were followed for 26 or 32 years and 1528 rectal and colon cancer cases with available tumor pathological data were documented. The association between BMI and colorectal cancer risk significantly differed depending on the presence or absence of poorly-differentiated foci (P heterogeneity  = 0.006). Higher BMI was associated with a higher risk of colorectal carcinoma without poorly-differentiated foci (≥30.0 vs. 18.5-22.4 kg/m 2 : multivariable-adjusted hazard ratio, 1.87; 95% confidence interval, 1.49-2.34; P trend   0.03, with the adjusted α of 0.01). High BMI was associated with risk of colorectal cancer subtype containing no poorly-differentiated focus. Our findings suggest that carcinogenic influence of excess energy balance might be stronger for tumors that retain better intestinal differentiation throughout the tumor areas.

  3. PLZF Expression during Colorectal Cancer Development and in Normal Colorectal Mucosa according to Body Size, as Marker of Colorectal Cancer Risk

    Directory of Open Access Journals (Sweden)

    Francesco Mariani

    2013-01-01

    Full Text Available Promyelocytic leukemia zinc finger protein (PLZF is a protein involved in various signaling, growth regulatory, and differentiation pathways, including development/function of some T cells. Here, we aimed at the detection of PLZF during colorectal carcinogenesis, using immunofluorescence, and at the evaluation of the colocalization of PLZF with CD2 and CD56 positive cells (T, γδ, NK, and NKT cells, using confocal-microscopy, along colorectal carcinogenesis, since its earliest stages, that is, dysplastic aberrant crypt foci (ACF. Furthermore, we analyzed PLZF in the normal colonic mucosa (NM according to anthropometric parameters of the subject. NM exhibited strong CD56 fluorescent staining. This infiltration was lost in both ACF and colorectal carcinoma (CRC, while PLZF presence increased from NM to ACF and CRC. Strong association was found between CD56+ colonic mucosa cell infiltration and body mass index. Interestingly, an increased stromal PLZF-reactivity was present in NM of obese subjects. This study shows that overexpression of PLZF and exclusion of NK cells in dysplastic microenvironment are very early events in the stepwise sequence leading to CRC and that lower levels of CD56+ cells in NM, together with increased levels of PLZF+ cells, can be a reflection of colon cancer risk due to obesity.

  4. Tissue levels of fish fatty acids and risk of colorectal adenomas: a case-control study (Netherlands).

    NARCIS (Netherlands)

    Busstra, M.C.; Siezen, C.L.; Grubben, M.J.A.L.; Kranen, H.J. van; Nagengast, F.M.; Veer, P. van 't

    2003-01-01

    Epidemiological and animal studies have suggested that a high ratio of n-3 fish fatty acids to arachidonic acid (AA), might protect against colorectal carcinogenesis. Competition of n-3 and n-6 fatty acids, especially AA, for the enzyme cyclooxygenase-2 may be responsible for this effect. To examine

  5. Tissue levels of fish fatty acids and risk of colorectal adenomas: a case-control study (Netherlands)

    NARCIS (Netherlands)

    Busstra, M.C.; Siezen, C.L.E.; Grubben, M.J.A.L.; Kranen, H.J.; Nagengast, F.M.; Veer, van 't P.

    2003-01-01

    Epidemiological and animal studies have suggested that a high ratio of n-3 fish fatty acids to arachidonic acid (AA), might protect against colorectal carcinogenesis. Competition of n-3 and n-6 fatty acids, especially AA, for the enzyme cyclooxygenase-2 may be responsible for this effect. To examine

  6. Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Bongaerts, B.W.C.; Wouters, K.A.D.; Kester, A.D.M.; Schouten, L.J.; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Engeland, M. van; Weijenberg, M.P.

    2008-01-01

    Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamin B2 and vitamin B6, methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related

  7. POLE somatic mutations in advanced colorectal cancer.

    Science.gov (United States)

    Guerra, Joana; Pinto, Carla; Pinto, Diana; Pinheiro, Manuela; Silva, Romina; Peixoto, Ana; Rocha, Patrícia; Veiga, Isabel; Santos, Catarina; Santos, Rui; Cabreira, Verónica; Lopes, Paula; Henrique, Rui; Teixeira, Manuel R

    2017-12-01

    Despite all the knowledge already gathered, the picture of somatic genetic changes in colorectal tumorigenesis is far from complete. Recently, germline and somatic mutations in the exonuclease domain of polymerase epsilon, catalytic subunit (POLE) gene have been reported in a small subset of microsatellite-stable and hypermutated colorectal carcinomas (CRCs), affecting the proofreading activity of the enzyme and leading to misincorporation of bases during DNA replication. To evaluate the role of POLE mutations in colorectal carcinogenesis, namely in advanced CRC, we searched for somatic mutations by Sanger sequencing in tumor DNA samples from 307 cases. Microsatellite instability and mutation analyses of a panel of oncogenes were performed in the tumors harboring POLE mutations. Three heterozygous mutations were found in two tumors, the c.857C>G, p.Pro286Arg, the c.901G>A, p.Asp301Asn, and the c.1376C>T, p.Ser459Phe. Of the POLE-mutated CRCs, one tumor was microsatellite-stable and the other had low microsatellite instability, whereas KRAS and PIK3CA mutations were found in one tumor each. We conclude that POLE somatic mutations exist but are rare in advanced CRC, with further larger studies being necessary to evaluate its biological and clinical implications. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  8. Altered JS-2 expression in colorectal cancers and its clinical pathological relevance.

    Science.gov (United States)

    Lam, Alfred King-Yin; Gopalan, Vinod; Nassiri, Mohammad Reza; Kasim, Kais; Dissanayake, Jayampathy; Tang, Johnny Chuek-On; Smith, Robert Anthony

    2011-10-01

    JS-2 is a novel gene located at 5p15.2 and originally detected in primary oesophageal cancer. There is no study on the role of JS-2 in colorectal cancer. The aim of this study is to determine the gene copy number and expression of JS-2 in a large cohort of patients with colorectal tumours and correlate these to the clinicopathological features of the cancer patients. We evaluated the DNA copy number and mRNA expression of JS-2 in 176 colorectal tissues (116 adenocarcinomas, 30 adenomas and 30 non-neoplastic tissues) using real-time polymerase chain reaction. JS-2 expression was also evaluated in two colorectal cancer cell lines and a benign colorectal cell line. JS-2 amplification was noted in 35% of the colorectal adenocarcinomas. Significant differences in relative expression levels for JS-2 mRNA between different colorectal tissues were noted (p = 0.05). Distal colorectal adenocarcinoma had significantly higher copy number than proximal adenocarcinoma (p = 0.005). The relative expression level of JS-2 was different between colonic and rectal adenocarcinoma (p = 0.007). Mucinous adenocarcinoma showed higher JS-2 expression than non-mucinous adenocarcinoma (p = 0.02). Early T-stage cancers appear to have higher JS-2 copy number and lower expression of JS-2 mRNA than later stage cancers (p = 0.001 and 0.03 respectively). Colorectal cancer cell lines showed lower expression of JS-2 than the benign colorectal cell line. JS-2 copy number change and expression were shown for the first time to be altered in the carcinogenesis of colorectal cancer. In addition, genetic alteration of JS-2 was found to be related to location, pathological subtypes and staging of colorectal cancer. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. A network-based biomarker approach for molecular investigation and diagnosis of lung cancer

    Directory of Open Access Journals (Sweden)

    Chen Bor-Sen

    2011-01-01

    Full Text Available Abstract Background Lung cancer is the leading cause of cancer deaths worldwide. Many studies have investigated the carcinogenic process and identified the biomarkers for signature classification. However, based on the research dedicated to this field, there is no highly sensitive network-based method for carcinogenesis characterization and diagnosis from the systems perspective. Methods In this study, a systems biology approach integrating microarray gene expression profiles and protein-protein interaction information was proposed to develop a network-based biomarker for molecular investigation into the network mechanism of lung carcinogenesis and diagnosis of lung cancer. The network-based biomarker consists of two protein association networks constructed for cancer samples and non-cancer samples. Results Based on the network-based biomarker, a total of 40 significant proteins in lung carcinogenesis were identified with carcinogenesis relevance values (CRVs. In addition, the network-based biomarker, acting as the screening test, proved to be effective in diagnosing smokers with signs of lung cancer. Conclusions A network-based biomarker using constructed protein association networks is a useful tool to highlight the pathways and mechanisms of the lung carcinogenic process and, more importantly, provides potential therapeutic targets to combat cancer.

  10. Unique insight into microenvironmental changes in colorectal cancer

    DEFF Research Database (Denmark)

    Willumsen, Nicholas; Bager, Cecilie L; Bay-Jensen, Anne-Christine

    2017-01-01

    Matrix metalloprotease (MMP)-mediated tissue remodeling is one of the malignant changes driving colorectal cancer. Measurement of altered MMP expression/activity is not sufficient to fully understand the effect of MMP-mediated tissue remodeling. Biomarkers are required that specifically reflect t...

  11. Pharmacogenomic Biomarkers

    Directory of Open Access Journals (Sweden)

    Sandra C. Kirkwood

    2002-01-01

    Full Text Available Pharmacogenomic biomarkers hold great promise for the future of medicine and have been touted as a means to personalize prescriptions. Genetic biomarkers for disease susceptibility including both Mendelian and complex disease promise to result in improved understanding of the pathophysiology of disease, identification of new potential therapeutic targets, and improved molecular classification of disease. However essential to fulfilling the promise of individualized therapeutic intervention is the identification of drug activity biomarkers that stratify individuals based on likely response to a particular therapeutic, both positive response, efficacy, and negative response, development of side effect or toxicity. Prior to the widespread clinical application of a genetic biomarker multiple scientific studies must be completed to identify the genetic variants and delineate their functional significance in the pathophysiology of a carefully defined phenotype. The applicability of the genetic biomarker in the human population must then be verified through both retrospective studies utilizing stored or clinical trial samples, and through clinical trials prospectively stratifying patients based on the biomarker. The risk conferred by the polymorphism and the applicability in the general population must be clearly understood. Thus, the development and widespread application of a pharmacogenomic biomarker is an involved process and for most disease states we are just at the beginning of the journey towards individualized therapy and improved clinical outcome.

  12. Effects of Ginger Supplementation on Cell Cycle Biomarkers in the Normal-Appearing Colonic Mucosa of Patients at Increased Risk for Colorectal Cancer: Results from a Pilot, Randomized, Controlled Trial

    Science.gov (United States)

    Citronberg, Jessica; Bostick, Roberd; Ahearn, Thomas; Turgeon, D. Kim; Ruffin, Mack T.; Djuric, Zora; Sen, Ananda; Brenner, Dean E.; Zick, Suzanna M.

    2013-01-01

    To estimate the effects of ginger on apoptosis, proliferation, and differentiation in the normal-appearing colonic mucosa, we randomized 20 people at increased risk for colorectal cancer to 2.0 g of ginger or placebo daily for 28 days in a pilot trial. Overall expression and distributions of Bax, Bcl-2, p21, hTERT and MIB-1 (Ki-67) in colorectal crypts in rectal mucosa biopsies were measured using automated immunohistochemistry and quantitative image analysis. Relative to placebo, Bax expression in the ginger group decreased 15.6% (p = 0.78) in the whole crypts, 6.6% (p = 0.95) in the upper 40% (differentiation zone) of crypts, and 21.7% (p = 0.67) in the lower 60% (proliferative zone) of crypts; however, there was a 19% increase (p = 0.14) in Bax expression in the upper 40% relative to the whole crypt. While p21 and Bcl-2 expression remained relatively unchanged, hTERT expression in the whole crypts decreased by 41.2% (p = 0.05); the estimated treatment effect on hTERT expression was larger in the upper 40% of crypts (−47.9%; p = 0.04). In the ginger group, MIB-1 expression decreased in the whole crypts, upper 40% of crypts, and lower 60% of crypts by 16.9% (p = 0.39), 46.8% (p = 0.39), and 15.3% (p = 0.41), respectively. These pilot study results suggest that ginger may reduce proliferation in the normal-appearing colorectal epithelium and increase apoptosis and differentiation relative to proliferation—especially in the differentiation zone of the crypts, and support a larger study to further investigate these results. PMID:23303903

  13. Tissue misrepair hypothesis for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Kondo, Sohei

    1991-01-01

    Dose-response curves for chronic leukemia in A-bomb survivors and liver tumors in patients given Thorotrast (colloidal thorium dioxide) show large threshold effects. The existence of these threshold effects can be explained by the following hypothesis. A high dose of radiation causes a persistent wound in a cellrenewable tissue. Disorder of the injured cell society partly frees the component cells from territorial restraints on their proliferation, enabling them to continue development of their cellular functions toward advanced autonomy. This progression might be achieved by continued epigenetic and genetic changes as a result of occasional errors in the otherwise concerted healing action of various endogeneous factors recruited for tissue repair. Carcinogenesis is not simply a single-cell problem but a cell-society problem. Therefore, it is not warranted to estimate risk at low doses by linear extrapolation from cancer data at high doses without knowledge of the mechanism of radiation carcinogenesis. (author) 57 refs

  14. Introduction to Genetic Mechanisms of Carcinogenesis

    International Nuclear Information System (INIS)

    Yang, W.K.

    1983-01-01

    Recent technical advances in nucleic acid research and molecular biology have made it possible to explore the complicated genetic systems of eukaryotic cells. One of the fields showing rapid progress concerns genes and gene regulatory functions related to neoplastic processes. Thus, the 35th Annual Conference of the Biology Division of Oak Ridge National Laboratory, held at Gatlinburg, April 12-15, 1982, was organized with the intention to bring together investigators working on seemingly diverse fields of cancer research to discuss and exchange their views on the genetic mechanisms of carcinogenesis. The meeting was attended by workers from chemical, physical as well as biological carcinogenesis fields, by classical geneticists as well as by molecular biologists, and by researchers interested in experimental as well as in human cancers. Included in this volume are papers by the invited speakers of the symposium as well as by those presenting poster papers at the meeting

  15. Lymphotoxin prevention of diethylnitrosamine carcinogenesis in vivo

    International Nuclear Information System (INIS)

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

    1982-01-01

    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

  16. Radiation carcinogenesis and related radiobiology. Special listing

    International Nuclear Information System (INIS)

    1978-01-01

    This Special Listing of Current Cancer Research Projects is a service of the International Cancer Research Data Bank (ICRDB) program of the National Cancer Institute. Each listing contains descriptions of ongoing projects in one selected cancer research area. The descriptions are provided by cancer scientists in about 50 different countries. Research areas covered in this listing are: Human cancer and exposure to radiation; experimental radiation carcinogenesis and radiation biology

  17. The chemopreventive action of bromelain, from pineapple stem (Ananas comosus L.), on colon carcinogenesis is related to antiproliferative and proapoptotic effects.

    Science.gov (United States)

    Romano, Barbara; Fasolino, Ines; Pagano, Ester; Capasso, Raffaele; Pace, Simona; De Rosa, Giuseppe; Milic, Natasa; Orlando, Pierangelo; Izzo, Angelo A; Borrelli, Francesca

    2014-03-01

    Colorectal cancer is an important health problem across the world. Here, we investigated the possible antiproliferative/proapoptotic effects of bromelain (from the pineapple stem Ananas comosus L., family Bromeliaceae) in a human colorectal carcinoma cell line and its potential chemopreventive effect in a murine model of colon cancer. Proliferation and apoptosis were evaluated in human colon adenocarcinoma (Caco-2) cells by the (3) H-thymidine incorporation assay and caspase 3/7 activity measurement, respectively. Extracellular signal-related kinase (ERK) and Akt expression were evaluated by Western blot analysis, reactive oxygen species production by a fluorimetric method. In vivo, bromelain was evaluated using the azoxymethane murine model of colon carcinogenesis. Bromelain reduced cell proliferation and promoted apoptosis in Caco-2 cells. The effect of bromelain was associated to downregulation of pERK1/2/total, ERK, and pAkt/Akt expression as well as to reduction of reactive oxygen species production. In vivo, bromelain reduced the development of aberrant crypt foci, polyps, and tumors induced by azoxymethane. Bromelain exerts antiproliferative and proapoptotic effects in colorectal carcinoma cells and chemopreventive actions in colon carcinogenesis in vivo. Bromelain-containing foods and/or bromelain itself may represent good candidates for colorectal cancer chemoprevention. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer.

    Science.gov (United States)

    Galamb, Orsolya; Kalmár, Alexandra; Péterfia, Bálint; Csabai, István; Bodor, András; Ribli, Dezső; Krenács, Tibor; Patai, Árpád V; Wichmann, Barnabás; Barták, Barbara Kinga; Tóth, Kinga; Valcz, Gábor; Spisák, Sándor; Tulassay, Zsolt; Molnár, Béla

    2016-08-02

    The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, β-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

  19. Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis

    Directory of Open Access Journals (Sweden)

    Micaella Kantor

    2017-01-01

    Full Text Available MAP (MUTYH-associated polyposis is a syndrome, described in 2002, which is associated with colorectal adenomas, with enhanced colorectal carcinogenesis. This review synthesizes the available literature on MAP and outlines its pathogenesis, association with colorectal tumorigenesis, screening, treatment, and the subtle differences between it and its close cousins—FAP and AFAP. The preponderance of data is collected using MAP guidelines. However, although AFAP and MAP appear similar, potentially important distinctions exist, warranting targeted diagnostic criteria and treatment approaches. We suggest that it may be prudent to screen for MAP earlier than in current clinical practice, as it has been shown that sequence variants are associated with more severe disease, presenting with an earlier onset of colorectal cancer. Finally, we issue a call-to-action for much-needed further data to establish clear clinical and diagnostic criteria.

  20. SPECIAL FEATURES OF CARCINOGENESIS OF COLON ADENOCARCINOMA

    Directory of Open Access Journals (Sweden)

    G. A. Raskin

    2015-01-01

    Full Text Available Colorectal cancer is one of the most common malignancies and the leading cause of cancer-related death. There are 4 basic colon carcinogenic steps: malignant transformation of adenoma into carcinoma; HNPCC (hereditary nonpolyposis colon cancer; cancer «de novo»; chronic colitis malignant transformation. All of them, except for Lynch syndrome, are increasingly focused on stem tissue-committed cells as mutation targets and the source of malignancies. Subsequently, cancer stem cells are considered as the cause of chemoresistance of tumors, metastases and relapses. Thus, the study of the cell population can dramatically change approaches to the treatment of patients with colorectal adenocarcinoma.

  1. Genetic alterations during radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Kodama, Seiji

    1995-01-01

    This paper reviews radiation-induced genetic alterations and its carcinogenesis, focusing on the previous in vitro assay outcome. A colony formation assay using Syrian hamster fetal cells and focus formation assay using mouse C3H10T1/2 cells are currently available to find malignant transformation of cells. Such in vitro assays has proposed the hypothesis that radiation-induced carcinogenesis arises from at least two-stage processes; i.e., that an early step induced by irradiation plays an important role in promoting the potential to cause the subsequent mutation. A type of genetic instability induced by radiation results in a persistently elevated frequency of spontaneous mutations, so-called the phenomenon of delayed reproductive death. One possible mechanism by which genetic instability arises has been shown to be due to the development of abnormality in the gene group involved in the maintenance mechanism of genome stability. Another possibility has also been shown to stem from the loss of telomere (the extremities of a chromosome). The importance of search for radiation-induced genetic instability is emphasized in view of the elucidation of carcinogenesis. (N.K.)

  2. [Aspirin and colorectal cancer].

    Science.gov (United States)

    Grancher, Adrien; Michel, Pierre; Di Fiore, Frédéric; Sefrioui, David

    2018-02-01

    Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  3. Diets That Promote Colon Inflammation Associate With Risk of Colorectal Carcinomas That Contain Fusobacterium nucleatum.

    Science.gov (United States)

    Liu, Li; Tabung, Fred K; Zhang, Xuehong; Nowak, Jonathan A; Qian, Zhi Rong; Hamada, Tsuyoshi; Nevo, Daniel; Bullman, Susan; Mima, Kosuke; Kosumi, Keisuke; da Silva, Annacarolina; Song, Mingyang; Cao, Yin; Twombly, Tyler S; Shi, Yan; Liu, Hongli; Gu, Mancang; Koh, Hideo; Li, Wanwan; Du, Chunxia; Chen, Yang; Li, Chenxi; Li, Wenbin; Mehta, Raaj S; Wu, Kana; Wang, Molin; Kostic, Aleksander D; Giannakis, Marios; Garrett, Wendy S; Hutthenhower, Curtis; Chan, Andrew T; Fuchs, Charles S; Nishihara, Reiko; Ogino, Shuji; Giovannucci, Edward L

    2018-04-24

    Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and TNF receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on empirical dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota. Colonization by Fusobacterium nucleatum has been associated with presence and features of colorectal adenocarcinoma. We investigated the association between diets that promote inflammation (based on EDIP score) and colorectal cancer subtypes classified by level of F nucleatum in the tumor microenvironment. We calculated EDIP scores based on answers to questionnaires collected from participants in the Nurses' Health Study (through June 1, 2012) and the Health Professionals Follow-up Study (through January 31, 2012). Participants in both cohorts reported diagnoses of rectal or colon cancer in biennial questionnaires; deaths from unreported colorectal cancer cases were identified through the National Death Index and next of kin. Colorectal tumor tissues were collected from hospitals where the patients underwent tumor resection and F nucleatum DNA was quantified by a PCR assay. We used multivariable duplication-method Cox proportional hazard regression to assess the associations of EDIP scores with risks of colorectal cancer subclassified by F nucleatum status. During 28 years of follow up of 124,433 participants, we documented 951 incident cases of colorectal carcinoma with tissue F nucleatum data. Higher EDIP scores associated with

  4. DCLK1 immunoreactivity in colorectal neoplasia

    Directory of Open Access Journals (Sweden)

    Bellows CF

    2012-04-01

    Full Text Available Giuseppe Gagliardi1, Monica Goswami1, Roberto Passera2, Charles F Bellows11Department of Surgery and Pathology, Tulane University, New Orleans, LA, USA; 2Division of Nuclear Medicine Azienda Ospedaliero-Universitaria San Giovanni Battista, Turin, ItalyIntroduction: Microtubule-associated doublecortin and CaM kinase-like-1 (DCLK1 is a novel candidate marker for intestinal stem cells. The aim of our study was to assess DCLK1 immunoreactivity in colorectal carcinogenesis and its correlation with prognosis.Methods: DCLK1 immunostaining was performed in colorectal tissue from 71 patients, including 18 adenomatous polyps, 40 primary adenocarcinomas, and 14 metastatic lesions. Each case was evaluated by a combined scoring method based on the intensity of staining (score 0–3 and the percentage of tissue staining positive (score 0–3. Immunoexpression for DCLK1 was considered as positive when the combined score was 2–6 and negative with a score of 0–1.Results: Overall, 14/18 (78% of polyps, 30/40 (75% of primary adenocarcinomas, and 7/14 (50% of distant metastases were positive for DCLK1. In adenomatous polyps and primary cancer there was no association between DCLK1 staining score and tumor pathology. However, after curative colorectal cancer resection, patients whose tumor had a high (≥5 combined staining score had increased cancer-specific mortality compared to patients with low (0–4 staining score (hazard ratio 5.89; 95% confidence interval: 1.22–28.47; P = 0.027.Conclusion: We found that DCLK1 is frequently expressed in colorectal neoplasia and may be associated with poor prognosis. Further studies are necessary to validate the use of DCLK1 as a prognostic marker.Keywords: DCLK1, DCAMKL-1, gastrointestinal stem cell, cancer stem cell, adenomatous polyps, liver metastasis, immunohistochemistry

  5. GSTT2 promoter polymorphisms and colorectal cancer risk

    Directory of Open Access Journals (Sweden)

    Ahn Sun-A

    2007-01-01

    Full Text Available Abstract Background Glutathione S-transferases are a group of enzymes that participate in detoxification and defense mechanisms against toxic carcinogens and other compounds. These enzymes play an important role in human carcinogenesis. In the present study, we sought to determine whether GSTT2 promoter single nucleotide polymorphisms (SNPs are associated with colorectal cancer risk. Methods A total of 436 colorectal cancer patients and 568 healthy controls were genotyped for three GSTT2 promoter SNPs (-537G>A, -277T>C and -158G>A, using real-time TaqMan assay and direct sequencing. An electrophoretic mobility shift assay (EMSA was performed to determine the effects of polymorphisms on protein binding to the GSTT2 promoter. Results The -537A allele (-537G/A or A/A was significantly associated with colorectal cancer risk (OR = 1.373, p = 0.025, while the -158A allele (-158G/A or A/A was involved in protection against colorectal cancer (OR = 0.539, p = 0.032. Haplotype 2 (-537A, -277T, -158G was significantly associated with colorectal cancer risk (OR = 1.386, p = 0.021, while haplotype 4 (-537G, -277C, -158A protected against colorectal cancer (OR = 0.539, p = 0.032. EMSA data revealed lower promoter binding activity in the -537A allele than its -537G counterpart. Conclusion Our results collectively suggest that SNPs and haplotypes of the GSTT2 promoter region are associated with colorectal cancer risk in the Korean population.

  6. Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

    Science.gov (United States)

    Shinozaki, Eiji; Yoshino, Takayuki; Yamazaki, Kentaro; Muro, Kei; Yamaguchi, Kensei; Nishina, Tomohiro; Yuki, Satoshi; Shitara, Kohei; Bando, Hideaki; Mimaki, Sachiyo; Nakai, Chikako; Matsushima, Koutatsu; Suzuki, Yutaka; Akagi, Kiwamu; Yamanaka, Takeharu; Nomura, Shogo; Fujii, Satoshi; Esumi, Hiroyasu; Sugiyama, Masaya; Nishida, Nao; Mizokami, Masashi; Koh, Yasuhiro; Abe, Yukiko; Ohtsu, Atsushi; Tsuchihara, Katsuya

    2017-11-07

    Patients with BRAF V600E -mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAF V600E (BRAF non-V600E mutations) contribute to anti-EGFR antibody resistance. This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort. In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAF V600E (6.0%), and 7 patients with BRAF non-V600E mutations (4.7%), respectively. The response rates in RAS, BRAF V600E , and BRAF non-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF non-V600E mutations was 2.4 months, similar to that in RAS or BRAF V600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months). Although BRAF non-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAF non-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

  7. DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness.

    Science.gov (United States)

    Toiyama, Yuji; Inoue, Yasuhiro; Yasuda, Hiromi; Saigusa, Susumu; Yokoe, Takeshi; Okugawa, Yoshinaga; Tanaka, Koji; Miki, Chikao; Kusunoki, Masato

    2011-02-01

    We investigated changes in the gene expression profile in colon cancer in order to identify gene markers that may be useful in the management of this disease. The Cancer Genome Anatomy Project was used to detect differences in gene expression between normal and cancer tissue. The overexpression of dipeptidase-1 (DPEP1) in cancer tissue was confirmed in a sample of 76 patients by real-time PCR. To identify the function of DPEP1, RNA interference (RNAi) was used to inactivate this gene in the colon cancer cell line. Immunohistochemical analysis was performed to characterize the pattern of DPEP1 expression in colon cancer. DPEP1 expression in cancer was significantly higher than that in normal tissue. However, DPEP1 expression decreased with pathological differentiation, lymph-node and distant metastasis. Patients with tumors with decreased DPEP1 expression showed a poorer prognosis, and this was also true of patients with tumors who are treated with curative intent. RNAi-mediated DPEP1 reduction in the colon cancer cell line did not result in cell proliferation or apoptosis, but was associated with an increased invasive ability. DPEP1 protein was observed on the apical side of the cancer cells, and is expressed in the early stages of carcinogenesis, even in adenomas of both sporadic colorectal cancer and familial adenomatous polyposis patients. DPEP1 expression in normal colonic mucosa is very low, but it is highly expressed in colorectal adenoma and cancer specimens and is negatively correlated with parameters of pathological aggressiveness and poor prognosis. DPEP1 is expressed in the early stages of colon carcinogenesis and affects cancer cell invasiveness.

  8. Colorectal Cancer: A Personal Journey

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Colorectal Cancer Colorectal Cancer: A Personal Journey Past Issues / Summer 2016 Table ... Carmen Marc Valvo is an outspoken voice for colorectal cancer screening. Photo Courtesy of: Phil Fisch Photography Designer ...

  9. Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk

    DEFF Research Database (Denmark)

    Hoeft, B.; Linseisen, J.; Beckmann, L.

    2010-01-01

    as contributing factor to colon carcinogenesis. We examined the association between genetic variability in 43 fatty acid metabolism-related genes and colorectal risk in 1225 CRC cases and 2032 controls participating in the European Prospective Investigation into Cancer and Nutrition study. Three hundred......Colorectal cancer (CRC) is the third most common malignant tumor and the fourth leading cause of cancer death worldwide. The crucial role of fatty acids for a number of important biological processes suggests a more in-depth analysis of inter-individual differences in fatty acid metabolizing genes...... variants with CRC risk. Our results support the key role of prostanoid signaling in colon carcinogenesis and suggest a relevance of genetic variation in fatty acid metabolism-related genes and CRC risk....

  10. Clinical and Biological Features of Interval Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Yu Mi Lee

    2017-05-01

    Full Text Available Interval colorectal cancer (I-CRC is defined as a CRC diagnosed within 60 months after a negative colonoscopy, taking into account that 5 years is the “mean sojourn time.” It is important to prevent the development of interval cancer. The development of interval colon cancer is associated with female sex, old age, family history of CRC, comorbidities, diverticulosis, and the skill of the endoscopist. During carcinogenesis, sessile serrated adenomas/polyps (SSA/Ps share many genomic and colonic site characteristics with I-CRCs. The clinical and biological features of I-CRC should be elucidated to prevent the development of interval colon cancer.

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

    Science.gov (United States)

    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.

  12. Dysregulation of microRNAs in colonic field carcinogenesis: implications for screening.

    Directory of Open Access Journals (Sweden)

    Dhananjay P Kunte

    Full Text Available Colorectal cancer (CRC screening tests often have a trade-off between efficacy and patient acceptability/cost. Fecal tests (occult blood, methylation engender excellent patient compliance but lack requisite performance underscoring the need for better population screening tests. We assessed the utility of microRNAs (miRNAs as markers of field carcinogenesis and their potential role for CRC screening using the azoxymethane (AOM-treated rat model. We found that 63 miRNAs were upregulated and miR-122, miR-296-5p and miR-503# were downregulated in the uninvolved colonic mucosa of AOM rats. We monitored the expression of selected miRNAs in colonic biopsies of AOM rats at 16 weeks and correlated it with tumor development. We noted that the tumor bearing rats had significantly greater miRNA modulation compared to those without tumors. The miRNAs showed good diagnostic performance with an area under the receiver operator curve (AUROC of >0.7. We also noted that the miRNA induction in the colonic mucosa was mirrorred in the mucus layer fecal colonocytes isolated from AOM rat stool and the degree of miRNA induction was greater in the tumor bearing rats compared to those without tumors. Lastly, we also noted significant miRNA modulation in the Pirc rats- the genetic model of colon carcinogenesis, both in the uninvolved colonic mucosa and the fecal colonocytes. We thus demonstrate that miRNAs are excellent markers of field carcinogenesis and could accurately predict future neoplasia. Based on our results, we propose an accurate, inexpensive, non-invasive miRNA test for CRC risk stratification based on rectal brushings or from abraded fecal colonocytes.

  13. Personalized treatment for advanced colorectal cancer: KRAS and beyond

    International Nuclear Information System (INIS)

    Patel, Gargi Surendra; Karapetis, Christos S

    2013-01-01

    Targeted therapies have improved the survival of patients with advanced colorectal cancer (CRC). However, further improvements in patient outcomes may be gained by the development of predictive biomarkers in order to select individuals who are most likely to benefit from treatment, thus personalizing treatment. Using the epidermal growth-factor receptor (EGFR) pathway, we discuss the existing and potential predictive biomarkers in clinical development for use with EGFR-targeted agents in metastatic CRC. The data and technological issues surrounding such biomarkers as expression of EGFR or its family members or ligands, KRAS-, NRAS-, and BRAF-mutation status, PI3K/PTEN expression, and imaging and clinical biomarkers, such as rash and hypomagnesemia, are summarized. Although the discovery of KRAS mutations has improved patient selection for EGFR-targeted treatments, further biomarkers are required, especially for those patients who exhibit KRAS mutations rather than the wild-type gene

  14. Interaction Between Dietary Factors and Inflammation in Prostate Carcinogenesis

    National Research Council Canada - National Science Library

    De Marzo, Angelo M

    2007-01-01

    We are investigating whether inflammation can enhance prostate carcinogenesis in a rat model of dietary charred meat carcinogen induced cancers, and, whether antioxidant and other chemopreventative...

  15. Interactions between Dietary Factors and Inflammation in Prostate Carcinogenesis

    National Research Council Canada - National Science Library

    DeMarzo, Angelo M

    2006-01-01

    We are investigating whether inflammation can enhance prostate carcinogenesis in a rat model of dietary charred meat carcinogen induced cancers, and, whether antioxidant and other chemopreventative...

  16. Metachronous colorectal carcinoma

    DEFF Research Database (Denmark)

    Bülow, Steffen; Svendsen, L B; Mellemgaard, A

    1990-01-01

    During the period 1943-67, 903 Danish patients aged less than 40 years had colorectal carcinoma. The patients were followed up for up to 41 years and during this period 44 of 501 (9 per cent) operated on for cure developed a metachronous colorectal carcinoma. The cumulative risk of a metachronous...... colorectal carcinoma was 30 per cent after up to 41 years of observation. The occurrence of a metachronous colorectal carcinoma was evenly distributed in the observation period. The cumulative survival rate after operation for a metachronous colorectal carcinoma was 41 per cent after 20 years of observation....... We propose a lifelong follow-up programme after resection of colorectal carcinoma for cure in this age group, including annual Hemoccult test and colonoscopy at 3-year intervals....

  17. Application of evolutionary games to modeling carcinogenesis.

    Science.gov (United States)

    Swierniak, Andrzej; Krzeslak, Michal

    2013-06-01

    We review a quite large volume of literature concerning mathematical modelling of processes related to carcinogenesis and the growth of cancer cell populations based on the theory of evolutionary games. This review, although partly idiosyncratic, covers such major areas of cancer-related phenomena as production of cytotoxins, avoidance of apoptosis, production of growth factors, motility and invasion, and intra- and extracellular signaling. We discuss the results of other authors and append to them some additional results of our own simulations dealing with the possible dynamics and/or spatial distribution of the processes discussed.

  18. 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.

  19. Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation

    International Nuclear Information System (INIS)

    Greco, Sonia A; Leggett, Barbara A; Whitehall, Vicki LJ; Chia, June; Inglis, Kelly J; Cozzi, Sarah-Jane; Ramsnes, Ingunn; Buttenshaw, Ronald L; Spring, Kevin J; Boyle, Glen M; Worthley, Daniel L

    2010-01-01

    Thrombospondin-4 (THBS4) is a member of the extracellular calcium-binding protein family and is involved in cell adhesion and migration. The aim of this study was to evaluate the potential role of deregulation of THBS4 expression in colorectal carcinogenesis. Of particular interest was the possible silencing of expression by methylation of the CpG island in the gene promoter. Fifty-five sporadic colorectal tumours stratified for the CpG Island Methylator Phenotype (CIMP) were studied. Immunohistochemical staining of THBS4 protein was assessed in normal and tumour specimens. Relative levels of THBS4 transcript expression in matched tumours and normal mucosa were also determined by quantitative RT-PCR. Colony forming ability was examined in 8 cell lines made to overexpress THBS4. Aberrant promoter hypermethylation was investigated as a possible mechanism of gene disruption using MethyLight. Methylation was also assessed in the normal colonic tissue of 99 patients, with samples biopsied from four regions along the length of the colon. THBS4 expression was significantly lower in tumour tissue than in matched normal tissue. Immunohistochemical examination demonstrated that THBS4 protein was generally absent from normal epithelial cells and tumours, but was occasionally expressed at low levels in the cytoplasm towards the luminal surface in vesicular structures. Forced THBS4 over-expression caused a 50-60% repression of tumour colony growth in all eight cell lines examined compared to control cell lines. Tumours exhibited significantly higher levels of methylation than matched normal mucosa, and THBS4 methylation correlated with the CpG island methylator phenotype. There was a trend towards decreased gene expression in tumours exhibiting high THBS4 methylation, but the correlation was not significant. THBS4 methylation was detectable in normal mucosal biopsies where it correlated with increasing patient age and negatively with the occurrence of adenomas elsewhere in the

  20. Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation

    Directory of Open Access Journals (Sweden)

    Greco Sonia A

    2010-09-01

    Full Text Available Abstract Background Thrombospondin-4 (THBS4 is a member of the extracellular calcium-binding protein family and is involved in cell adhesion and migration. The aim of this study was to evaluate the potential role of deregulation of THBS4 expression in colorectal carcinogenesis. Of particular interest was the possible silencing of expression by methylation of the CpG island in the gene promoter. Methods Fifty-five sporadic colorectal tumours stratified for the CpG Island Methylator Phenotype (CIMP were studied. Immunohistochemical staining of THBS4 protein was assessed in normal and tumour specimens. Relative levels of THBS4 transcript expression in matched tumours and normal mucosa were also determined by quantitative RT-PCR. Colony forming ability was examined in 8 cell lines made to overexpress THBS4. Aberrant promoter hypermethylation was investigated as a possible mechanism of gene disruption using MethyLight. Methylation was also assessed in the normal colonic tissue of 99 patients, with samples biopsied from four regions along the length of the colon. Results THBS4 expression was significantly lower in tumour tissue than in matched normal tissue. Immunohistochemical examination demonstrated that THBS4 protein was generally absent from normal epithelial cells and tumours, but was occasionally expressed at low levels in the cytoplasm towards the luminal surface in vesicular structures. Forced THBS4 over-expression caused a 50-60% repression of tumour colony growth in all eight cell lines examined compared to control cell lines. Tumours exhibited significantly higher levels of methylation than matched normal mucosa, and THBS4 methylation correlated with the CpG island methylator phenotype. There was a trend towards decreased gene expression in tumours exhibiting high THBS4 methylation, but the correlation was not significant. THBS4 methylation was detectable in normal mucosal biopsies where it correlated with increasing patient age and

  1. Dietary methyl donors, methyl metabolizing enzymes, and epigenetic regulators: Diet-gene interactions and promoter CpG island hypermethylation in colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Wouters, K.A.D.; Gottschalk, R.W.H.; Schooten, F.J. van; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Engeland, M. van; Weijenberg, M.P.

    2011-01-01

    Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). Among 609 CRC cases and 1,663 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852), we estimated CRC risk according to methyl donor intake across genotypes of folate

  2. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study.

    Science.gov (United States)

    Botma, Akke; Vasen, Hans F A; van Duijnhoven, Fränzel J B; Kleibeuker, Jan H; Nagengast, Fokko M; Kampman, Ellen

    2013-02-01

    Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in LS patients was assessed. In the GEOLynch cohort of 486 persons with LS, dietary information was collected, using a food frequency questionnaire. Dietary pattern scores were obtained by principal components analysis. Hazard ratios (HR) between dietary patterns and colorectal adenomas were calculated using Cox regression models. Robust sandwich variance estimates were used to control for dependency within families. Final models were adjusted for age, sex, smoking habits, colorectal adenoma history, and extent of colon resection. During a median follow-up of 20 months, colorectal adenomas were detected in 58 persons. Four dietary patterns were identified: a "Prudent," "Meat," "Snack," and "Cosmopolitan" pattern. Individuals within the highest tertile of the "Prudent" pattern had a HR of 0.73 (95% confidence interval [CI], 0.32-1.66) for colorectal adenomas, compared with the lowest tertile. Those with high "Meat" pattern scores had a HR of 1.70 (95% CI, 0.83-3.52). A high "Snack" pattern was associated with an increased risk of colorectal adenomas (HR, 2.16; 95% CI, 1.03-4.49). A HR of 1.25 (95% CI, 0.61-2.55) was observed for persons in the highest tertile of the "Cosmopolitan" pattern. These findings suggest that dietary patterns may be associated with development of colorectal adenoma in patients with Lynch syndrome. The directions of these findings are corroborative with those observed in studies investigating sporadic colorectal cancer. Copyright © 2012 American Cancer Society.

  3. Association between phytosterol intake and colorectal cancer risk: a case-control study.

    Science.gov (United States)

    Huang, Jing; Xu, Ming; Fang, Yu-Jing; Lu, Min-Shan; Pan, Zhi-Zhong; Huang, Wu-Qing; Chen, Yu-Ming; Zhang, Cai-Xia

    2017-03-01

    A study in rodent models showed that phytosterols protected against colon carcinogenesis, probably by inhibiting dysregulated cell cycle progression and inducing cellular apoptosis. However, epidemiological studies on the relationship between phytosterols and colorectal cancer risk are quite limited. The aim of this study was to investigate dietary phytosterol intake in relation to colorectal cancer risk in the Chinese population. A case-control study was conducted from July 2010 to June 2016, recruiting 1802 eligible colorectal cancer cases plus 1813 age (5-year interval) and sex frequency-matched controls. Dietary information was collected by using a validated FFQ. The OR and 95 % CI of colorectal cancer risk were assessed by multivariable logistic regression models. A higher total intake of phytosterols was found to be associated with a 50 % reduction in colorectal cancer risk. After adjusting for various confounders, the OR of the highest quartile intake compared with the lowest quartile intake was 0·50 (95 % CI 0·41, 0·61, P trendphytosterols. An inverse association was also found between the consumption of β-sitosterol, campesterol, campestanol and colorectal cancer risk. However, stigmasterol intake was related to an increased risk of colorectal cancer. No statistically significant association was found between β-sitostanol and colorectal cancer risk. Stratified analysis by sex showed that the positive association of stigmasterol intake with colorectal cancer risk was found only in women. These data indicated that the consumption of total phytosterols, β-sitosterol, campesterol and campestanol is inversely associated with colorectal cancer risk in a Chinese population.

  4. Curcumin: the spicy modulator of breast carcinogenesis.

    Science.gov (United States)

    Banik, Urmila; Parasuraman, Subramani; Adhikary, Arun Kumar; Othman, Nor Hayati

    2017-07-19

    Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer.

  5. Radiation carcinogenesis: Epidemiology and biological significance

    International Nuclear Information System (INIS)

    Boice, J.D.; Fraumeni, J.F.

    1984-01-01

    Epidemiologic studies of populations exposed to radiation have led to the identification of a preventable cause of cancer, but in the long run perhaps the most important contribution of radiation studies will be to provide insights into the basic processes of human carcinogenesis. In this volume, key investigators of major epidemiologic projects summarize their observations to date, including information to help assess the effects of low-level exposures. Experimentalists and theorists emphasize the relevance of laboratory and epidemiologic data in elucidating carcinogenic risks and mechanisms in man. This volume was prepared with several objectives in mind: (a) organize and synthesize knowledge on radiation carcinogenesis through epidemiologic and experimental approaches; (b) illustrate and explore ways of utilizing this information to gain insights into the fundamental mechanisms of cancer development; (c) stimulate the formation of hypotheses suited to experimental or epidemiologic testing, theoretical modeling, and multidisciplinary approaches; and (d) identify recent advances that clarify dose-response relationships and the influence of low-dose exposures, provide leads to carcinogenic mechanisms and host-environmental interactions, and suggest strategies for future research and preventive action

  6. Predictive and Prognostic Factors in Colorectal Cancer: A Personalized Approach

    Directory of Open Access Journals (Sweden)

    Timothy A. Rockall

    2011-03-01

    Full Text Available It is an exciting time for all those engaged in the treatment of colorectal cancer. The advent of new therapies presents the opportunity for a personalized approach to the patient. This approach considers the complex genetic mechanisms involved in tumorigenesis in addition to classical clinicopathological staging. The potential predictive and prognostic biomarkers which have stemmed from the study of the genetic basis of colorectal cancer and therapeutics are discussed with a focus on mismatch repair status, KRAS, BRAF, 18qLOH, CIMP and TGF-β.

  7. The expression of cytoskeleton regulatory protein Mena in colorectal lesions.

    Science.gov (United States)

    Gurzu, Simona; Jung, I; Prantner, I; Ember, I; Pávai, Z; Mezei, T

    2008-01-01

    The actin regulatory proteins Ena/VASP (Enabled/Vasodilator stimulated phosphoprotein) family is involved in the control of cell motility and adhesion. They are important in the actin-dependent processes where dynamic actin reorganization it is necessary. The deregulation of actin cycle could have an important role in the cells' malignant transformation, tumor invasion or metastasis. Recently studies revealed that the human orthologue of murine Mena is modulated during the breast carcinogenesis. In our study, we tried to observe the immunohistochemical expression of mammalian Ena (Mena) in the colorectal polyps and carcinomas. We analyzed 10 adenomatous polyps (five with dysplasia) and 36 adenocarcinomas. We used the indirect immunoperoxidase staining. BD Biosciences have provided the Mena antibody. We observed that Mena was not expressed in the normal colorectal mucosa neither in polyps without dysplasia, but its expression was very high in polyps with high dysplasia. In colorectal carcinomas, Mena marked the tumoral cells in 80% of cases. In 25% of positive cases, the intensity was 3+, in 60% 2+ and in the other 15% 1+. The Mena intensity was higher in the microsatellite stable tumors (MSS) and was correlated with vascular invasion, with intensity of angiogenesis marked with CD31 and CD105 and with c-erbB-2 and p53 expression. This is the first study in the literature about Mena expression in colorectal lesions.

  8. Initiation-promotion skin carcinogenesis and immunological competence.

    Science.gov (United States)

    Curtis, G L; Stenbäck, F; Ryan, W L

    1975-10-01

    The immune competence of mice during initiation-promotion skin carcinogenesis was determined by skin allograft rejection and lymphocyte mitogenesis. The carcinogen 7, 12-dimethylbenzanthracene inhibited the cellular immune competence of mice while lymphocytes from croton oil treated mice had enhanced PWM response. Chlorphenesin, a stimulator of cellular immunity, was found to inhibit tumorigenesis in initiation-promotion skin carcinogenesis when injected during promotion.

  9. Epigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis.

    Science.gov (United States)

    Locke, Warwick J; Clark, Susan J

    2012-11-15

    Epigenetic gene regulation has influence over a diverse range of cellular functions, including the maintenance of pluripotency, differentiation, and cellular identity, and is deregulated in many diseases, including cancer. Whereas the involvement of epigenetic dysregulation in cancer is well documented, much of the mechanistic detail involved in triggering these changes remains unclear. In the current age of genomics, the development of new sequencing technologies has seen an influx of genomic and epigenomic data and drastic improvements in both resolution and coverage. Studies in cancer cell lines and clinical samples using next-generation sequencing are rapidly delivering spectacular insights into the nature of the cancer genome and epigenome. Despite these improvements in technology, the timing and relationship between genetic and epigenetic changes that occur during the process of carcinogenesis are still unclear. In particular, what changes to the epigenome are playing a driving role during carcinogenesis and what influence the temporal nature of these changes has on cancer progression are not known. Understanding the early epigenetic changes driving breast cancer has the exciting potential to provide a novel set of therapeutic targets or early-disease biomarkers or both. Therefore, it is important to find novel systems that permit the study of initial epigenetic events that potentially occur during the first stages of breast cancer. Non-malignant human mammary epithelial cells (HMECs) provide an exciting in vitro model of very early breast carcinogenesis. When grown in culture, HMECs are able to temporarily escape senescence and acquire a pre-malignant breast cancer-like phenotype (variant HMECs, or vHMECs). Cultured HMECs are composed mainly of cells from the basal breast epithelial layer. Therefore, vHMECs are considered to represent the basal-like subtype of breast cancer. The transition from HMECs to vHMECs in culture recapitulates the epigenomic

  10. Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol.

    Science.gov (United States)

    Romano, Barbara; Borrelli, Francesca; Pagano, Ester; Cascio, Maria Grazia; Pertwee, Roger G; Izzo, Angelo A

    2014-04-15

    Colon cancer is a major public health problem. Cannabis-based medicines are useful adjunctive treatments in cancer patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS, i.e. CBD botanical drug substance, on colorectal cancer cell proliferation and in experimental models of colon cancer in vivo. Proliferation was evaluated in colorectal carcinoma (DLD-1 and HCT116) as well as in healthy colonic cells using the MTT assay. CBD BDS binding was evaluated by its ability to displace [(3)H]CP55940 from human cannabinoid CB1 and CB2 receptors. In vivo, the effect of CBD BDS was examined on the preneoplastic lesions (aberrant crypt foci), polyps and tumours induced by the carcinogenic agent azoxymethane (AOM) as well as in a xenograft model of colon cancer in mice. CBD BDS and CBD reduced cell proliferation in tumoral, but not in healthy, cells. The effect of CBD BDS was counteracted by selective CB1 and CB2 receptor antagonists. Pure CBD reduced cell proliferation in a CB1-sensitive antagonist manner only. In binding assays, CBD BDS showed greater affinity than pure CBD for both CB1 and CB2 receptors, with pure CBD having very little affinity. In vivo, CBD BDS reduced AOM-induced preneoplastic lesions and polyps as well as tumour growth in the xenograft model of colon cancer. CBD BDS attenuates colon carcinogenesis and inhibits colorectal cancer cell proliferation via CB1 and CB2 receptor activation. The results may have some clinical relevance for the use of Cannabis-based medicines in cancer patients. Copyright © 2013 Elsevier GmbH. All rights reserved.

  11. The morphological growth patterns of colorectal liver metastases are prognostic for overall survival

    DEFF Research Database (Denmark)

    Nielsen, Kåre; Rolff, Hans C; Eefsen, Rikke L

    2014-01-01

    Colorectal metastases in the liver grow according to three histological patterns: a pushing pattern, a replacement pattern, and a desmoplastic pattern. The objective of the current study was to explore the prognostic significance of these three growth patterns for survival. The study included 217....... Eventually, the growth patterns may contribute to a histology-based prognostic biomarker for patients with colorectal liver metastases.Modern Pathology advance online publication, 23 May 2014; doi:10.1038/modpathol.2014.4....

  12. Synchronous colorectal liver metastases

    NARCIS (Netherlands)

    A.E.M. van der Pool (Anne)

    2011-01-01

    textabstractColorectal cancer is one of the most common malignancies worldwide and ranks second in cancer-related deaths in many parts of the Western world. Once in the lymph or blood vessels, colorectal cancer can quickly spread and the liver is known to be a favourable site for metastases. The

  13. 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.

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

    International Nuclear Information System (INIS)

    Tanaka, Takuji; Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei; Mori, Takayuki; Watanabe, Naoki; Naiki, Takafumi; Moriwaki, Hisataka; Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi

    2014-01-01

    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

  15. Telomere Length – a New Biomarker in Medicine

    Directory of Open Access Journals (Sweden)

    Agnieszka Kozłowska

    2015-12-01

    Full Text Available A number of xenobiotics in the environment and workplace influences on our health and life. Biomarkers are tools for measuring such exposures and their effects in the organism. Nowadays, telomere length, epigenetic changes, mutations and changes in gene expression pattern have become new molecular biomarkers. Telomeres play the role of molecular clock, which influences on expectancy of cell life and thus aging, the formation of damages, development diseases and carcinogenesis. The telomere length depends on mechanisms of replication and the activity of telomerase. Telomere length is currently used as a biomarker of susceptibility and/or exposure. This paper describes the role of telomere length as a biomarker of aging cells, oxidative stress, a marker of many diseases including cancer, and as a marker of environmental and occupational exposure.

  16. Information dynamics in carcinogenesis and tumor growth.

    Science.gov (United States)

    Gatenby, Robert A; Frieden, B Roy

    2004-12-21

    The storage and transmission of information is vital to the function of normal and transformed cells. We use methods from information theory and Monte Carlo theory to analyze the role of information in carcinogenesis. Our analysis demonstrates that, during somatic evolution of the malignant phenotype, the accumulation of genomic mutations degrades intracellular information. However, the degradation is constrained by the Darwinian somatic ecology in which mutant clones proliferate only when the mutation confers a selective growth advantage. In that environment, genes that normally decrease cellular proliferation, such as tumor suppressor or differentiation genes, suffer maximum information degradation. Conversely, those that increase proliferation, such as oncogenes, are conserved or exhibit only gain of function mutations. These constraints shield most cellular populations from catastrophic mutator-induced loss of the transmembrane entropy gradient and, therefore, cell death. The dynamics of constrained information degradation during carcinogenesis cause the tumor genome to asymptotically approach a minimum information state that is manifested clinically as dedifferentiation and unconstrained proliferation. Extreme physical information (EPI) theory demonstrates that altered information flow from cancer cells to their environment will manifest in-vivo as power law tumor growth with an exponent of size 1.62. This prediction is based only on the assumption that tumor cells are at an absolute information minimum and are capable of "free field" growth that is, they are unconstrained by external biological parameters. The prediction agrees remarkably well with several studies demonstrating power law growth in small human breast cancers with an exponent of 1.72+/-0.24. This successful derivation of an analytic expression for cancer growth from EPI alone supports the conceptual model that carcinogenesis is a process of constrained information degradation and that malignant

  17. (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.

  18. Radiation carcinogenesis in mouse thymic lymphomas

    International Nuclear Information System (INIS)

    Kominami, Ryo; Niwa, Ohtsura

    2006-01-01

    Ionizing radiation is a well-known carcinogen for various human tissues and a complete carcinogen that is able to initiate and promote neoplastic progression. Studies of radiation-induced mouse thymic lymphomas, one of the classic models in radiation carcinogenesis, demonstrated that even the unirradiated thymus is capable of developing into full malignancy when transplanted into the kidney capsule or subcutaneous tissue of irradiated mice. This suggests that radiation targets tissues other than thymocytes to allow expansion of cells with tumorigenic potential in the thymus. The idea is regarded as the ''indirect mechanism'' for tumor development. This paper reviews the indirect mechanism and genes affecting the development of thymic lymphomas that we have analyzed. One is the Bcl11b/Rit1 tumor suppressor gene and the other is Mtf-1 gene affecting tumor susceptibility. (author)

  19. 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.

  20. Dysregulation of Autophagy Contributes to Anal Carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Evie H Carchman

    Full Text Available Autophagy is an intracellular catabolic process that removes and recycles unnecessary/dysfunctional cellular components, contributing to cellular health and survival. Autophagy is a highly regulated cellular process that responds to several intracellular signals, many of which are deregulated by human papillomavirus (HPV infection through the expression of HPV-encoded oncoproteins. This adaptive inhibitory response helps prevent viral clearance. A strong correlation remains between HPV infection and the development of squamous cell carcinoma (SCC of the anus, particularly in HIV positive and other immunosuppressed patients. We hypothesize that autophagy is inhibited by HPV-encoded oncoproteins thereby promoting anal carcinogenesis (Fig 1.HPV16 transgenic mice (K14E6/E7 and non-transgenic mice (FVB/N, both of which do not spontaneously develop anal tumors, were treated topically with the chemical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA, to induce anal cancer. The anuses at different time points of treatment (5, 10, 15 and 20 weeks were analyzed using immunofluorescence (IF for two key autophagy marker proteins (LC3β and p62 in addition to histological grading. The anuses from the K14E6/E7 mice were also analyzed for visual evidence of autophagic activity by electron microscopy (EM. To see if there was a correlation to humans, archival anal specimens were assessed histologically for grade of dysplasia and then analyzed for LC3β and p62 protein content. To more directly examine the effect of autophagic inhibition on anal carcinogenesis, nontransgenic mice that do not develop anal cancer with DMBA treatment were treated with a known pharmacologic inhibitor of autophagy, chloroquine, and examined for tumor development and analyzed by IF for autophagic proteins.Histologically, we observed the progression of normal anoderm to invasive SCC with DMBA treatment in K14E6/E7 mice but not in nontransgenic, syngeneic FVB/N background control mice

  1. 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.

  2. Effect of complex polyphenols on colon carcinogenesis.

    Science.gov (United States)

    Caderni, G; Remy, S; Cheynier, V; Morozzi, G; Dolara, P

    1999-06-01

    Complex polyphenols and tannins from wine (WCPT) are being considered increasingly as potential cancer chemopreventive agents, since epidemiological studies suggest that populations consuming a high amount of polyphenols in the diet may have a lower incidence of some types of cancer. We studied the effect of WCPT on a series of parameters related to colon carcinogenesis in rats. WCPT were administered to F344 rats at a dose of 14 or 57 mg/kg/d, mixed with the diet. The higher dose is about ten times the exposure to polyphenols of a moderate drinker of red wine. In rats treated with WCPT, we measured fecal bile acids and long chain fatty acids, colon mucosa cell proliferation, apoptosis and, after administration of colon carcinogens, the number and size of aberrant crypt foci (ACF) and nuclear aberrations. Colon mucosa proliferation was not varied by chronic administration (90 d) of WCPT (14 or 57 mg/kg/d). The highest dose of WCPT decreased the number of cells in the colon crypts, but did not increase apoptosis. WCPT (57 mg/kg) administered before or after the administration of azoxymethane (AOM) did not vary the number or multiplicity of ACF in the colon. The number of nuclear aberrations (NA) in colon mucosa was studied after administration of 1,2-dimethylhydrazine (DMH) and 2-amino-3-methylimidazo (4,5-f)quinoline (IQ), colon-specific carcinogens which require metabolic activation. The effect of DMH and IQ was not varied by pre-feeding WCPT (57 mg/kg) for 10 d. Similarly, the levels of total, secondary bile acids and long chain fatty acids did not varied significantly in animals fed WCPT for 90 d. WCPT administration does not influence parameters related to colon carcinogenesis in the rat.

  3. Radiation-induced mammary carcinogenesis in rodent models. What's different from chemical carcinogenesis?

    International Nuclear Information System (INIS)

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Iizuka, Daisuke; Daino, Kazuhiro; Takabatake, Takashi; Okamoto, Mieko; Kakinuma, Shizuko; Shimada, Yoshiya

    2009-01-01

    Ionizing radiation is one of a few well-characterized etiologic factors of human breast cancer. Laboratory rodents serve as useful experimental models for investigating dose responses and mechanisms of cancer development. Using these models, a lot of information has been accumulated about mammary gland cancer, which can be induced by both chemical carcinogens and radiation. In this review, we first list some experimental rodent models of breast cancer induction. We then focus on several topics that are important in understanding the mechanisms and risk modification of breast cancer development, and compare radiation and chemical carcinogenesis models. We will focus on the pathology and natural history of cancer development in these models, genetic changes observed in induced cancers, indirect effects of carcinogens, and finally risk modification by reproductive factors and age at exposure to the carcinogens. In addition, we summarize the knowledge available on mammary stem/progenitor cells as a potential target of carcinogens. Comparison of chemical and radiation carcinogenesis models on these topics indicates certain similarities, but it also indicates clear differences in several important aspects, such as genetic alterations of induced cancers and modification of susceptibility by age and reproductive factors. Identification of the target cell type and relevant translational research for human risk management may be among the important issues that are addressed by radiation carcinogenesis models. (author)

  4. Coffee Consumption and the Risk of Colorectal Cancer.

    Science.gov (United States)

    Schmit, Stephanie L; Rennert, Hedy S; Rennert, Gad; Gruber, Stephen B

    2016-04-01

    Coffee contains several bioactive compounds relevant to colon physiology. Although coffee intake is a proposed protective factor for colorectal cancer, current evidence remains inconclusive. We investigated the association between coffee consumption and risk of colorectal cancer in 5,145 cases and 4,097 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study in northern Israel. We also examined this association by type of coffee, by cancer site (colon and rectum), and by ethnic subgroup (Ashkenazi Jews, Sephardi Jews, and Arabs). Coffee data were collected by interview using a validated, semi-quantitative food frequency questionnaire. Coffee consumption was associated with 26% lower odds of developing colorectal cancer [OR (drinkers vs. non-drinkers), 0.74; 95% confidence interval (CI), 0.64-0.86; P consumption alone (OR, 0.82; 95% CI, 0.68-0.99; P = 0.04) and for boiled coffee (OR, 0.82; 95% CI, 0.71-0.94; P = 0.004). Increasing consumption of coffee was associated with lower odds of developing colorectal cancer. Compared with 2.5 servings/day (OR, 0.46; 95% CI, 0.39-0.54; P colorectal cancer (Ptrend cancers. Coffee consumption may be inversely associated with risk of colorectal cancer in a dose-response manner. Global coffee consumption patterns suggest potential health benefits of the beverage for reducing the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 634-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. Mass Spectrometry-Based N-Glycomics of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Manveen K. Sethi

    2015-12-01

    Full Text Available Colorectal cancer (CRC is one of the most prevalent cancers worldwide. An increased molecular understanding of the CRC pathology is warranted to gain insights into the underlying molecular and cellular mechanisms of the disease. Altered protein glycosylation patterns are associated with most diseases including malignant transformation. Recent advances in mass spectrometry and bioinformatics have accelerated glycomics research and present a new paradigm for cancer biomarker discovery. Mass spectrometry (MS-based glycoproteomics and glycomics, therefore, hold considerable promise to improve the discovery of novel biomarkers with utility in disease diagnosis and therapy. This review focuses on the emerging field of glycomics to present a comprehensive review of advances in technologies and their application in studies aimed at discovering novel glycan-based biomarkers. We will also discuss some of the challenges associated with using glycans as biomarkers.

  6. The CpG island methylator phenotype (CIMP) in colorectal cancer.

    Science.gov (United States)

    Nazemalhosseini Mojarad, Ehsan; Kuppen, Peter Jk; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza

    2013-01-01

    It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations in APC and other genes that activate Wnt pathway, characterized by chromosomal instability (CIN) phenotype, and (iii) global genome hypermethylation, resulting in switch off of tumor suppressor genes, indicated as CpG island methylator phenotype (CIMP). Each of these pathways is characterized by specific pathological features, mechanisms of carcinogenesis and process of tumor development. The molecular aspects of these pathways have been used clinically in the diagnosis, screening and management of patients with colorectal cancer. In this review we especially describe various aspects of CIMP, one of the important and rather recently discovered pathways that lead to colorectal cancer.

  7. Treatment of metastatic colorectal cancer: focus on panitumumab

    International Nuclear Information System (INIS)

    Tay, Rebecca Y; Wong, Rachel; Hawkes, Eliza A

    2015-01-01

    Targeted agents are an important therapeutic option in the treatment of metastatic colorectal cancer (mCRC). Panitumumab is a recombinant, fully humanized, immunoglobulin G2 monoclonal antibody that targets the epidermal growth factor receptor (EGFR) with efficacy in mCRC as monotherapy and in combination with chemotherapy. Kirsten rat sarcoma (KRAS) mutation status has emerged as an important biomarker to predict response to anti-EGFR therapy. Optimal timing for panitumumab use in the mCRC treatment algorithm has not been established. This review discusses the mechanism of action, predictive biomarkers, and role of panitumumab in the treatment of mCRC

  8. Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance.

    Science.gov (United States)

    Li, Jinyun; Ye, Dong; Wang, Lei; Peng, Yingying; Li, Qun; Deng, Hongxia; Zhou, Chongchang

    2018-01-01

    The mutL homolog-1 ( MLH1 ) is a DNA mismatch repair gene and has been reported to be frequently methylated in numerous cancers. However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear. Hence, we conducted a systematic meta-analysis based on 19 articles (including 1384 ECs, 345 premalignant lesions, and 1244 healthy controls). Our analysis revealed that the frequency of MLH1 methylation was significantly elevated during EC carcinogenesis. In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20-2.66), advanced tumor grade (OR=3.7; 95% CI =2.37-5.77), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88), distant metastasis (OR=7.60; 95% CI =1.23-47.19), advanced clinical stage (OR=4.46; 95% CI =2.88-6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00-2.69). The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively. Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC. Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC.

  9. 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.

  10. 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.

  11. Screening for colorectal cancer

    DEFF Research Database (Denmark)

    Nielsen, Hans J.; Jakobsen, Karen V.; Christensen, Ib J.

    2011-01-01

    Emerging results indicate that screening improves survival of patients with colorectal cancer. Therefore, screening programs are already implemented or are being considered for implementation in Asia, Europe and North America. At present, a great variety of screening methods are available including...... into improvements of screening for colorectal cancer includes blood-based biological markers, such as proteins, DNA and RNA in combination with various demographically and clinically parameters into a "risk assessment evaluation" (RAE) test. It is assumed that such a test may lead to higher acceptance among...... procedures for colorectal cancer. Therefore, results of present research, validating RAE tests, are awaited with interest....

  12. Exosomes participate in the carcinogenesis and the malignant behavior of gastric cancer.

    Science.gov (United States)

    Yan, Yunmeng; Fu, Guangzhen; Ye, Yafei; Ming, Liang

    2017-05-01

    In order to summarize the role of exosomes in invasion and metastasis in gastric cancer (GC). Exosomes are vesicles of endocytic origin ranging from 30 to 100 nm in size; they are composed of a lipid bilayer and contain DNA, mRNA, miRNA, circular RNA and multiple proteins. Recently, increasing evidence shows that exosomes play a crucial role in the tumorigenesis of GC. In this review, we focus on the latest findings on GC exosomes, mainly summarizing their role in invasion and metastasis in GC. Then, exosomes? potential functions as novel diagnostic and therapeutic biomarkers for GC are briefly discussed. At last, we prospect the clinical application perspective of exosomes in GC. Exosomes play a vital role in gastric cancer carcinogenesis and metastasis.

  13. Prognostic and predictive factors in colorectal cancer.

    Science.gov (United States)

    Bolocan, A; Ion, D; Ciocan, D N; Paduraru, D N

    2012-01-01

    Colorectal cancer (CRC) is an important public health problem; it is a leading cause of cancer mortality in the industrialized world, second to lung cancer: each year there are nearly one million new cases of CRC diagnosed worldwide and half a million deaths (1). This review aims to summarise the most important currently available markers for CRC that provide prognostic or predictive information. Amongst others, it covers serum markers such as CEA and CA19-9, markers expressed by tumour tissues, such as thymidylate synthase, and also the expression/loss of expression of certain oncogenes and tumour suppressor genes such as K-ras and p53. The prognostic value of genomic instability, angiogenesis and proliferative indices, such as the apoptotic index, are discussed. The advent of new therapies created the pathway for a personalized approach of the patient. This will take into consideration the complex genetic mechanisms involved in tumorigenesis, besides the classical clinical and pathological stagings. The growing number of therapeutic agents and known molecular targets in oncology lead to a compulsory study of the clinical use of biomarkers with role in improving response and survival, as well as in reducing toxicity and establishing economic stability. The potential predictive and prognostic biomarkers which have arisen from the study of the genetic basis of colorectal cancer and their therapeutical significance are discussed. RevistaChirurgia.

  14. Folate status, folate-related genes and serum miR-21 expression: Implications for miR-21 as a biomarker

    Directory of Open Access Journals (Sweden)

    Emma Louise Beckett

    2015-12-01

    General significance: This study demonstrates that serum miR-21 expression correlates with folate status and related genetic status. This may have consequences for the proposed use of miR-21 as a colorectal cancer biomarker.

  15. In vivo cell kinetics in breast carcinogenesis

    International Nuclear Information System (INIS)

    Bai, Maria; Agnantis, Niki J; Kamina, Sevasti; Demou, Asimina; Zagorianakou, Panayiota; Katsaraki, Aphroditi; Kanavaros, Panayiotis

    2001-01-01

    Disruption of the balance between apoptosis and proliferation is considered to be an important factor in the development and progression of tumours. In the present study we determined the in vivo cell kinetics along the spectrum of apparently normal epithelium, hyperplasia, preinvasive lesions and invasive carcinoma, in breast tissues affected by fibrocystic changes in which preinvasive and/or invasive lesions developed, as a model of breast carcinogenesis. A total of 32 areas of apparently normal epithelium and 135 ductal proliferative and neoplastic lesions were studied. More than one epithelial lesion per case were analyzed. The apoptotic index (AI) and the proliferative index (PI) were expressed as the percentage of TdT-mediated dUTP-nick end-labelling (TUNEL) and Ki-67-positive cells, respectively. The PI/AI (P/A index) was calculated for each case. The AIs and PIs were significantly higher in hyperplasia than in apparently normal epithelium (P = 0.04 and P = 0.0005, respectively), in atypical hyperplasia than in hyperplasia (P = 0.01 and P = 0.04, respectively) and in invasive carcinoma than in in situ carcinoma (P < 0.001 and P < 0.001, respectively). The two indices were similar in atypical hyperplasia and in in situ carcinoma. The P/A index increased significantly from normal epithelium to hyperplasia (P = 0.01) and from preinvasive lesions to invasive carcinoma (P = 0.04) whereas it was decreased (non-significantly) from hyperplasia to preinvasive lesions. A strong positive correlation between the AIs and the PIs was found (r = 0.83, P < 0.001). These findings suggest accelerating cell turnover along the continuum of breast carcinogenesis. Atypical hyperplasias and in situ carcinomas might be kinetically similar lesions. In the transition from normal epithelium to hyperplasia and from preinvasive lesions to invasive carcinoma the net growth of epithelial cells results from a growth imbalance in favour of proliferation. In the transition from hyperplasia

  16. The Dose Response Relationship for Radiation Carcinogenesis

    Science.gov (United States)

    Hall, Eric

    2008-03-01

    Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the

  17. 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.

  18. Hereditary colorectal cancer diagnostics

    DEFF Research Database (Denmark)

    Klarskov, Louise; Holck, Susanne; Bernstein, Inge

    2012-01-01

    BackgroundThe hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease......-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid...... in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain.Objective and methodsTo perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX...

  19. Gallstones and colorectal cancer

    DEFF Research Database (Denmark)

    Jørgensen, Torben; Rafaelsen, Søren Rafael

    1992-01-01

    The prevalence of gallstone disease in 145 consecutive patients with colorectal cancer was compared with gallstone prevalence in 4,159 subjects randomly selected from a population. The group of patients had a significantly higher prevalence of gallstone disease than the population (odds ratio = 1...... substantial evidence for an association between gallstones and colorectal cancer, an association which is not due to cholecystectomy being a predisposing factor to colorectal cancer. Sporadic findings of an association between cholecystectomy and colorectal cancer can be explained by the above relationship........59; 95 percent confidence limits 1.04-2.45), whereas cholecystectomies occurred with equal frequency in the two groups. There was a nonsignificant trend toward more right-sided cancers in patients with gallstones than in patients without. These results, together with available literature, give...

  20. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context....

  1. Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer

    Science.gov (United States)

    Pan, Pan; Kang, Siwen; Wang, Youwei; Liu, Ka; Oshima, Kiyoko; Huang, Yi-Wen; Zhang, Jianying; Yearsley, Martha; Yu, Jianhua; Wang, Li-Shu

    2017-01-01

    Natural killer (NK) cells are an essential component of innate immunity against cancer development. Many studies have been conducted to evaluate immune-modulating effects using dietary compounds. Our laboratory has been investigating the chemopreventive potential of black raspberries (BRBs) and previously demonstrated their beneficial modulation of genetic and epigenetic biomarkers in patients with colorectal cancer (CRC). The current study investigated their potential on modulating NK cells. To avoid the excessive inflammation caused by the dextran sulfate sodium (DSS) treatment that leads to colitis, we treated the mice with overnight DSS so that it would slightly irritate the colon but still promote colon carcinogenesis with 100% incidence in both the ApcMin/+ mice and azoxymethane (AOM)-treated mice. A significant decrease of tissue-infiltrating NK cells along the progression of microadenoma-to-adenoma and adenoma-to-adenocarcinoma was observed in the ApcMin/+/DSS and AOM/DSS mice, respectively. Depletion of NK cells significantly promoted the development of CRC, suggesting a critical role of NK cells in combating CRC progression. BRBs significantly suppressed the CRC progression and increased the number of tissue-infiltrating NK cells in both mouse models. Moreover, we further determined BRBs’ effects on NK cells in the human biopsy specimens collected from our previously completed clinical trial, in which CRC patients consumed BRBs for an average of 4 weeks during a presurgical window. We observed an increased number and an enhanced cytotoxicity of NK cells by BRB intervention. The current study provides evidence that BRBs have the potential to enhance the tumor immunesurveillance of NK cells that can be beneficial in the setting of CRC prevention and treatment. PMID:28861089

  2. Colorectal cancer screening

    OpenAIRE

    Plumb, A. A.; Halligan, S.

    2015-01-01

    Colorectal cancer is a major public health burden worldwide. There is clear-cut evidence that screening will reduce colorectal cancer mortality and the only contentious issue is which screening tool to use. Most evidence points towards screening with fecal occult blood testing. The immunochemical fecal occult blood tests have a higher sensitivity than the guaiac-based tests. In addition, their automation and haemoglobin quantification allows a threshold for colonoscopy to be selected that can...

  3. Screening for colorectal cancer.

    Science.gov (United States)

    He, Jin; Efron, Jonathan E

    2011-01-01

    March is national colorectal cancer awareness month. It is estimated that as many as 60% of colorectal cancer deaths could be prevented if all men and women aged 50 years or older were screened routinely. In 2000, Katie Couric's televised colonoscopy led to a 20% increase in screening colonoscopies across America, a stunning rise called the "Katie Couric Effect". This event demonstrated how celebrity endorsement affects health behavior. Currently, discussion is ongoing about the optimal strategy for CRC screening, particularly the costs of screening colonoscopy. The current CRC screening guidelines are summarized in Table 2. Debates over the optimum CRC screening test continue in the face of evidence that 22 million Americans aged 50 to 75 years are not screened for CRC by any modality and 25,000 of those lives may have been saved if they had been screened for CRC. It is clear that improving screening rates and reducing disparities in underscreened communities and population subgroups could further reduce colorectal cancer morbidity and mortality. National Institutes of Health consensus identified the following priority areas to enhance the use and quality of colorectal cancer screening: Eliminate financial barriers to colorectal cancer screening and appropriate follow-up of positive results of colorectal cancer screening. Develop systems to ensure the high quality of colorectal cancer screening programs. Conduct studies to determine the comparative effectiveness of the various colorectal cancer screening methods in usual practice settings. Encouraging population adherence to screening tests and allowing patients to select the tests they prefer may do more good (as long as they choose something) than whatever procedure is chosen by the medical profession as the preferred test.

  4. 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.

  5. Comfrey (Symphytum Officinale. l.) and Experimental Hepatic Carcinogenesis: A Short-term Carcinogenesis Model Study.

    Science.gov (United States)

    Gomes, Maria Fernanda Pereira Lavieri; de Oliveira Massoco, Cristina; Xavier, José Guilherme; Bonamin, Leoni Villano

    2010-06-01

    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 χ(2)) 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.

  6. 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

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

    Science.gov (United States)

    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. . ©2015 American Association for Cancer Research.

  8. Carcinogenesis induced by low-dose radiation

    Directory of Open Access Journals (Sweden)

    Piotrowski Igor

    2017-11-01

    Full Text Available Although the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure.

  9. Dysbiosis of the microbiome in gastric carcinogenesis.

    Science.gov (United States)

    Castaño-Rodríguez, Natalia; Goh, Khean-Lee; Fock, Kwong Ming; Mitchell, Hazel M; Kaakoush, Nadeem O

    2017-11-21

    The gastric microbiome has been proposed as an etiological factor in gastric carcinogenesis. We compared the gastric microbiota in subjects presenting with gastric cancer (GC, n = 12) and controls (functional dyspepsia (FD), n = 20) from a high GC risk population in Singapore and Malaysia. cDNA from 16S rRNA transcripts were amplified (515F-806R) and sequenced using Illumina MiSeq 2 × 250 bp chemistry. Increased richness and phylogenetic diversity but not Shannon's diversity was found in GC as compared to controls. nMDS clustered GC and FD subjects separately, with PERMANOVA confirming a significant difference between the groups. H. pylori serological status had a significant impact on gastric microbiome α-diversity and composition. Several bacterial taxa were enriched in GC, including Lactococcus, Veilonella, and Fusobacteriaceae (Fusobacterium and Leptotrichia). Prediction of bacterial metabolic contribution indicated that serological status had a significant impact on metabolic function, while carbohydrate digestion and pathways were enriched in GC. Our findings highlight three mechanisms of interest in GC, including enrichment of pro-inflammatory oral bacterial species, increased abundance of lactic acid producing bacteria, and enrichment of short chain fatty acid production pathways.

  10. Pulmonary carcinogenesis from plutonium-containing particles

    International Nuclear Information System (INIS)

    Thomas, R.G.; Smith, D.M.; Anderson, E.C.

    1980-01-01

    Induction of lung tumors by various types of radiation is of paramount concern to the nuclear industry. The data presented were obtained by exposing the pulmonary system of Syrian hamsters to particles of zirconium oxide containing various amounts of either plutonium-238 or -239 as the alpha radiation source. These particles were injected intravenously and lodged permanently in the capillary bed of the lung. When less than 20% of the lung tissue was irradiated, simulating the ''hot particle'' mode, tumors were not evident with lung burdens up to 500 nCi plutonium. More diffuse irradiation significantly increased the tumor incidence, with lung burdens of 50 to 150 nCi. When plutonium-laden microspheres were administered intratracheally, tumor production was considerably increased and the addition of 3 mg of iron oxide intratracheally further increased the incidence. Using the zirconium oxide matrix for the carrier of plutonium in aerosol particles produced tumor incidences of up to 50% in Syrian hamsters exposed by inhalation. Initial pulmonary (alveolar) burdens reached 100 nCi of plutonium. Similar inhalation studies using plutonium dioxide alone (no matrix) failed to produce any increase in lung tumorigenesis. The results are discussed in terms of possible mechanisms necessary for lung carcinogenesis. (H.K.)

  11. 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.

  12. Molecular epidemiology of radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Trosko, J.E.

    1996-01-01

    The role of ionizing radiation in carcinogenesis is discussed. Every cell contains proto-oncogenes, which if damaged may lead to cell transformation. Every cell also contains tumor suppressor genes, which guard against transformation. Thus, transformation would seem to require a double injury to the DNA in a cell. Ionizing radiation is known to be a relatively weak mutagen, but a good clastogen (inducer of chromosome breaks, deletions and rearrangements). Ionizing radiation may therefore be a 'promoter' of cancer, i.e. a stimulant of the clonal expansion of transformed cells, if it kills enough cells to induce compensatory hyperplasia - i.e. rapid growth of cells. Ionizing radiation may be a 'progressor', if it deactivates tumor suppressor genes tending to suppress the growth of existing clones of transformed cells resulting from any of numerous causes. It may therefore be an oversimplification to say that radiation causes cancer; rather, it seems to be a weak initiator, an indirect promoter, and a late-stage progressor. 2 figs

  13. Experimental carcinogenesis induced by incorporated plutonium

    International Nuclear Information System (INIS)

    Oghiso, Yoichi

    1999-01-01

    The carcinogenic effects of an alpha-emitter, 239 Pu, were investigated by animal experiments as focused on both pulmonary tumors after inhalation exposures to insoluble oxide aerosols and tumor spectra induced by injection of soluble citrate. The life-span study using Wistar strain rats exposed to Pu dioxide aerosols has shown differential dose-related responses of malignancies and histopathological phenotypes of lung tumors, suggesting a threshold dose around 1.0 Gy of the lung dose. As abnormality of tumor-related genes could be supposed for the background of pulmonary carcinogenesis, the mutations of p53 tumor suppressor gene were examined by PCR-SSCP analysis using DNA fragments extracted from lung tumors. While mutations were detected in 23 cases (about 28%) among 82 lung tumors, their relations to either malignancies, histological phenotypes, dose, or oncogenesis are not yet to be elucidated. The life-span study using C3H strain mice injected with Pu citrate has shown contrast dose responses between osteosarcomas and lymphoid tumors around 10 Gy of the skeletal dose, and further indicated specific tumor spectra differed from low LET radiation exposures as shown by much more frequency of B cell type leukemic lymphomas and none of myeloid leukemias. (author)

  14. Radiation carcinogenesis from a membrane perspective

    Energy Technology Data Exchange (ETDEWEB)

    Petkau, A

    1980-01-01

    Radiation damage in phospholipid membranes involves free radical chain reactions which propagate on their own. These reactions oxidize the constituent fatty acids (LH) to alkyl radicals (L) which upon oxygenation, form lipid hydroperoxides (LOOH), some of which absorb light at 232 nm. The response (R) of these membranes to irradiation from tritium (/sup 3/H) in tritiated water increases with dose (D) in accordance with R = aD/sup m/, where m = 1.44 +- 0.30 in the absence of superoxide dismutase and 0.80 +- 0.14 in its presence. The parameter a is expressible in terms of dose rate (..delta..D/..delta..t) by a = c (..delta..D/..delta..t)/sup -n/, where n = 1.18 +- 0.05 in the absence of superoxide dismutase and 0.82 +- 0.02 in its presence. Thus, R = cD/sup m/..delta..D/..delta..t)/sup -n/ where the values of m, n depend on the presence or absence of the free radical scavenger, superoxide dismutase. From this composite relationship, the response per annum for 100 to 250 millirem/y is calculable and found to differ qualitatively, that is, in the absence of superoxide dismutase the response increases whereas in the enzyme's presence it decreases. The latter trend is reminiscent of the correlation between radiation dose rate and the per annum malignant mortality rate in humans. This coincidence is interesting in that LOOH are linked in the literature to several forms of carcinogenesis.

  15. Inflammation, oxidative DNA damage, and carcinogenesis

    International Nuclear Information System (INIS)

    Lewis, J.G.; Adams, D.O.

    1987-01-01

    Inflammation has long been associated with carcinogenesis, especially in the promotion phase. The mechanism of action of the potent inflammatory agent and skin promoter 12-tetradecanoyl phorbol-13-acetate (TPA) is unknown. It is though that TPA selectively enhances the growth of initiated cells, and during this process, initiated cells progress to the preneoplastic state and eventually to the malignant phenotype. The authors and others have proposed that TPA may work, in part, by inciting inflammation and stimulating inflammatory cells to release powerful oxidants which then induce DNA damage in epidermal cells. Macrophages cocultured with target cells and TPA induce oxidized thymine bases in the target cells. This process is inhibited by both catalase and inhibitors of lipoxygenases, suggesting the involvement of both H 2 O 2 and oxidized lipid products. In vivo studies demonstrated that SENCAR mice, which are sensitive to promotion by TPA, have a more intense inflammatory reaction in skin that C57LB/6 mice, which are resistant to promotion by TPA. In addition, macrophages from SENCAR mice release more H 2 O 2 and metabolites of AA, and induce more oxidative DNA damage in cocultured cells than macrophages from C57LB/6 mice. These data support the hypothesis that inflammation and the release of genotoxic oxidants may be one mechanism whereby initiated cells receive further genetic insults. They also further complicate risk assessment by suggesting that some environmental agents may work indirectly by subverting host systems to induce damage rather than maintaining homeostasis

  16. 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.

  17. N-glycosylation of Colorectal Cancer Tissues

    Science.gov (United States)

    Balog, Crina I. A.; Stavenhagen, Kathrin; Fung, Wesley L. J.; Koeleman, Carolien A.; McDonnell, Liam A.; Verhoeven, Aswin; Mesker, Wilma E.; Tollenaar, Rob A. E. M.; Deelder, André M.; Wuhrer, Manfred

    2012-01-01

    Colorectal cancer is the third most common cancer worldwide with an annual incidence of ∼1 million cases and an annual mortality rate of ∼655,000 individuals. There is an urgent need for identifying novel targets to develop more sensitive, reliable, and specific tests for early stage detection of colon cancer. Post-translational modifications are known to play an important role in cancer progression and immune surveillance of tumors. In the present study, we compared the N-glycan profiles from 13 colorectal cancer tumor tissues and corresponding control colon tissues. The N-glycans were enzymatically released, purified, and labeled with 2-aminobenzoic acid. Aliquots were profiled by hydrophilic interaction liquid chromatography (HILIC-HPLC) with fluorescence detection and by negative mode MALDI-TOF-MS. Using partial least squares discriminant analysis to investigate the N-glycosylation changes in colorectal cancer, an excellent separation and prediction ability were observed for both HILIC-HPLC and MALDI-TOF-MS data. For structure elucidation, information from positive mode ESI-ion trap-MS/MS and negative mode MALDI-TOF/TOF-MS was combined. Among the features with a high separation power, structures containing a bisecting GlcNAc were found to be decreased in the tumor, whereas sulfated glycans, paucimannosidic glycans, and glycans containing a sialylated Lewis type epitope were shown to be increased in tumor tissues. In addition, core-fucosylated high mannose N-glycans were detected in tumor samples. In conclusion, the combination of HILIC and MALDI-TOF-MS profiling of N-glycans with multivariate statistical analysis demonstrated its potential for identifying N-glycosylation changes in colorectal cancer tissues and provided new leads that might be used as candidate biomarkers. PMID:22573871

  18. Collective studies on carcinogenesis due to exposure to radiation

    International Nuclear Information System (INIS)

    Yamashita, Hisao

    1980-01-01

    Carcinogenesis was found in 150 of 25,692 patients who had received radiotherapy for benign diseases. Of primary diseases subjected to radiotherapy, skin diseases were the most. Carcinogenesis was found in 26 of 7,230 patients with skin diseases (0.36%) and 18 in 2286 patients with tuberculous cervical lymphadenitis (0.79%). The sites of carcinogenesis was the skin in 51 patients, the hypopharynx in 43, and the larynx in 18. Carcinogenesis was also found in 140 of 220,361 patients who had received radiotherapy for malignant tumors. As primary cancer, cancer of the cervix uteri was found in 59 of 48,662 patients, and breast cancer was found in 20 of 27,967 patients. As radiation-induced cancer, leukemia was found in 18 patients, soft tissue sarcoma in 18, skin cancer in 10, osteosarcoma in 6, cancer of the hypopharynx in 6, and cancer of the cervical esophagus in 6. It is necessary to differentiate cancer due to exposure to radiation from delayed recurrent cancer and double cancer. Irradiation fields should be restricted as small as possible in order to reduce carcinogenesis. As leukemia and carcinoma were found in a-bomb survivors exposed to very small dose of a-bomb radiation, carcinogenic mechanisms by chromosome aberrations, carcinogenic rates from a viewpoint of epidemiology, and other factors which influenced carcinogenesis are being investigated. (Tsunoda, M.)

  19. Tumor Necrosis Factor-α is Associated with Positive Lymph Node Status in Patients with Recurrence of Colorectal Cancer – Indications for Anti-TNF-α Agents in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    M. Grimm

    2010-01-01

    Full Text Available Introduction: The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood. Apoptosis and induction of inflammation by tumor released cytokines as tumor escape mechanisms have been proposed to play an important role in colorectal carcinogenesis.

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

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Vogel, Ulla Birgitte; Godiksen, Sine

    2013-01-01

    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...

  1. Cyclooxygenase-2 inhibitors in colorectal cancer prevention: point.

    Science.gov (United States)

    Arber, Nadir

    2008-08-01

    The limited success of current treatments for most advanced common malignancies highlights the importance of cancer prevention. Clinical trials on cyclooxygenase (COX) inhibitor drugs showed the potential of chemoprevention as a strategy for reducing cancer incidence, although not without associated side effects. The attractiveness of these drugs partly stems from an ability to engage multiple mechanisms of action by their potential to influence multiple components of the carcinogenesis pathway, from initiation to progression. There are two isoforms of the COX enzymes. COX-1 is constitutively expressed in normal tissues and serves as a "housekeeper" of mucosal integrity, whereas COX-2 is an immediate early response gene that is highly inducible by neoplastic and inflammatory stimuli. COX-2 is significantly overexpressed in colorectal neoplasms, making it an attractive therapeutic target. The drug market has been revolutionized by the development of preparations targeted selectively against COX-2, and a proof of concept has been achieved. Chemoprevention of colorectal cancer is already possible with celecoxib, but it is still not the ultimate drug of choice especially because of the cardiovascular risk associated with COX-2 inhibitors. Better patient selection and more effective and safer drugs are needed. Celecoxib is probably best used in a subset of individuals at moderate to high colorectal cancer risk and low risk of cardiovascular disease.

  2. Carbohydrate, dietary glycaemic index and glycaemic load, and colorectal cancer risk: a case-control study in China.

    Science.gov (United States)

    Huang, Jing; Fang, Yu-Jing; Xu, Ming; Luo, Hong; Zhang, Nai-Qi; Huang, Wu-Qing; Pan, Zhi-Zhong; Chen, Yu-Ming; Zhang, Cai-Xia

    2018-04-01

    A carbohydrate-rich diet results in hyperglycaemia and hyperinsulinaemia; it may further induce the carcinogenesis of colorectal cancer. However, epidemiological evidence among Chinese population is quite limited. The aim of this study was to investigate total carbohydrate, non-fibre carbohydrate, total fibre, starch, dietary glycaemic index (GI) and glycaemic load (GL) in relation to colorectal cancer risk in Chinese population. A case-control study was conducted from July 2010 to April 2017, recruiting 1944 eligible colorectal cancer cases and 2027 age (5-year interval) and sex frequency-matched controls. Dietary information was collected by using a validated FFQ. The OR and 95 % CI of colorectal cancer risk were assessed by multivariable logistic regression models. There was no clear association between total carbohydrate intake and colorectal cancer risk. The adjusted OR was 0·85 (95 % CI 0·70, 1·03, P trend=0·08) comparing the highest with the lowest quartile. Total fibre was related to a 53 % reduction in colorectal cancer risk (adjusted ORquartile 4 v. 1 0·47; 95 % CI 0·39, 0·58). However, dietary GI was positively associated with colorectal cancer risk, with an adjusted ORquartile 4 v. 1 of 3·10 (95 % CI 2·51, 3·85). No significant association was found between the intakes of non-fibre carbohydrate, starch and dietary GL and colorectal cancer risk. This study indicated that dietary GI was positively associated with colorectal cancer risk, but no evidence supported that total carbohydrate, non-fibre carbohydrate, starch or high dietary GL intake were related to an increased risk of colorectal cancer in a Chinese population.

  3. 6 Common Cancers - Colorectal Cancer

    Science.gov (United States)

    ... Home Current Issue Past Issues 6 Common Cancers - Colorectal Cancer Past Issues / Spring 2007 Table of Contents For ... of colon cancer. Photo: AP Photo/Ron Edmonds Colorectal Cancer Cancer of the colon (large intestine) or rectum ( ...

  4. Colorectal Cancer Risk Assessment Tool

    Science.gov (United States)

    ... 11/12/2014 Risk Calculator About the Tool Colorectal Cancer Risk Factors Download SAS and Gauss Code Page ... Rectal Cancer: Prevention, Genetics, Causes Tests to Detect Colorectal Cancer and Polyps Cancer Risk Prediction Resources Update November ...

  5. Epigenetics and Colorectal Cancer Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bardhan, Kankana; Liu, Kebin, E-mail: Kliu@gru.edu [Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912 (United States)

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  6. Epigenetics and colorectal cancer pathogenesis.

    Science.gov (United States)

    Bardhan, Kankana; Liu, Kebin

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  7. Epigenetics and Colorectal Cancer Pathogenesis

    International Nuclear Information System (INIS)

    Bardhan, Kankana; Liu, Kebin

    2013-01-01

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy

  8. Epigenetics and Colorectal Cancer Pathogenesis

    Directory of Open Access Journals (Sweden)

    Kebin Liu

    2013-06-01

    Full Text Available Colorectal cancer (CRC develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  9. Implications of tyrosine phosphoproteomics in cervical carcinogenesis

    Directory of Open Access Journals (Sweden)

    DeFord James

    2008-01-01

    Full Text Available Abstract Background Worldwide cervical cancer remains a leading cause of mortality from gynecologic malignancies. The link between cervical cancer and persistent infection with HPV has been established. At a molecular level little is known about the transition from the precancerous state to invasive cancer. To elucidate this process, cervical biopsies from human specimens were obtained from precancerous state to stage III disease. Methods Cervical biopsies were obtained from patients with a diagnosis of cervical cancer undergoing definitive surgery or staging operation. Biopsies were obtained from patients with precancerous lesions at the time of their excisional procedure. Control samples were obtained from patients undergoing hysterectomy for benign conditions such as fibroids. Samples were subjected to proteomic profiling using two dimensional gel electrophoresis with subsequent trypsin digestion followed by MALDI-TOF protein identification. Candidate proteins were then further studied using western blotting, immunoprecipitation and immunohistochemistry. Results Annexin A1 and DNA-PKcs were found to be differentially expressed. Phosphorylated annexin A1 was up regulated in diseased states in comparison to control and its level was strongly detected in the serum of cervical cancer patients compared to controls. DNA-PKcs was noted to be hyperphosphorylated and fragmented in cancer when compared to controls. By immunohistochemistry annexin A1 was noted in the vascular environment in cancer and certain precancerous samples. Conclusion This study suggests a probable role for protein tyrosine phosphorylation in cervical carcinogenesis. Annexin A1 and DNA-PK cs may have synergistic effects with HPV infection. Precancerous lesions that may progress to cervical cancer may be differentiated from lesions that will not base on similar immunohistochemical profile to invasive squamous cell carcinoma.

  10. PRL-3, an emerging marker of carcinogenesis, is strongly associated with poor prognosis.

    Science.gov (United States)

    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.

  11. Enhancement of colon carcinogenesis by the combination of indole-3 carbinol and synbiotics in hemin-fed rats.

    Science.gov (United States)

    de Moura, Nelci A; Caetano, Brunno F R; de Moraes, Leonardo N; Carvalho, Robson F; Rodrigues, Maria A M; Barbisan, Luis F

    2018-02-01

    The risk of developing colorectal cancer (CRC) could be associated with red and processed meat intake. Experimental data supports that hemin iron, found abundantly in red meat, promotes CRC in mice and rats, while indole-3 carbinol (I3C) and synbiotics (syn) exert anti-carcinogenic activities in most studies of colon carcinogenesis. This study aimed to investigate the modifying effects of I3C and syn (inulin + Bifidobacterium lactis), given separately or together, on dimethylhidrazine (DMH)-induced colon carcinogenesis in hemin-fed rats. All animals were given four subcutaneous DMH injections and then, two weeks after carcinogen exposure, they began a basal diet containing hemin, hemin + I3C, hemin + syn, or hemin + I3C + syn for 23 weeks. The combination of I3C + syn significantly increased fecal water genotoxicity, tumor volume and invasiveness when compared to the hemin-fed control group. The groups fed I3C or syn alone had a significant reduction in the number of preneoplastic aberrant crypt foci (ACF) lesions compared to the hemin-fed group. Dietary I3C also reduced fecal water genotoxicity. Gene expression analysis of colorectal tumors demonstrated that the combination of dietary I3C + syn increased transcript levels for Raf1 and decreased tumor progression and invasiveness related to the genes Cdh1 and Appl1. This analysis also revealed that the Tnf and Cdh1 genes were significantly up- and down-regulated, respectively, in tumors of rats that received I3C, in comparison with the hemin-fed group. These findings reveal that the joint administration of I3C and syn enhanced the development of colon tumors induced by DMH in hemin-fed rats, while they potentially reduced ACF development when given alone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Developments in Colorectal Cancer Screening

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Colorectal Cancer Developments in Colorectal Cancer Screening Past Issues / Summer 2016 Table of ... at the National Cancer Institute, shared developments in colorectal cancer screening methods with NIH MedlinePlus magazine. What ...

  13. Improving Quality in Colorectal Surgery

    NARCIS (Netherlands)

    J.C. Slieker (Juliette)

    2014-01-01

    markdownabstract__Abstract__ Colorectal surgery is an important aspect of our current health system, due to the high incidence of colorectal cancer combined with an ageing population, improved long-term outcomes after colorectal surgery, and the perfectioning of the operative and postoperative

  14. The importance of circulating tumor products as „liquid biopsies” in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Alina Miscoci

    2018-04-01

    Full Text Available Liquid biopsies represent an array of plasma analysis tests that are studied to evaluate and identify circulating tumor products, especially circulating tumor cells (CTCs and circulating tumor DNA (ctDNA. Examining such biomarkers in the plasma of colorectal cancer patients has attracted attention due to its clinical significance in the treatment of malignant diseases. Given that tissue samples are sometimes challenging to procure or unsatisfactory for genomic profiling from patients with colorectal cancer, trustworthy biomarkers are mandatory for guiding treatment, monitoring therapeutic response, and detecting recurrence. This review considers the relevance of flowing tumor products like circulating tumor cells (CTCs, circulating tumor DNA (ctDNA, circulating messenger RNA (mRNA, circulating micro RNA (miRNA, circulating exosomes, and tumor educated platelets (TEPs for patients with colorectal cancer.

  15. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing with a w......Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context....

  16. Mechanisms linking excess adiposity and carcinogenesis promotion

    Directory of Open Access Journals (Sweden)

    Ana I. Pérez-Hernández

    2014-05-01

    Full Text Available Obesity constitutes one of the most important metabolic diseases being associated to insulin resistance development and increased cardiovascular risk. Association between obesity and cancer has also been well-established for several tumor types, such as breast cancer in postmenopausal women, colorectal and prostate cancer. Cancer is the first death cause in developed countries and the second one in developing countries, with high incidence rates around the world. Furthermore, it has been estimated that 15-20% of all cancer deaths may be attributable to obesity. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment. In this sense, obesity may lead to cancer development through dysfunctional adipose tissue and altered signaling pathways. In this review, three main pathways relating obesity and cancer development are examined: i inflammatory changes leading to macrophage polarization and altered adipokine profile; ii insulin resistance development; and iii adipose tissue hypoxia. Since obesity and cancer present a high prevalence, the association between these conditions is of great public health significance and studies showing mechanisms by which obesity lead to cancer development and progression are needed to improve prevention and management of these diseases.

  17. Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study.

    Science.gov (United States)

    Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S; Zhang, Libin; Wu, Kana; Smith-Warner, Stephanie A; Ogino, Shuji; Chan, Andrew T; Meyerhardt, Jeffrey; Giovannucci, Edward; Fuchs, Charles; Cho, Eunyoung; Michaud, Dominique S; Stampfer, Meir J; Yu, Yau-Hua; Kim, David; Zhang, Xuehong

    2017-02-01

    Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. © 2016 UICC.

  18. Epigenetic-Mediated Downregulation of μ-Protocadherin in Colorectal Tumours

    Science.gov (United States)

    Mateusz, Bujko; Paulina, Kober; Małgorzata, Statkiewicz; Michal, Mikula; Marcin, Ligaj; Lech, Zwierzchowski; Jerzy, Ostrowski; Aleksander, Siedlecki Janusz

    2015-01-01

    Carcinogenesis involves altered cellular interaction and tissue morphology that partly arise from aberrant expression of cadherins. Mucin-like protocadherin is implicated in intercellular adhesion and its expression was found decreased in colorectal cancer (CRC). This study has compared MUPCDH (CDHR5) expression in three key types of colorectal tissue samples, for normal mucosa, adenoma, and carcinoma. A gradual decrease of mRNA levels and protein expression was observed in progressive stages of colorectal carcinogenesis which are consistent with reports of increasing MUPCDH 5′ promoter region DNA methylation. High MUPCDH methylation was also observed in HCT116 and SW480 CRC cell lines that revealed low gene expression levels compared to COLO205 and HT29 cell lines which lack DNA methylation at the MUPCDH locus. Furthermore, HCT116 and SW480 showed lower levels of RNA polymerase II and histone H3 lysine 4 trimethylation (H3K4me3) as well as higher levels of H3K27 trimethylation at the MUPCDH promoter. MUPCDH expression was however restored in HCT116 and SW480 cells in the presence of 5-Aza-2′-deoxycytidine (DNA methyltransferase inhibitor). Results indicate that μ-protocadherin downregulation occurs during early stages of tumourigenesis and progression into the adenoma-carcinoma sequence. Epigenetic mechanisms are involved in this silencing. PMID:25972897

  19. OTX1 promotes colorectal cancer progression through epithelial-mesenchymal transition

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Kun; Cai, Xin-Yi; Li, Qiang; Yang, Zhi-Bin; Xiong, Wei; Shen, Tao; Wang, Wei-Ya; Li, Yun-Feng, E-mail: ynsliyunfeng@163.com

    2014-01-31

    Highlights: • OTX1 is overexpression in colorectal cancer tissues. • Overexpression of OTX1 promotes colorectal cancer cell proliferation and invasion in vitro and tumor growth in vivo. • Depletion of OTX1 inhibits colorectal cancer cell proliferation and invasion in vitro. • Overexpression of OTX1 is linked to the EMT-like phenotype. - Abstract: Orthodenticle homeobox 1 (OTX1), a transcription factor containing a bicoid-like homeodomain, plays a role in brain and sensory organ development. In this study, we report that OTX1 is overexpressed in human colorectal cancer (CRC) and OTX1 overexpression is associated with higher stage. Functional analyses reveal that overexpression of OTX1 results in accumulation of CRC cell proliferation and invasion in vitro and tumor growth in vivo, whereas ablation of OTX1 expression significantly inhibits the proliferative and invasive capability of CRC cells in vitro. Together, our results indicate that OTX1 is involved in human colon carcinogenesis and may serve as a potential therapeutic target for human colorectal cancer.

  20. OTX1 promotes colorectal cancer progression through epithelial-mesenchymal transition

    International Nuclear Information System (INIS)

    Yu, Kun; Cai, Xin-Yi; Li, Qiang; Yang, Zhi-Bin; Xiong, Wei; Shen, Tao; Wang, Wei-Ya; Li, Yun-Feng

    2014-01-01

    Highlights: • OTX1 is overexpression in colorectal cancer tissues. • Overexpression of OTX1 promotes colorectal cancer cell proliferation and invasion in vitro and tumor growth in vivo. • Depletion of OTX1 inhibits colorectal cancer cell proliferation and invasion in vitro. • Overexpression of OTX1 is linked to the EMT-like phenotype. - Abstract: Orthodenticle homeobox 1 (OTX1), a transcription factor containing a bicoid-like homeodomain, plays a role in brain and sensory organ development. In this study, we report that OTX1 is overexpressed in human colorectal cancer (CRC) and OTX1 overexpression is associated with higher stage. Functional analyses reveal that overexpression of OTX1 results in accumulation of CRC cell proliferation and invasion in vitro and tumor growth in vivo, whereas ablation of OTX1 expression significantly inhibits the proliferative and invasive capability of CRC cells in vitro. Together, our results indicate that OTX1 is involved in human colon carcinogenesis and may serve as a potential therapeutic target for human colorectal cancer

  1. [Use of micro RNAs in the diagnosis and prognosis of colorectal cancer (CCR)].

    Science.gov (United States)

    Arredondo-Valdez, Abril Reneé; Wence-Chavez, Laura; Rosales-Reynoso, Mónica Alejandra

    2016-01-01

    The aim of this review is to present a general overview about the importance of micro RNAs (miRNAs) in colorectal carcinoma. First, we focused on the mechanisms whereby the miRNAs regulate the expression of target genes, and how an altered regulation of them is associated with several types of cancer, including colorectal carcinoma. Later, examples of some miRNAs that have been associated with cancer development and how the expression patterns of specific miRNAs can be used as potential biomarkers for prognosis, diagnosis and therapeutic outcome in colorectal carcinoma are addressed. Finally, several polymorphisms presents in the miRNAs that have been associated to risk and prognosis in colorectal carcinoma are described.

  2. Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer.

    Directory of Open Access Journals (Sweden)

    Eva Pastille

    2017-09-01

    Full Text Available Inflammatory bowel diseases (IBD are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host's immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs. This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered.

  3. Colorectal cancer screening

    OpenAIRE

    McLoughlin, Monica Ramona

    2008-01-01

    Colorectal cancer is a major public health burden and is the most common cause of mortality from cancer in Europe. Over the last two decades robust evidence from randomised clinical trials and case-control series have confirmed that the mortality from colorectal cancer can be reduced by screening. The challenge over the next decade is how to implement this in clinical practice. This is what we set out to answer with this thesis. Not all individuals are equal when it comes to screening and tho...

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

    International Nuclear Information System (INIS)

    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

  5. Initiator of carcinogenesis selectively and stably inhibits stem cell differentiation: a concept that initiation of carcinogenesis involves multiple phases

    International Nuclear Information System (INIS)

    Scott, R.E.; Maercklein, P.B.

    1985-01-01

    A concept of carcinogenesis was recently devised in our laboratory that suggests the development of defects in the control of cell differentiation is associated with an early phase of carcinogenesis. To test this proposal directly, the effects of an initiator of carcinogenesis (i.e., UV irradiation) on proadipocyte stem cell differentiation and proliferation was assayed. In this regard, 3T3 T proadipocytes represent a nontransformed mesenchymal stem cell line that possesses the ability to regulate its differentiation at a distinct state in the G 1 phase of the cell cycle as well as the ability to regulate its proliferation at two additional G 1 states. The results establish that a slow dosage of 254 nm UV irradiation selectivity and stably inhibits the differentiation of a high percentage of proadipocyte stem cells without significantly altering their ability to regulate cellular proliferation in growth factor-deficient or nutrient-deficient culture conditions. Differentiation-defect proadipocyte stem cells are demonstrated not to be completely transformed but to show an increased spontaneous transformation rate, as evidenced by the formation of type III foci in high density cell cultures. These data support the role of defects in the control of differentiation in the inhibition of carcinogenesis. These observations support a concept that the initiation of carcinogenesis involves multiple phases

  6. The evaluation of diagnostic value of the tumor markers: CCSA-2 and CEA in colorectal cancer.

    Science.gov (United States)

    Knychalski, Bartłomiej; Lukieńczuk, Tadeusz

    2012-02-01

    Finding the biomarker or biomarkers with high sensitivity and specificity in colorectal cancer, and thus a high diagnostic value will determine their clinical usefulness in clinical practice. An effective noninvasive blood test would be an ideal method to detect colorectal cancer. Discovered in 2007 a novel tumor marker CCSA-2 showes a promising results in patients with colorectal cancer. THE AIM OF THE STUDY was the evaluation of diagnostic and clinical value of a novel marker - colon cancer specific antigen-2 (CCSA-2) in colorectal adenocarcinoma in comparison to carcinoembryonic antigen (CEA) in patients operated during the years 2008 to 2010 at Wrocław Medical University 1st Department and Clinic of General, Gastroenterological and Endocrinologic Surgery. The study was performed on 40 patients with colorectal cancer and 40 patients in control group consisted of healthy subjects who had colonoscopy examinations with negative results (no pathology in the colon was found). The obtained results were statistically analyzed using nonparametric tests - Mann Whitney U and Kruskal-Wallis and Spearman's rank correlation coefficients. To determine the clinical value of CCSA-2 and CEA in those groups, their sensitivity and specifity was evaluated using ROC analysis. This analysis determines the accuracy and diagnostic value of both tests. There was a positive correlation between markers in patients with colorectal cancer and a statistically significant relationship according to which respondents with higher concentrations of CCSA-2 also have higher concentrations of CEA (R=0.754, ptumor markers increase and correlate with the clinical progression of the disease. Accuracy of CCSA-2 test using ROC analysis showed a slightly lower measurement of antigen CCSA-2 as diagnostic value in colorectal cancer in comparison to measurement of antigen CEA (accuracy of tests: CCSA-2 - 52%, CEA - 60%). CCSA-2 as a single tumor marker has a low diagnostic value in colorectal cancer because

  7. Disease Heterogeneity and Immune Biomarkers in Preclinical Mouse Models of Ovarian Carcinogenesis

    Science.gov (United States)

    2015-10-01

    cell function. Immune checkpoint blockade has been proven effective in recent clinical trials mostly in melanoma, lung and renal carcinomas. Our...noted between mice with ovarian and oviduct tumors, suggesting that both anatomical locations are similar in inducing an immune suppressive phenotype in...survival based on the anatomical site of mutation activation. (A) Nuclear grade of primary tumor tissues of the ovary, oviduct and the uterus

  8. Elevated Levels of Somatic Mutation as a Biomarker of Environmental Effects Contributing to Breast Carcinogenesis

    Science.gov (United States)

    2006-07-01

    with early term pregnancy conferring a persistent protective effect [5]. Exposure to ionizing radiation, while a lifetime risk factor for breast cancer...lactational differentiation, such as occurs during term pregnancy , confers resistance to carcinogene- sis [26,27]. We have developed a novel human...anemia. Science 297, 606–609. 19. D’Andrea, A. D. and Grompe, M. (2003) The Fanconi anaemia /BRCA pathway. Nat. Rev. Cancer 3, 23–34. 20. Xia, F., Taghian

  9. Systematic enrichment analysis of gene expression profiling studies identifies consensus pathways implicated in colorectal cancer development

    Directory of Open Access Journals (Sweden)

    Jesús Lascorz

    2011-01-01

    Full Text Available Background: A large number of gene expression profiling (GEP studies on colorectal carcinogenesis have been performed but no reliable gene signature has been identified so far due to the lack of reproducibility in the reported genes. There is growing evidence that functionally related genes, rather than individual genes, contribute to the etiology of complex traits. We used, as a novel approach, pathway enrichment tools to define functionally related genes that are consistently up- or down-regulated in colorectal carcinogenesis. Materials and Methods: We started the analysis with 242 unique annotated genes that had been reported by any of three recent meta-analyses covering GEP studies on genes differentially expressed in carcinoma vs normal mucosa. Most of these genes (218, 91.9% had been reported in at least three GEP studies. These 242 genes were submitted to bioinformatic analysis using a total of nine tools to detect enrichment of Gene Ontology (GO categories or Kyoto Encyclopedia of Genes and Genomes (KEGG pathways. As a final consistency criterion the pathway categories had to be enriched by several tools to be taken into consideration. Results: Our pathway-based enrichment analysis identified the categories of ribosomal protein constituents, extracellular matrix receptor interaction, carbonic anhydrase isozymes, and a general category related to inflammation and cellular response as significantly and consistently overrepresented entities. Conclusions: We triaged the genes covered by the published GEP literature on colorectal carcinogenesis and subjected them to multiple enrichment tools in order to identify the consistently enriched gene categories. These turned out to have known functional relationships to cancer development and thus deserve further investigation.

  10. Management of Colorectal Trauma

    Science.gov (United States)

    2011-01-01

    Although the treatment strategy for colorectal trauma has advanced during the last part of the twentieth century and the result has improved, compared to other injuries, problems, such as high septic complication rates and mortality rates, still exist, so standard management for colorectal trauma is still a controversial issue. For that reason, we designed this article to address current recommendations for management of colorectal injuries based on a review of literature. According to the reviewed data, although sufficient evidence exists for primary repair being the treatment of choice in most cases of nondestructive colon injuries, many surgeons are still concerned about anastomotic leakage or failure, and prefer to perform a diverting colostomy. Recently, some reports have shown that primary repair or resection and anastomosis, is better than a diverting colostomy even in cases of destructive colon injuries, but it has not fully established as the standard treatment. The same guideline as that for colonic injury is applied in cases of intraperitoneal rectal injuries, and, diversion, primary repair, and presacral drainage are regarded as the standards for the management of extraperitoneal rectal injuries. However, some reports state that primary repair without a diverting colostomy has benefit in the treatment of extraperitoneal rectal injury, and presacral drainage is still controversial. In conclusion, ideally an individual management strategy would be developed for each patient suffering from colorectal injury. To do this, an evidence-based treatment plan should be carefully developed. PMID:21980586

  11. Vanillin Differentially Affects Azoxymethane-Injected Rat Colon Carcinogenesis and Gene Expression

    Science.gov (United States)

    Ho, Ket Li; Chong, Pei Pei; Yazan, Latifah Saiful

    2012-01-01

    Abstract Vanillin is the substance responsible for the flavor and smell of vanilla, a widely used flavoring agent. Previous studies reported that vanillin is a good antimutagen and anticarcinogen. However, there are also some contradicting findings showing that vanillin was a comutagen and cocarcinogen. This study investigated whether vanillin is an anticarcinogen or a cocarcinogen in rats induced with azoxymethane (AOM). Rats induced with AOM will develop aberrant crypt foci (ACF). AOM-challenged rats were treated with vanillin orally and intraperitoneally at low and high concentrations and ACF density, multiplicity, and distribution were observed. The gene expression of 14 colorectal cancer-related genes was also studied. Results showed that vanillin consumed orally had no effect on ACF. However, high concentrations (300 mg/kg body weight) of vanillin administered through intraperitoneal injection could increase ACF density and ACF multiplicity. ACF were mainly found in the distal colon rather than in the mid-section and proximal colon. The expression of colorectal cancer biomarkers, protooncogenes, recombinational repair, mismatch repair, and cell cycle arrest, and tumor suppressor gene expression were also affected by vanillin. Vanillin was not cocarcinogenic when consumed orally. However, it was cocarcinogenic when being administered intraperitoneally at high concentration. Hence, the use of vanillin in food should be safe but might have cocarcinogenic potential when it is used in high concentration for therapeutic purposes. PMID:23216109

  12. Colorectal Cancer Rates by Race and Ethnicity

    Science.gov (United States)

    ... Associated Lung Ovarian Prostate Skin Uterine Cancer Home Colorectal Cancer Rates by Race and Ethnicity Language: English (US) ... Tweet Share Compartir The rate of people getting colorectal cancer or dying from colorectal cancer varies by race ...

  13. Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling.

    Science.gov (United States)

    Roy, Hemant K; Kunte, Dhananjay P; Koetsier, Jennifer L; Hart, John; Kim, Young L; Liu, Yang; Bissonnette, Marc; Goldberg, Michael; Backman, Vadim; Wali, Ramesh K

    2006-08-01

    Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

  14. Radioimmunodetection of colorectal cancer

    International Nuclear Information System (INIS)

    Kim, E.E.; Deland, F.H.; Casper, S.; Corgan, R.L.; Primus, F.J.; Goldenberg, D.M.

    1980-01-01

    This study examines the accuracy of colorectal cancer radioimmunodetection. Twenty-seven patients with a history of histologically-confirmed colonic or rectal carcinoma received a high-titer, purified goat anti-CEA IgG labelled with 131 I at a total dose of at least 1.0 μCi. Various body views were scanned at 24 and 48 hours after administration of the radioantibody. Three additional cases were evaluated; one had a villous adenoma in the rectum and received the 131 I-labeled anti-CEA IgG, while two colonic carcinoma patients received normal goat IgG labelled with 131 I. All of the 7 cases with primary colorectal cancer showed true-positive tumor localization, while 20 of 25 sites of metastatic colorectal cancer detected by immune scintigraphy were corroborated by other detection measures. The sensitivity of the radioimmunodetection of colorectal cancers (primary and metastatic) was found to be 90% (true-positive rate), the putative specificity (true-negative rate) was 94%, and the apparent overall accuracy of the technique was 93%. Neither the case of a villous adenoma receiving the anti-CEA IgG nor the two cases of colonic cancer receiving normal goat IgG showed tumor radiolocalization. Very high circulating CEA titers did not appear to hinder successful tumor radiolocalization. These findings suggest that in colorectal cancers the method of CEA radioimmunodetection may be of value in preoperatively determining the location and extent of disease, in assessing possible recurrence or spread postoperatively, and in localizing the source of CEA production in patients with rising or elevated CEA titers. An ancilliary benefit could be a more tumor-specific detection test for confirming the findings of other, more conventional diagnostic measures

  15. Biomarkers of the Metabolic Syndrome and Breast Cancer Prognosis

    International Nuclear Information System (INIS)

    Zhu, Qiu-Li; Xu, Wang-Hong; Tao, Meng-Hua

    2010-01-01

    In spite of its public health importance, our understanding of the mechanisms of breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a constellation of biochemical abnormalities including visceral adiposity, hyperglycemia, hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all been related to late-stage disease and even to a poor prognosis of breast cancer through multiple interacting mechanisms. In this review, we aim to present a summary of recent advances in the understanding of the contribution of the MS to breast cancer with the emphasis on the role of biomarkers of the MS in the prognosis of breast cancer

  16. Biomarkers of the Metabolic Syndrome and Breast Cancer Prognosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Qiu-Li; Xu, Wang-Hong [Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032 (China); Tao, Meng-Hua [Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214 (United States)

    2010-04-28

    In spite of its public health importance, our understanding of the mechanisms of breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a constellation of biochemical abnormalities including visceral adiposity, hyperglycemia, hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all been related to late-stage disease and even to a poor prognosis of breast cancer through multiple interacting mechanisms. In this review, we aim to present a summary of recent advances in the understanding of the contribution of the MS to breast cancer with the emphasis on the role of biomarkers of the MS in the prognosis of breast cancer.

  17. Osteopontin Promotes Cell Migration and Invasion, and Inhibits Apoptosis and Autophagy in Colorectal Cancer by activating the p38 MAPK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ren-hong Huang

    2017-04-01

    Full Text Available Background: Osteopontin (OPN is highly expressed in colorectal cancer (CRC and is associated with disease progression in vivo. High levels of OPN have been demonstrated to predict low survival rates in CRC. Autophagy is a process of self-digestion, which is thought to play a significant role in carcinogenesis. However, the mechanisms of OPN's effects on CRC cell autophagy have not been elucidated. Therefore, we aimed to investigate possible mechanisms of OPN's effects on CRC autophagy. Methods: HCT116 cell proliferation, apoptosis, and migration and invasion ability were identified by cell counting k¡t-8 assay, flow cytometry, wound healing assay, and transwell chamber invasion assay, respectively. The ratios of proteins LC3-II/LC3-I, P62, and Atg7 were analyzed by Western-blot. Expressions of Beclin-1, Atg4b, Bnip3, and Vps34, both in transcriptional and translational levels, were analyzed and compared by RT-PCR and Western blot. Immunofluorescence and co-focusing experiments were used to investigate the formation of autophagosomes. Results: The results showed that OPN can promote cell proliferation, migration, and invasion, as well as inhibit cell apoptosis. It was also demonstrated that OPN could inhibit cell autophagy. Further experiments revealed that the inhibitory effect of OPN on autophagy could be reversed by blocking the p38 MAPK pathway in HCT116 cells. Conclusion: OPN is involved in HCT116 cell progression and is capable of inhibiting cell autophagy possibly by activating the p38 MAPK signaling pathway, implying that OPN could be a potential novel molecular therapeutic biomarker in patients with CRC.

  18. Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics.

    Science.gov (United States)

    Burgio, Ernesto; Migliore, Lucia

    2015-04-01

    For at least 30 years cancer has been defined as a genetic disease and explained by the so-called somatic mutation theory (SMT), which has dominated the carcinogenesis field. Criticism of the SMT has recently greatly increased, although still not enough to force all SMT supporters to recognize its limits. Various researchers point out that cancer appears to be a complex process concerning a whole tissue; and that genomic mutations, although variably deleterious and unpredictably important in determining the establishment of the neoplastic phenotype, are not the primary origin for a malignant neoplasia. We attempt to describe the inadequacies of the SMT and demonstrate that epigenetics is a more logical cause of carcinogenesis. Many previous models of carcinogenesis fall into two classes: (i) in which some biological changes inside cells alone lead to malignancy; and (ii) requiring changes in stroma/extracellular matrix. We try to make clear that in the (ii) model genomic instability is induced by persistent signals coming from the microenvironment, provoking epigenetic and genetic modifications in tissue stem cells that can lead to cancer. In this perspective, stochastic mutations of DNA are a critical by-product rather then the primary cause of cancer. Indirect support for such model of carcinogenesis comes from the in vitro and vivo experiments showing apparent 'reversion' of cancer phenotypes obtained via physiological factors of cellular differentiation (cytokines and other signaling molecules) or drugs, even if the key mutations are not 'reversed'.

  19. A challenge to mutation theory of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Watanabe, Masami

    2006-01-01

    This paper presents an objection against the commonly accepted mutation theory in radiation carcinogenesis. First, author's studies of X-ray irradiated syrian hamster embryo (SHE) cells on malignant morphological changes and mutational change of HGPRT gene showed that the changing patterns were quite different, and as well, other studies in mice gave the essentially similar results. Thus radiation-induced carcinogenesis in cells does not simply occur by an accumulation of radiation-induced mutation. Second, as cultured cells usually used for oncogenesis studies already have the infinitively proliferative ability, the author used the primary cell culture obtained from the rodent embryo. Even those cells became immortal to be cancerous after repeated culture passage with the higher frequency of 10 3 -10 4 relative to somatic cell mutation. Cells thus seem to be easily changeable to cancerous ones. Bystander effect can cause transformation in non-irradiated cells and genetic instability by radiation can form the potentially unstable chromatin region, which induces telomere instability. The author has found that, while short-lived radicals yielded by X-ray irradiation attack DNA to induce cell death and chromosome aberration, long-lived radicals in biomolecules do not, but can cause mutation and carcinogenesis, which are reduced by vitamine C supplementation. The author concludes that the primary target in the radiation carcinogenesis in cells and even in the whole individuals is conceivably protein and not DNA. (T.I.)

  20. Ultraviolet radiation-induced carcinogenesis: mechanisms and experimental models

    International Nuclear Information System (INIS)

    Ramasamy, Karthikeyan; Shanmugam, Mohana; Balupillai, Agilan; Govindhasamy, Kanimozhi; Gunaseelan, Srithar; Muthusamy, Ganesan; Robert, Beualah Mary; Nagarajan, Rajendra Prasad

    2017-01-01

    Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits numerous cellular and molecular events which include the generation of inflammatory mediators, DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling pathways. UVR-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. UVR-induced carcinogenic mechanism has been well studied using various animal and cellular models. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes served as excellent cellular model systems for the understanding of UVR-mediated carcinogenic events. Apart from this, scientists developed reconstituted three-dimensional normal human skin equivalent models for the study of UVR signaling pathways. Moreover, hairless mice such as SKH-1, devoid of Hr gene, served as a valuable model for experimental carcinogenesis. Scientists have also used transgenic mice and dorsal portion shaved Swiss albino mice for UVR carcinogenesis studies. In this review, we have discussed the current progress in the study on ultraviolet B (UVB)-mediated carcinogenesis and outlined appropriate experimental models for both ultraviolet A- and UVB-mediated carcinogenesis. (author)

  1. Chronology of p53 protein accumulation in gastric carcinogenesis

    NARCIS (Netherlands)

    Craanen, M. E.; Blok, P.; Dekker, W.; Offerhaus, G. J.; Tytgat, G. N.

    1995-01-01

    p53 Protein accumulation in early gastric carcinoma was studied in relation to the histological type (Lauren classification) and the type of growth pattern, including the chronology of p53 protein accumulation during carcinogenesis. Forty five, paraffin embedded gastrectomy specimens from early

  2. 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...

  3. 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

  4. Risk of colorectal cancer in relation to frequency and total amount of red meat consumption. Systematic review and meta-analysis

    OpenAIRE

    Smolińska, Katarzyna; Paluszkiewicz, Piotr

    2010-01-01

    Introduction The colon and rectum are common sites of food-related cancer in developed countries. Recent studies strongly suggest that red meat intake is associated with colon cancer, whereas for rectal cancer such an association still needs to be proved. The aim of the study was to assess the role of total amount and frequency of red meat intake in colorectal carcinogenesis based on published data using meta-analysis methods. Material and methods The literature published until 2009 was selec...

  5. Combination of biomarkers

    DEFF Research Database (Denmark)

    Thurfjell, Lennart; Lötjönen, Jyrki; Lundqvist, Roger

    2012-01-01

    The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury.......The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury....

  6. EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer

    Science.gov (United States)

    Boye, K; Nesland, J M; Sandstad, B; Haugland Haugen, M; Mælandsmo, G M; Flatmark, K

    2012-01-01

    Background: Proteolytic enzymes and their regulators have important biological roles in colorectal cancer by stimulating invasion and metastasis, which makes these factors attractive as potential prognostic biomarkers. Methods: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN) was characterised using immunohistochemistry in primary tumours from a cohort of 277 prospectively recruited colorectal cancer patients, and associations with expression of S100A4, clinicopathological parameters and patient outcome were investigated. Results: One hundred and ninety-eight samples (72%) displayed positive membrane staining of the tumour cells, whereas 10 cases (4%) were borderline positive. EMMPRIN expression was associated with shorter metastasis-free, disease-specific and overall survival in both univariate and multivariate analyses. The prognostic impact was largely confined to TNM stage III, and EMMPRIN-negative stage III patients had an excellent prognosis. Furthermore, EMMPRIN was significantly associated with expression of S100A4, and the combined expression of these biomarkers conferred an even poorer prognosis. However, there was no evidence of direct regulation between the two proteins in the colorectal cancer cell lines HCT116 and SW620 in siRNA knockdown experiments. Conclusion: EMMPRIN is a promising prognostic biomarker in colorectal cancer, and our findings suggest that it could be used in the selection of stage III patients for adjuvant therapy. PMID:22782346

  7. Genomic and oncoproteomic advances in detection and treatment of colorectal cancer.

    LENUS (Irish Health Repository)

    McHugh, Seamus M

    2012-02-01

    AIMS: We will examine the latest advances in genomic and proteomic laboratory technology. Through an extensive literature review we aim to critically appraise those studies which have utilized these latest technologies and ascertain their potential to identify clinically useful biomarkers. METHODS: An extensive review of the literature was carried out in both online medical journals and through the Royal College of Surgeons in Ireland library. RESULTS: Laboratory technology has advanced in the fields of genomics and oncoproteomics. Gene expression profiling with DNA microarray technology has allowed us to begin genetic profiling of colorectal cancer tissue. The response to chemotherapy can differ amongst individual tumors. For the first time researchers have begun to isolate and identify the genes responsible. New laboratory techniques allow us to isolate proteins preferentially expressed in colorectal cancer tissue. This could potentially lead to identification of a clinically useful protein biomarker in colorectal cancer screening and treatment. CONCLUSION: If a set of discriminating genes could be used for characterization and prediction of chemotherapeutic response, an individualized tailored therapeutic regime could become the standard of care for those undergoing systemic treatment for colorectal cancer. New laboratory techniques of protein identification may eventually allow identification of a clinically useful biomarker that could be used for screening and treatment. At present however, both expression of different gene signatures and isolation of various protein peaks has been limited by study size. Independent multi-centre correlation of results with larger sample sizes is needed to allow translation into clinical practice.

  8. Genomic and oncoproteomic advances in detection and treatment of colorectal cancer.

    LENUS (Irish Health Repository)

    McHugh, Seamus M

    2009-01-01

    AIMS: We will examine the latest advances in genomic and proteomic laboratory technology. Through an extensive literature review we aim to critically appraise those studies which have utilized these latest technologies and ascertain their potential to identify clinically useful biomarkers. METHODS: An extensive review of the literature was carried out in both online medical journals and through the Royal College of Surgeons in Ireland library. RESULTS: Laboratory technology has advanced in the fields of genomics and oncoproteomics. Gene expression profiling with DNA microarray technology has allowed us to begin genetic profiling of colorectal cancer tissue. The response to chemotherapy can differ amongst individual tumors. For the first time researchers have begun to isolate and identify the genes responsible. New laboratory techniques allow us to isolate proteins preferentially expressed in colorectal cancer tissue. This could potentially lead to identification of a clinically useful protein biomarker in colorectal cancer screening and treatment. CONCLUSION: If a set of discriminating genes could be used for characterization and prediction of chemotherapeutic response, an individualized tailored therapeutic regime could become the standard of care for those undergoing systemic treatment for colorectal cancer. New laboratory techniques of protein identification may eventually allow identification of a clinically useful biomarker that could be used for screening and treatment. At present however, both expression of different gene signatures and isolation of various protein peaks has been limited by study size. Independent multi-centre correlation of results with larger sample sizes is needed to allow translation into clinical practice.

  9. Intrabilary obstruction by colorectal metastases

    OpenAIRE

    Traeger, Luke; Kiroff, George

    2018-01-01

    Abstract Intrabiliary colorectal metastases are rare. We present a case of an 84-year-old man who developed obstructive jaundice secondary to intrabiliary growth of colorectal metastases. The patient presented with three weeks of jaundice and significant weight loss in the preceding months. The patient’s background included metastatic colorectal carcinoma, with a previous right hemicolectomy and left hepatectomy for liver metastases. A MRCP showed an obstruction of the biliary tract transitio...

  10. Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.

    Science.gov (United States)

    Kravchenko, Julia; Akushevich, Igor; Seewaldt, Victoria L; Abernethy, Amy P; Lyerly, H Kim

    2011-07-01

    The observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.

  11. Lysyl oxidase in colorectal cancer

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine T

    2013-01-01

    Colorectal cancer is the third most prevalent form of cancer worldwide and fourth-leading cause of cancer-related mortality, leading to ~600,000 deaths annually, predominantly affecting the developed world. Lysyl oxidase is a secreted, extracellular matrix-modifying enzyme previously suggested...... to act as a tumor suppressor in colorectal cancer. However, emerging evidence has rapidly implicated lysyl oxidase in promoting metastasis of solid tumors and in particular colorectal cancer at multiple stages, affecting tumor cell proliferation, invasion, and angiogenesis. This emerging research has...... advancements in the field of colorectal cancer....

  12. Endoscopic management of colorectal adenomas.

    Science.gov (United States)

    Meier, Benjamin; Caca, Karel; Fischer, Andreas; Schmidt, Arthur

    2017-01-01

    Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy.

  13. Immunohistochemistry expression of TCF4 protein on carcinoma, adenoma and non neoplastic colorectal mucosa

    Directory of Open Access Journals (Sweden)

    Leonardo Huber Tauil

    2014-01-01

    Full Text Available Purpose: To detect and quantify the immunoreactivity of TCF4 protein in colorectal carci- noma, colorectal adenoma and non-neoplasic colorectal epithelium. Methods: We studied 129 individuals: 40 with colorectal cancer, 52 with colorectal ad- enoma and 37 with non-neoplastic colorectal epithelium. The colorectal adenoma and carcinoma samples were obtained from patients who underwent surgical procedures, and colonoscopies and samples of non-neoplastic colorectal epithelium were taken from patients who died from cardiovascular diseases, without diseases of the large intestine. Samples of different tissues were included in paraffin blocks, and the immunohistochem- ical expression of protein TCF4 was analyzed using the technique of tissue microarray (TMA with polyclonal antibody TCF4. The immunoreactivity was analyzed and classified as positive and negative. Results: The immunohistochemical expression of TCF4 protein was significantly higher (p < 0.01 in colorectal carcinoma than in the non-neoplastic colorectal epithelium and adenoma. There was no difference (p = 0.76 between TCF4 protein immunohistochemical expression in colorectal adenoma and non-neoplastic colorectal tissue. Conclusions: TCF4 protein showed a more intense expression in colorectal carcinoma than in non-neoplastic colorectal epithelium and adenoma, indicating that this protein is in- volved in colorectal carcinogenesis. Resumo: Objetivos: Detectar e quantificar a imunoexpressão da proteína TCF4 no carcinoma e no adenoma colorretal e no epitélio colorretal não neoplásico. Método: Foram estudados 129 indivíduos: 40 com carcinoma colorretal, 52 com adenoma colorretal e 37 com epitélio colorretal não neoplásico. Os tecidos de adenoma e carcinoma colorretais foram representados por amostras da lesão retirada de doentes submetidos a procedimentos cirúrgicos e colonoscópicos, e as amostras de epitélio colorretal não neo- plásico foram retiradas de doentes falecidos por

  14. Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor.

    Science.gov (United States)

    Liu, Li; Nishihara, Reiko; Qian, Zhi Rong; Tabung, Fred K; Nevo, Daniel; Zhang, Xuehong; Song, Mingyang; Cao, Yin; Mima, Kosuke; Masugi, Yohei; Shi, Yan; da Silva, Annacarolina; Twombly, Tyler; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Kosumi, Keisuke; Inamura, Kentaro; Nowak, Jonathan A; Drew, David A; Lochhead, Paul; Nosho, Katsuhiko; Wu, Kana; Wang, Molin; Garrett, Wendy S; Chan, Andrew T; Fuchs, Charles S; Giovannucci, Edward L; Ogino, Shuji

    2017-12-01

    Dietary patterns affect systemic and local intestinal inflammation, which have been linked to colorectal carcinogenesis. Chronic inflammation can interfere with the adaptive immune response. We investigated whether the association of a diet that promotes intestinal inflammation with risk of colorectal carcinoma was stronger for tumors with lower lymphocytic reactions than tumors with higher lymphocytic reactions. We collected data from the molecular pathological epidemiology databases of 2 prospective cohort studies: the Nurses' Health Study (since 1976) and the Health Professionals Follow-Up Study (since 1986). We used duplication-method time-varying Cox proportional cause-specific hazards regression to assess the association of empirical dietary inflammatory pattern (EDIP) score (derived from food frequency questionnaire data) with colorectal carcinoma subtype. Foods that contribute to high EDIP scores include red and processed meats, refined grains, carbonated beverages, and some vegetables; foods that contribute to low EDIP scores include beer, wine, coffee, tea, yellow and leafy vegetables, and fruit juice. Colorectal tissue samples were analyzed histologically for patterns of lymphocytic reactions (Crohn's-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes). During follow-up of 124,433 participants, we documented 1311 incident colon and rectal cancer cases with available tissue data. The association between the EDIP and colorectal cancer risk was significant (P trend  = .02), and varied with degree of peritumoral lymphocytic reaction (P heterogeneity colorectal cancer with an absent or low peritumoral lymphocytic reaction (highest vs lowest EDIP score quintile hazard ratio, 2.60; 95% confidence interval, 1.60-4.23; P trend .80). In 2 prospective cohort studies, we associated inflammatory diets with a higher risk of colorectal cancer subtype that contains little or no peritumoral

  15. Colorectal Cancer Screening

    OpenAIRE

    Quintero, Enrique; Saito, Yutaka; Hassan, Cessare; Senore, Carlo

    2012-01-01

    Colorectal cancer, which is the leading cancer in Singapore, can be prevented by increased use of screening and polypectomy. A range of screening strategies such as stool-based tests, flexible sigmoidoscopy, colonoscopy and computed tomography colonography are available, each with different strengths and limitations. Primary care physicians should discuss appropriate screening modalities with their patients, tailored to their individual needs. Physicians, patients and the government should wo...

  16. Snake Venom As An Effective Tool Against Colorectal Cancer.

    Science.gov (United States)

    Uzair, Bushra; Atlas, Nagina; Malik, Sidra Batool; Jamil, Nazia; Salaam, Temitope Ojuolape; Rehman, Mujaddad Ur; Khan, Barkat Ali

    2018-06-13

    Cancer is considered one of the most predominant causes of morbidity and mortality all over the world and colorectal cancer is the most common fatal cancers, triggering the second cancer related death. Despite progress in understanding carcinogenesis and development in chemotherapeutics, there is an essential need to search for improved treatment. More than the half a century, cytotoxic and cytostatic agents have been examined as a potential treatment of cancer, among these agents; remarkable progresses have been reported by the use of the snake venom. Snake venoms are secreting materials of lethal snakes are store in venomous glands. Venoms are composite combinations of various protein, peptides, enzymes, toxins and non proteinaceous secretions. Snake venom possesses immense valuable mixtures of proteins and enzymes. Venoms have potential to combat with the cancerous cells and produce positive effect. Besides the toxicological effects of venoms, several proteins of snake venom e.g. disintegrins, phospholipases A2, metalloproteinases, and L-amino acid oxidases and peptides e.g. bradykinin potentiators, natriuretic, and analgesic peptides have shown potential as pharmaceutical agents, including areas of diagnosis and cancer treatment. In this review we have discussed recent remarkable research that has involved the dynamic snake venoms compounds, having anticancer bustle especially in case of colorectal cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review.

    Science.gov (United States)

    Liang, Tie-Jun; Wang, Hong-Xu; Zheng, Yan-Yan; Cao, Ying-Qing; Wu, Xiaoyu; Zhou, Xin; Dong, Shu-Xiao

    2017-07-11

    Adenomatous polyposis coli (APC) promoter hypermethylation has been frequently observed in colorectal cancer (CRC). The association between APC promoter methylation and clinicopathological significance in CRC is under investigation. We performed a meta-analysis to quantitatively evaluate the significance of APC methylation in CRC. The study included a total of 24 articles and 2025 CRC patients. The frequency of APC promoter hypermethylation was significantly higher in colorectal adenoma than in normal colorectal tissue, OR was 5.76, 95% CI, 2.45-13.56; pAPC promoter more frequently hypermethylated in CRC stage I compared to normal colorectal tissue, OR was 13.42, 95% CI, 3.66-49.20; pAPC promoter hypermethylation, pooled OR was 9.80, 95%CI, 6.07-15.81; pAPC methylation was not associated with grade, stage of CRC as well as tumor location, patients' gender, and smoking behavior. The results indicate that APC promoter hypermethylation is an early event in carcinogenesis of CRC, could be a valuable diagnostic marker for early-stage CRC. APC methylation is not significantly associated with overall survival in patients with CRC. APC is a potential drug target for development of personalized treatment.

  18. Dietary meat intake in relation to colorectal adenoma in asymptomatic women.

    Science.gov (United States)

    Ferrucci, Leah M; Sinha, Rashmi; Graubard, Barry I; Mayne, Susan T; Ma, Xiaomei; Schatzkin, Arthur; Schoenfeld, Philip S; Cash, Brooks D; Flood, Andrew; Cross, Amanda J

    2009-05-01

    No previous study has concurrently assessed the associations between meat intake, meat-cooking methods and doneness levels, meat mutagens (heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons), heme iron, and nitrite from meat and colorectal adenoma in asymptomatic women undergoing colonoscopy. Of the 807 eligible women in a cross-sectional multicenter colonoscopy screening study, 158 prevalent colorectal adenoma cases and 649 controls satisfactorily completed the validated food frequency and meat questionnaires. Using an established meat mutagen database and new heme iron and nitrite databases, we comprehensively investigated the components of meat that may be involved in carcinogenesis. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) within quartiles of meat-related variables. Red meat was associated positively with colorectal adenoma (OR fourth vs. first quartile = 2.02; 95% CI = 1.06-3.83; P trend = 0.38). Intake of pan-fried meat (OR = 1.72; 95% CI = 0.96-3.07; P trend = 0.01) and the HCA: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (OR = 1.90; 95% CI = 1.05-3.42; P trend = 0.07) were also associated with an increased risk of colorectal adenoma. The new databases yielded lower estimates of heme iron and nitrite than previous assessment methods, although the two methods were highly correlated for both exposures. Although not statistically significant, there were positive associations between iron and heme iron from meat and colorectal adenoma. In asymptomatic women undergoing colonoscopy, colorectal adenomas were associated with high intake of red meat, pan-fried meat, and the HCA MeIQx. Other meat-related exposures require further investigation.

  19. Predictive Value of Carcinoembryonic and Carbohydrate Antigen 19-9 Related to Some Clinical, Endoscopic and Histological Colorectal Cancer Characteristics

    Directory of Open Access Journals (Sweden)

    Tomašević Ratko

    2016-09-01

    Full Text Available Background: Colorectal cancer (CRC is an important oncological and public health problem worldwide, including Serbia. Unfortunately, half of the patients are recognized in an advanced stage of the disease, therefore, early detection through specific tumor biomarkers, such as carcinoembryonic (CEA and carbohydrate antigen 19-9 (CA 19-9, is the only way to cope with CRC expansion.

  20. Evaluation of Serum CEA, CA19-9, CA72-4, CA125 and Ferritin as Diagnostic Markers and Factors of Clinical Parameters for Colorectal Cancer

    OpenAIRE

    Gao, Yanfeng; Wang, Jinping; Zhou, Yue; Sheng, Sen; Qian, Steven Y.; Huo, Xiongwei

    2018-01-01

    Blood-based protein biomarkers have recently shown as simpler diagnostic modalities for colorectal cancer, while their association with clinical pathological characteristics is largely unknown. In this study, we not only examined the sensitivity and reliability of single/multiple serum markers for diagnosis, but also assessed their connection with pathological parameters from a total of 279 colorectal cancer patients. Our study shown that glycoprotein carcinoembryonic antigen (CEA) owns the h...

  1. Age-specific incidence of all neoplasms after colorectal cancer.

    Science.gov (United States)

    Levi, Fabio; Randimbison, Lalao; Blanc-Moya, Rafael; La Vecchia, Carlo

    2014-10-01

    Patients diagnosed with a specific neoplasm tend to have a subsequent excess risk of the same neoplasm. The age incidence of a second neoplasm at the same site is approximately constant with age, and consequently the relative risk is greater at younger age. It is unclear whether such a line of reasoning can be extended from a specific neoplasm to the incidence of all neoplasms in subjects diagnosed with a defined neoplasm. We considered the age-specific incidence of all non-hormone-related epithelial neoplasms after a first primary colorectal cancer (n = 9542) in the Vaud Cancer Registry data set. In subjects with a previous colorectal cancer, the incidence rate of all other epithelial non-hormone-related cancers was stable around 800 per 100,000 between age 30 and 60 years, and rose only about twofold to reach 1685 at age 70 to 79 years and 1826 per 100,000 at age 80 years or older. After excluding synchronous cancers, the rise was only about 1.5-fold, that is, from about 700 to 1000. In the general population, the incidence rate of all epithelial non-hormone-related cancers was 29 per 100,000 at age 30 to 39 years, and rose 30-fold to 883 per 100,000 at age 70 to 79 years. Excluding colorectal cancers, the rise of all non-hormone-related cancers was from 360 per 100,000 at age 40 to 49 years to 940 at age 70 to 79 years after colorectal cancer, and from 90 to 636 per 100,000 in the general population (i.e., 2.6- vs. 7.1-fold). The rise of incidence with age of all epithelial non-hormone-related second cancers after colorectal cancer is much smaller than in the general population. This can possibly be related to the occurrence of a single mutational event in a population of susceptible individuals, although alternative models are plausible within the complexity of the process of carcinogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. The dutch surgical colorectal audit

    NARCIS (Netherlands)

    Leersum, N.J. van; Snijders, H.S.; Henneman, D.; Kolfschoten, N.E.; Gooiker, G.A.; Berge, M.G. Ten; Eddes, E.H.; Wouters, M.W.; Tollenaar, R.A.E.M.; Bemelman, W.A.; Dam, R.M. van; Elferink, M.A.; Karsten, T.M.; Krieken, J.H. van; Lemmens, V.E.; Rutten, H.J.; Manusama, E.R.; Velde, C.J. van de; Meijerink, W.J.H.J.; Wiggers, T.; Harst, E. van der; Dekker, J.W.T.; Boerma, D.

    2013-01-01

    INTRODUCTION: In 2009, the nationwide Dutch Surgical Colorectal Audit (DSCA) was initiated by the Association of Surgeons of the Netherlands (ASN) to monitor, evaluate and improve colorectal cancer care. The DSCA is currently widely used as a blueprint for the initiation of other audits, coordinated

  3. Colorectal Cancer—Patient Version

    Science.gov (United States)

    Colorectal cancer often begins as a growth called a polyp inside the colon or rectum. Finding and removing polyps can prevent colorectal cancer. Start here to find information on colon and rectal cancer treatment, causes and prevention, screening, research, and statistics.

  4. The Dutch surgical colorectal audit

    NARCIS (Netherlands)

    van Leersum, N. J.; Snijders, H. S.; Henneman, D.; Kolfschoten, N. E.; Gooiker, G. A.; ten Berge, M. G.; Eddes, E. H.; Wouters, M. W. J. M.; Tollenaar, R. A. E. M.; Bemelman, W. A.; van Dam, R. M.; Elferink, M. A.; Karsten, Th M.; van Krieken, J. H. J. M.; Lemmens, V. E. P. P.; Rutten, H. J. T.; Manusama, E. R.; van de Velde, C. J. H.; Meijerink, W. J. H. J.; Wiggers, Th; van der Harst, E.; Dekker, J. W. T.; Boerma, D.

    2013-01-01

    In 2009, the nationwide Dutch Surgical Colorectal Audit (DSCA) was initiated by the Association of Surgeons of the Netherlands (ASN) to monitor, evaluate and improve colorectal cancer care. The DSCA is currently widely used as a blueprint for the initiation of other audits, coordinated by the Dutch

  5. Effect of dietary supplementation on the prognostic value of urinary and serum 8-isoprostaglandin F2α in chemically-induced mammary carcinogenesis in the rat

    Directory of Open Access Journals (Sweden)

    Białek Sławomir

    2011-03-01

    Full Text Available Abstract Backround The aim of the present study was to assess the effects of zinc or copper and polyphenolic compounds on the 8-isoprostaglandin F2α concentration in the serum and urine of rats with mammary cancer (adenocarcinoma induced with 7,12-dimethylbenz[a]antracene. The research focused on the kinetics of alterations in urinary 8-isoPGF2α at the early stage of carcinogenesis as well as the influence of dietary factors on the process. The impact of selected compounds on the intensity of DMBA - induced carcinogenesis was also assessed. Result and conclusions Administration of DMBA, a compound that inducers mammary tumors in experimental animals, increased the serum and urinary 8-isoPGF2α levels in study rats. In the rat model, diet supplementation with zinc, combined with selected polyphenolic compounds (resveratrol or genistein yielded a statistically significant decrease in the rat serum and urinary biomarker concentration with a simultaneously significant stimulation of carcinogenesis. The results indicate that there is an inverse correlation between the intensity of DMBA-induced carcinogenicity and the level of 8-isoPGF2α in urine and serum of rats.

  6. Cyr61 Expression is associated with prognosis in patients with colorectal cancer

    International Nuclear Information System (INIS)

    Jeong, Dongjun; Soo Lee, Moon; Kim, Chang-Jin; Jun Baek, Moo; Heo, Suhak; Sung Ahn, Tae; Lee, Sookyoung; Park, Soyoung; Kim, Hyungjoo; Park, Doosan; Byung Bae, Sang; Lee, Sung Soo

    2014-01-01

    Cysteine-rich 61 (Cyr61), a member of the CCN protein family, possesses diverse functionality in cellular processes such as adhesion, migration, proliferation, and survival. Cyr61 can also function as an oncogene or a tumour suppressor, depending on the origin of the cancer. Only a few studies have reported Cyr61 expression in colorectal cancer. In this study, we assessed the Cyr61 expression in 251 colorectal cancers with clinical follow up. We examined Cyr61 expression in 6 colorectal cancer cell lines (HT29, Colo205, Lovo, HCT116, SW480, SW620) and 20 sets of paired normal and colorectal cancer tissues by western blot. To validate the association of Cyr61 expression with clinicopathological parameters, we assessed Cyr61 expression using tissue microarray analysis of primary colorectal cancer by immunohistochemical analysis. We verified that all of the cancer cell lines expressed Cyr61; 2 cell lines (HT29 and Colo205) demonstrated Cyr61 expression to a slight extent, while 4 cell lines (Lovo, HCT116, SW480, SW620) demonstrated greater Cyr61 expression than HT29 and Colo205 cell lines. Among the 20 cases of paired normal and tumour tissues, greater Cyr61 expression was observed in 16 (80%) tumour tissues than in normal tissues. Furthermore, 157 out of 251 cases (62.5%) of colorectal cancer examined in this study displayed strong Cyr61 expression. Cyr61 expression was found to be associated with pN (p = 0.018). Moreover, Cyr61 expression was associated with statistically significant cancer-specific mortality (p = 0.029). The duration of survival was significantly lesser in patients with Cyr61 high expression than in patients with Cyr61 low expression (p = 0.001). These results suggest that Cyr61 expression plays several important roles in carcinogenesis and may also be a good prognostic marker for colorectal cancer. Our data confirmed that Cyr61 was expressed in colorectal cancers and the expression was correlated with worse prognosis of colorectal cancers

  7. Prognostic significance of fascin expression in advanced colorectal cancer: an immunohistochemical study of colorectal adenomas and adenocarcinomas

    International Nuclear Information System (INIS)

    Hashimoto, Yosuke; Skacel, Marek; Lavery, Ian C; Mukherjee, Abir L; Casey, Graham; Adams, Josephine C

    2006-01-01

    prognostic value as an early biomarker for more aggressive colorectal adenocarcinomas

  8. Exercise and Low-Dose Ibuprofen for Cognitive Impairment in Colorectal Cancer Patients Receiving Chemotherapy

    Science.gov (United States)

    2018-03-13

    Cognitive Impairment; Stage 0 Colorectal Cancer; Stage I Colorectal Cancer; Stage II Colorectal Cancer; Stage IIA Colorectal Cancer; Stage IIB Colorectal Cancer; Stage IIC Colorectal Cancer; Stage III Colorectal Cancer; Stage IIIA Colorectal Cancer; Stage IIIB Colorectal Cancer; Stage IIIC Colorectal Cancer

  9. Effectiveness of Bioactive Food Components in Experimental Colon Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Emília Hijová

    2009-01-01

    Full Text Available The aim of the present study was the evaluation of possible protective effects of selected bioactive food components in experimental N,N-dimethylhydrazine (DMH-induced colon carcinogenesis. Wistar albino rats (n = 92 were fed a high fat diet or conventional laboratory diet. Two weeks after the beginning of the trial, DMH injections were given to six groups of rats at the dose of 20 mg/kg b.w. twice weekly. The activity of bacterial enzymes in faeces and serum bile acid concentrations were determined. High fat diet, DMH injections, and their combination significantly increased the activies of β-galactosidase, β-glucuronidase, and α-glucosidase (p p < 0.001, as well as the bile acid concentration compared to the group at the highest risk. The protective effects of selected bioactive food components in experimentally induced colon carcinogenesis allow for their possible use in cancer prevention or treatment.

  10. 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.

  11. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Marilanda Ferreira Bellini

    2012-01-01

    Full Text Available TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH, overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.

  12. Expression of SRSF3 is Correlated with Carcinogenesis and Progression of Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Peiqi, Liu; Zhaozhong, Guo; Yaotian, Yin; Jun, Jia; Jihua, Guo; Rong, Jia

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck with high mortality rates. The mechanisms of initiation and development of OSCC remain largely unknown. Dysregulated alternative splicing of pre-mRNA has been associated with OSCC. Splicing factor SRSF3 is a proto-oncogene and overexpressed in multiple cancers. The aim of this study was to uncover the relationship between SRSF3 and carcinogenesis and progression of oral squamous cell carcinoma. The expression of SRSF3 in oral normal, dysplasia, or carcinoma tissues was analyzed by immunohistochemistry. The expression levels of EMT-related genes were quantified by real-time quantitative RT-PCR. The expression of SRSF3 in DMBA treated primary cultured oral epithelial cells were analyzed by western blot. SRSF3 is overexpressed in oral cancer and moderate or severe dysplasia tissues. Patients with high grade cancer or lymphatic metastasis showed up-regulated expression of SRSF3. Knockdown of SRSF3 repressed the expression of Snail and N-cadherin in vitro. Carcinogen DMBA treated primary cultured oral epithelial cells showed significantly increased SRSF3 level than in control cells. Our results suggested that SRSF3 is associated with the initiation and development of OSCC and may be a biomarker and therapeutic target of OSCC.

  13. 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.

  14. Comprehensive analysis of miRNAs expression profiles revealed potential key miRNA/mRNAs regulating colorectal cancer stem cell self-renewal.

    Science.gov (United States)

    Xu, Peng; Wang, Junhua; Sun, Bo; Xiao, Zhongdang

    2018-05-20

    Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood. Recently, miRNAs are reported to be relevant to the self-renewal ability of cancer stem cells. In this study, we first isolated colorectal cancer stem cell from colorectal cancer cell line HCT-116 by 1% low serum culture. Then we conducted a comprehensive analysis based on the miRNAs profiles data of both colorectal cancer stem cells and normal cultured colorectal cancer cells. Pathway analysis revealed multiple pathways including Jak-STAT, TGF-beta, PI3K-Akt and MAPK signaling pathway that are correlated to colorectal cancer. Further, we constructed a miRNA-mRNA network, based on which, several miRNA/mRNA pairs were ranked according to their impact index to the self-renewal of colorectal cancer stem cells. Further biological experiment showed that up-regulation of miR-92a-3p led to cell cycle arrest and reduced colony formation. This work provides clues to find the new potential biomarkers for colorectal cancer stem cell diagnosis and select effective miRNAs for targeted therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Experimental gastric carcinogenesis in Cebus apella nonhuman primates.

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    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

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

    OpenAIRE

    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 adminis...

  17. Novel and differential accumulation of mitochondrial DNA deletions in Swedish and vietnamese patients with colorectal cancer.

    Science.gov (United States)

    Dimberg, Jan; Hong, Thai Trinh; Skarstedt, Marita; Löfgren, Sture; Zar, Niklas; Matussek, Andreas

    2014-01-01

    Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis and aging. The mtDNA 4977 bp deletion is one of the most frequently observed mtDNA mutations in human tissues and may play a role in colorectal cancer (CRC). In the present study, we aimed to evaluate the frequency of mtDNA 4977 bp deletion in CRC tissues and its association with clinical factors. We determined the presence of the 4977 bp common deletion in cancer and normal paired tissue samples from 105 Swedish and 88 Vietnamese patients with CRC using polymerase chain reaction (PCR) assays. The mtDNA 4977 bp deletion was shown to be significantly more frequent in normal tissues in comparison with paired cancer tissues in both Swedish and Vietnamese patients. The 4977 bp common deletion was significantly more frequent in cancer tissues of the Vietnamese patients compared to the Swedish patients, and in Vietnamese cancer tissues, the 4977 bp deletion was significantly over represented in those with localized disease compared to those with disseminated disease. Moreover, we detected nine novel mtDNA deletions and found a significantly higher rate of these in CRC tissues in Swedish in comparison to Vietnamese patients. The mtDNA 4977 bp deletion seems to have an impact on the clinical outcome of CRC in Vietnamese patients, that the Swedish patients accumulate more of the detected novel deletions in CRC tissue compared to Vietnamese patients probably indicates divergent mechanisms in colorectal carcinogenesis.

  18. Discovery of a Novel Immune Gene Signature with Profound Prognostic Value in Colorectal Cancer: A Model of Cooperativity Disorientation Created in the Process from Development to Cancer.

    Directory of Open Access Journals (Sweden)

    Ning An

    Full Text Available Immune response-related genes play a major role in colorectal carcinogenesis by mediating inflammation or immune-surveillance evasion. Although remarkable progress has been made to investigate the underlying mechanism, the understanding of the complicated carcinogenesis process was enormously hindered by large-scale tumor heterogeneity. Development and carcinogenesis share striking similarities in their cellular behavior and underlying molecular mechanisms. The association between embryonic development and carcinogenesis makes embryonic development a viable reference model for studying cancer thereby circumventing the potentially misleading complexity of tumor heterogeneity. Here we proposed that the immune genes, responsible for intra-immune cooperativity disorientation (defined in this study as disruption of developmental expression correlation patterns during carcinogenesis, probably contain untapped prognostic resource of colorectal cancer. In this study, we determined the mRNA expression profile of 137 human biopsy samples, including samples from different stages of human colonic development, colorectal precancerous progression and colorectal cancer samples, among which 60 were also used to generate miRNA expression profile. We originally established Spearman correlation transition model to quantify the cooperativity disorientation associated with the transition from normal to precancerous to cancer tissue, in conjunction with miRNA-mRNA regulatory network and machine learning algorithm to identify genes with prognostic value. Finally, a 12-gene signature was extracted, whose prognostic value was evaluated using Kaplan-Meier survival analysis in five independent datasets. Using the log-rank test, the 12-gene signature was closely related to overall survival in four datasets (GSE17536, n = 177, p = 0.0054; GSE17537, n = 55, p = 0.0039; GSE39582, n = 562, p = 0.13; GSE39084, n = 70, p = 0.11, and significantly associated with disease

  19. Biologically based modelling and simulation of carcinogenesis at low doses

    International Nuclear Information System (INIS)

    Ouchi, Noriyuki B.

    2003-01-01

    The process of the carcinogenesis is studied by computer simulation. In general, we need a large number of experimental samples to detect mutations at low doses, but in practice it is difficult to get such a large number of data. To satisfy the requirements of the situation at low doses, it is good to study the process of carcinogenesis using biologically based mathematical model. We have mainly studied it by using as known as 'multi-stage model'; the model seems to get complicated, as we adopt the recent new findings of molecular biological experiments. Moreover, the basic idea of the multi-stage model is based on the epidemiologic data of log-log variation of cancer incidence with age, it seems to be difficult to compare with experimental data of irradiated cell culture system, which has been increasing in recent years. Taking above into consideration, we concluded that we had better make new model with following features: 1) a unit of the target system is a cell, 2) the new information of the molecular biology can be easily introduced, 3) having spatial coordinates for checking a colony formation or tumorigenesis. In this presentation, we will show the detail of the model and some simulation results about the carcinogenesis. (author)

  20. The relevance of cell transformation to carcinogenesis in vivo

    International Nuclear Information System (INIS)

    Little, J.B.

    1989-01-01

    Despite the caveats concerning rodent as opposed to human cell transformation systems, the author concludes there are several areas in which cell transformation studies with rodent cells have shown clear relevance to carcinogenesis in vivo, especially studies of carcinogenic effects of high LET radiation, particularly dependence on dose rate. In vitro studies firmly established the generality of promotion by phorbol esters tumour promotors. Initial studies on suppression of transformation, notably by protease inhibitors, has led to the confirmation of this phenomenon in in vivo carcinogenesis; development of inhibitor preparations from natural sources suitable for long-term supplementation in human diet, is under investigation. The potential importance of these modifiers is further emphasized by mechanistic studies suggesting that radiation may initiate a large fraction of exposed cell population, and expression of transformation may be controlled to a large extent by environmental conditions including the presence of promoting or suppressing agents. Finally, cell transformation systems offer the opportunity for mechanistic studies of the initial stages of carcinogenesis. Provocative results have arisen in several areas consistent with findings in experimental animals. (author)

  1. Cellular adaptation as an important response during chemical carcinogenesis

    International Nuclear Information System (INIS)

    Farber, E.

    1992-01-01

    Since disease processes are largely expressions of how living organisms react and respond to perturbations in the external and internal environments, adaptive or protective responses and their modulations and mechanisms are of the greatest concern in fundamental studies of disease pathogenesis. Such considerations are also of the greatest relevance in toxicology, including how living organisms respond to low levels of single and multiple xenobiotics and radiations. As the steps and mechanisms during cancer development are studied in greater depth, phenomena become apparent that suggest that adaptive reactions and responses may play important or even critical roles in the process of carcinogenesis. The question becomes whether the process of carcinogenesis is fundamentally an adversarial one (i.e., an abnormal cell in a vulnerable host), or is it more in the nature of a physiological selection or differentiation, which has survival value for the host as an adaptive phenomena? The very early initial interactions of mutagenic chemical carcinogens, radiations and viruses with DNA prejudice most to consider the adversarial 'abnormal' view as the appropriate one. Yet, the unusually common nature of the earliest altered rare cells that appear during carcinogenesis, their unusually bland nature, and their spontaneous differentiation to normal-appearing adult liver should be carefully considered

  2. Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?

    International Nuclear Information System (INIS)

    Gad, Sophie; Teboul, David; Lièvre, Astrid; Goasguen, Nicolas; Berger, Anne; Beaune, Philippe; Laurent-Puig, Pierre

    2004-01-01

    A novel member of the Wnt signalling pathway, Chibby, was recently identified. This protein inhibits Wnt/β-catenin mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of β-catenin) to bind to β-catenin. This suggests that Chibby could be a tumour suppressor protein. The C22orf2 gene coding Chibby is located on chromosome 22, a region recurrently lost in colorectal cancer. Activation of the Wnt pathway is a major feature of colorectal cancer and occurs through inactivation of APC or activation of β-catenin. All of this led us to analyse the possible implication of Chibby in colorectal carcinogenesis. First, 36 tumour and matched normal colonic mucosa DNA were genotyped with five microsatellite markers located on chromosome 22 to search for loss of heterozygosity. Then, mutation screening of the C22orf2 coding sequence and splice sites was performed in the 36 tumour DNA. Finally, expression of Chibby was analysed by quantitative RT-PCR on 10 patients, 4 with loss of heterozygosity (LOH) on chromosome 22. Loss of heterozygosity involving the C22orf2 region was detected in 11 out of 36 patients (30%). Sequencing analysis revealed a known variant, rs3747174, in exon 5: T321C leading to a silent amino acid polymorphism A107A. Allelic frequencies were 0.69 and 0.31 for T and C variants respectively. No other mutation was detected. Among the 10 patients studied, expression analysis revealed that Chibby is overexpressed in 2 tumours and underexpressed in 1. No correlations were found with 22q LOH status. As no somatic mutation was detected in C22orf2 in 36 colorectal tumour DNA, our results do not support the implication of Chibby as a tumour suppressor in colorectal carcinogenesis. This was supported by the absence of underexpression of Chibby among the tumour samples with 22q LOH. The implication of other Wnt pathway members remains to be identified to explain the part of colorectal tumours without mutation in APC and β-catenin

  3. Current and future molecular diagnostics in colorectal cancer and colorectal adenoma.

    Science.gov (United States)

    Tsang, Andy Hin-Fung; Cheng, Ka-Ho; Wong, Apple Siu-Ping; Ng, Simon Siu-Man; Ma, Brigette Buig-Yue; Chan, Charles Ming-Lok; Tsui, Nancy Bo-Yin; Chan, Lawrence Wing-Chi; Yung, Benjamin Yat-Ming; Wong, Sze-Chuen Cesar

    2014-04-14

    Colorectal cancer (CRC) is one of the most prevalent cancers in developed countries. On the other hand, CRC is also one of the most curable cancers if it is detected in early stages through regular colonoscopy or sigmoidoscopy. Since CRC develops slowly from precancerous lesions, early detection can reduce both the incidence and mortality of the disease. Fecal occult blood test is a widely used non-invasive screening tool for CRC. Although fecal occult blood test is simple and cost-effective in screening CRC, there is room for improvement in terms of the accuracy of the test. Genetic dysregulations have been found to play an important role in CRC development. With better understanding of the molecular basis of CRC, there is a growing expectation on the development of diagnostic tests based on more sensitive and specific molecular markers and those tests may provide a breakthrough to the limitations of current screening tests for CRC. In this review, the molecular basis of CRC development, the characteristics and applications of different non-invasive molecular biomarkers, as well as the technologies available for the detection were discussed. This review intended to provide a summary on the current and future molecular diagnostics in CRC and its pre-malignant state, colorectal adenoma.

  4. Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer.

    Science.gov (United States)

    Ichimura, Norihisa; Shinjo, Keiko; An, Byonggu; Shimizu, Yasuhiro; Yamao, Kenji; Ohka, Fumiharu; Katsushima, Keisuke; Hatanaka, Akira; Tojo, Masayuki; Yamamoto, Eiichiro; Suzuki, Hiromu; Ueda, Minoru; Kondo, Yutaka

    2015-08-01

    Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. ©2015 American Association for Cancer Research.

  5. Cardiac biomarkers in Neonatology

    OpenAIRE

    Vijlbrief, D.C.

    2015-01-01

    In this thesis, the role for cardiac biomarkers in neonatology was investigated. Several clinically relevant results were reported. In term and preterm infants, hypoxia and subsequent adaptation play an important role in cardiac biomarker elevation. The elevated natriuretic peptides are indicative of abnormal function; elevated troponins are suggestive for cardiomyocyte damage. This methodology makes these biomarkers of additional value in the treatment of newborn infants, separate or as a co...

  6. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Bergmann, Troels K; Henrichsen-Schnack, Tine

    2014-01-01

    BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK a......BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS...

  7. Genome-Wide Screening of Genes Showing Altered Expression in Liver Metastases of Human Colorectal Cancers by cDNA Microarray

    Directory of Open Access Journals (Sweden)

    Rempei Yanagawa

    2001-01-01

    Full Text Available In spite of intensive and increasingly successful attempts to determine the multiple steps involved in colorectal carcinogenesis, the mechanisms responsible for metastasis of colorectal tumors to the liver remain to be clarified. To identify genes that are candidates for involvement in the metastatic process, we analyzed genome-wide expression profiles of 10 primary colorectal cancers and their corresponding metastatic lesions by means of a cDNA microarray consisting of 9121 human genes. This analysis identified 40 genes whose expression was commonly upregulated in metastatic lesions, and 7 that were commonly downregulated. The upregulated genes encoded proteins involved in cell adhesion, or remodeling of the actin cytoskeleton. Investigation of the functions of more of the altered genes should improve our understanding of metastasis and may identify diagnostic markers and/or novel molecular targets for prevention or therapy of metastatic lesions.

  8. Metastatic paediatric colorectal carcinoma.

    LENUS (Irish Health Repository)

    Woods, R

    2012-03-01

    A 16-year-old girl presented to our unit with crampy abdominal pain, change in bowel habit, a subjective impression of weight loss and a single episode of haematochezia. She was found to have a rectosigmoid adenocarcinoma and proceeded to laparoscopic anterior resection, whereupon peritoneal metastases were discovered. She received chemotherapy and is alive and well ten month later with no radiological evidence of disease. Colorectal carcinoma is rare in the paediatric population but is increasing in incidence. Early diagnosis is critical to enable optimal outcomes.

  9. Diagnosis of colorectal tumors

    International Nuclear Information System (INIS)

    Vogl, T.J.; Pegios, W.; Jacobi, V.; Schaefer, S.; Abolmaali, N.; Luboldt, W.

    2003-01-01

    With the introduction of multislice CT extensive volumetric data sets can be quickly acquired in high spatial resolution. The high spatial resolution reduces partial volume effects and enables multiplanar reconstructions. Regarding the colorectum this means that the colon can be assessed if the colon is sufficiently cleaned and distended, and that transmural infiltration of colorectal carcinoma and liver metastases can be better detected. T-staging of colon cancer is less important than T-staging of rectal cancer. Based on the higher contrast MRI is superior to CT in T-staging of rectal cancer and in the differentiation between scarring tissue and recurrence of carcinoma. (orig.) [de

  10. Myeloperoxidase-positive cell infiltration of normal colorectal mucosa is related to body fatness and is predictive of adenoma occurrence.

    Science.gov (United States)

    Mariani, F; Boarino, V; Bertani, A; Merighi, A; Pedroni, M; Rossi, G; Mancini, S; Sena, P; Benatti, P; Roncucci, L

    2017-06-01

    Body fatness is a risk factor for colorectal cancer, and promotes an inflammatory environment. Indeed, inflammation in normal colorectal mucosa may be a factor linking body fatness to colorectal carcinogenesis. In this study, we evaluated myeloperoxidase (MPO)-positive cells infiltration of normal colorectal mucosa as a marker of cancer-promoting inflammation in overweight and obese subjects. One hundred and three subjects with normal colonoscopy entered the study. Waist circumference (WC) and body mass index (BMI) were measured, and MPO-positive cells on histological sections of biopsies of normal colorectal mucosa were counted under a light microscope. The occurrence of adenomas was then evaluated on follow-up colonoscopies. Mean MPO-positive cell count (±s.e.m.) was higher in subject with a WC equal or above the obesity cutoff values according to gender (2.63±0.20 vs 2.06±0.18, P=0.03), and in subjects with BMI equal or above 25 kg m - 2 (2.54±0.18 vs 1.97±0.20, P=0.03). A Cox proportional hazard model showed that mean MPO-positive cell count in normal colorectal mucosa was the only factor independently related to occurrence of adenomas in follow-up colonoscopies. Though preliminary, these results show that MPO-positive cell infiltration in normal colorectal mucosa is related with body fatness, as evaluated by WC and BMI, and it may be considered a useful and simple marker to estimate adenoma occurrence risk.

  11. Primary prevention of colorectal cancer.

    Science.gov (United States)

    Chan, Andrew T; Giovannucci, Edward L

    2010-06-01

    Colorectal cancer has been strongly associated with a Western lifestyle. In the past several decades, much has been learned about the dietary, lifestyle, and medication risk factors for this malignancy. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. For example, several studies have shown that high intake of red and processed meats, highly refined grains and starches, and sugars is related to increased risk of colorectal cancer. Replacing these factors with poultry, fish, and plant sources as the primary source of protein; unsaturated fats as the primary source of fat; and unrefined grains, legumes and fruits as the primary source of carbohydrates is likely to lower risk of colorectal cancer. Although a role for supplements, including vitamin D, folate, and vitamin B6, remains uncertain, calcium supplementation is likely to be at least modestly beneficial. With respect to lifestyle, compelling evidence indicates that avoidance of smoking and heavy alcohol use, prevention of weight gain, and maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and nonsteroidal anti-inflammatory drugs and postmenopausal hormones for women are associated with substantial reductions in colorectal cancer risk, though their utility is affected by associated risks. Taken together, modifications in diet and lifestyle should substantially reduce the risk of colorectal cancer and could complement screening in reducing colorectal cancer incidence.

  12. Downregulation of glutathione S-transferase M1 protein in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced mouse bladder carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Chuang, Jing-Jing [Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, Taiwan (China); Dai, Yuan-Chang [Department of Pathology, Chiayi Christian Hospital, Chiayi, Taiwan (China); Lin, Yung-Lun; Chen, Yang-Yi; Lin, Wei-Han [Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, Taiwan (China); Chan, Hong-Lin [Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, Hsinchu, Taiwan (China); Liu, Yi-Wen, E-mail: ywlss@mail.ncyu.edu.tw [Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, Taiwan (China)

    2014-09-15

    Bladder cancer is highly recurrent following specific transurethral resection and intravesical chemotherapy, which has prompted continuing efforts to develop novel therapeutic agents and early-stage diagnostic tools. Specific changes in protein expression can provide a diagnostic marker. In our present study, we investigated changes in protein expression during urothelial carcinogenesis. The carcinogen BBN was used to induce mouse bladder tumor formation. Mouse bladder mucosa proteins were collected and analyzed by 2D electrophoresis from 6 to 20 weeks after commencing continuous BBN treatment. By histological examination, the connective layer of the submucosa showed gradual thickening and the number of submucosal capillaries gradually increased after BBN treatment. At 12-weeks after the start of BBN treatment, the urothelia became moderately dysplastic and tumors arose after 20-weeks of treatment. These induced bladder lesions included carcinoma in situ and connective tissue invasive cancer. In protein 2D analysis, the sequentially downregulated proteins from 6 to 20 weeks included GSTM1, L-lactate dehydrogenase B chain, keratin 8, keratin 18 and major urinary proteins 2 and 11/8. In contrast, the sequentially upregulated proteins identified were GSTO1, keratin 15 and myosin light polypeptide 6. Western blotting confirmed that GSTM1 and NQO-1 were decreased, while GSTO1 and Sp1 were increased, after BBN treatment. In human bladder cancer cells, 5-aza-2′-deoxycytidine increased the GSTM1 mRNA and protein expression. These data suggest that the downregulation of GSTM1 in the urothelia is a biomarker of bladder carcinogenesis and that this may be mediated by DNA CpG methylation. - Highlights: • GSTM1 and NQO-1 proteins decreased in the mouse bladder mucosa after BBN treatment. • BBN induced GSTO1 and Sp1 protein expression in the mouse bladder mucosa. • 5-Aza-2′-deoxycytidine increased GSTM1 mRNA and protein in human bladder cancer cell. • GSTM1

  13. Social media in colorectal surgery.

    Science.gov (United States)

    Wexner, S D; Petrucci, A M; Brady, R R; Ennis-O'Connor, M; Fitzgerald, J E; Mayol, J

    2017-02-01

    The engagement of social media in healthcare continues to expand. For members of the colorectal community, social media has already made a significant impact on practice, education and patient care. The applications are unique such that they provide a platform for instant communication and information sharing with other users worldwide. The purpose of this article is to provide an overview of how social media has the potential to change clinical practice, training, research and patient care in colorectal surgery. Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.

  14. Reporting colorectal cancer.

    Science.gov (United States)

    Quirke, P; Morris, E

    2007-01-01

    The management of colorectal cancer is a team process. High-quality reporting of colorectal cancer is very important as the whole team relies upon the skill of the pathologist. Failure to report key features can lead to undertreatment of this disease. The use of a proforma has been demonstrated to be beneficial and we recommend staying with TNM5 due to scientific and reproducibility issues with TNM6. Important features in stage II/Dukes' B cases are extramural vascular invasion, peritoneal involvement, extent of extramural spread, incomplete resection and perforation. All of these may lead to adjuvant therapy being administered. The surgically created circumferential resection margin (CRM) and the mode of its creation are important features and the CRM retains its value after preoperative therapy. Regression grading should be applied only to fully resected tumours and the dissection and sampling must be standardized to allow comparison of results between trials and centres. When reporting local resections of early-stage cancers we need to look for features that predict spread to local lymph nodes to allow a full resection to be considered.

  15. Biomarkers in Autism

    Directory of Open Access Journals (Sweden)

    Robert eHendren

    2014-08-01

    Full Text Available Autism spectrum disorders (ASD are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression and measures of the body’s metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers.

  16. Meat, vegetables and genetic polymorphisms and the risk of colorectal carcinomas and adenomas

    International Nuclear Information System (INIS)

    Skjelbred, Camilla F; Sæbø, Mona; Hjartåker, Anette; Grotmol, Tom; Hansteen, Inger-Lise; Tveit, Kjell M; Hoff, Geir; Kure, Elin H

    2007-01-01

    The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population. We used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1, GSTT1, GSTP1 Ile 105 Val, EPHX1 Tyr 113 His and EPHX1 His 139 Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression. A higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2 nd quartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of the EPHX1 codon 113 polymorphism. An association was also observed for the EPHX1 codon 113 polymorphism in the low-risk adenomas, although not as obvious. Although, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma

  17. Does folic acid supplementation prevent or promote colorectal cancer? Results from model-based predictions.

    Science.gov (United States)

    Luebeck, E Georg; Moolgavkar, Suresh H; Liu, Amy Y; Boynton, Alanna; Ulrich, Cornelia M

    2008-06-01

    Folate is essential for nucleotide synthesis, DNA replication, and methyl group supply. Low-folate status has been associated with increased risks of several cancer types, suggesting a chemopreventive role of folate. However, recent findings on giving folic acid to patients with a history of colorectal polyps raise concerns about the efficacy and safety of folate supplementation and the long-term health effects of folate fortification. Results suggest that undetected precursor lesions may progress under folic acid supplementation, consistent with the role of folate role in nucleotide synthesis and cell proliferation. To better understand the possible trade-offs between the protective effects due to decreased mutation rates and possibly concomitant detrimental effects due to increased cell proliferation of folic acid, we used a biologically based mathematical model of colorectal carcinogenesis. We predict changes in cancer risk based on timing of treatment start and the potential effect of folic acid on cell proliferation and mutation rates. Changes in colorectal cancer risk in response to folic acid supplementation are likely a complex function of treatment start, duration, and effect on cell proliferation and mutations rates. Predicted colorectal cancer incidence rates under supplementation are mostly higher than rates without folic acid supplementation unless supplementation is initiated early in life (before age 20 years). To the extent to which this model predicts reality, it indicates that the effect on cancer risk when starting folic acid supplementation late in life is small, yet mostly detrimental. Experimental studies are needed to provide direct evidence for this dual role of folate in colorectal cancer and to validate and improve the model predictions.

  18. Epigenomic diversity of colorectal cancer indicated by LINE-1 methylation in a database of 869 tumors

    Directory of Open Access Journals (Sweden)

    Schernhammer Eva S

    2010-05-01

    Full Text Available Abstract Background Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. LINE-1 (L1 retrotransposon constitutes a substantial portion of the human genome, and LINE-1 methylation correlates with global DNA methylation status. LINE-1 hypomethylation in colon cancer has been strongly associated with poor prognosis. However, whether LINE-1 hypomethylators constitute a distinct cancer subtype remains uncertain. Recent evidence for concordant LINE-1 hypomethylation within synchronous colorectal cancer pairs suggests the presence of a non-stochastic mechanism influencing tumor LINE-1 methylation level. Thus, it is of particular interest to examine whether its wide variation can be attributed to clinical, pathologic or molecular features. Design Utilizing a database of 869 colorectal cancers in two prospective cohort studies, we constructed multivariate linear and logistic regression models for LINE-1 methylation (quantified by Pyrosequencing. Variables included age, sex, body mass index, family history of colorectal cancer, smoking status, tumor location, stage, grade, mucinous component, signet ring cells, tumor infiltrating lymphocytes, CpG island methylator phenotype (CIMP, microsatellite instability, expression of TP53 (p53, CDKN1A (p21, CTNNB1 (β-catenin, PTGS2 (cyclooxygenase-2, and FASN, and mutations in KRAS, BRAF, and PIK3CA. Results Tumoral LINE-1 methylation ranged from 23.1 to 90.3 of 0-100 scale (mean 61.4; median 62.3; standard deviation 9.6, and distributed approximately normally except for extreme hypomethylators [LINE-1 methylation Conclusions LINE-1 extreme hypomethylators appear to constitute a previously-unrecognized, distinct subtype of colorectal cancers, which needs to be confirmed by additional studies. Our tumor LINE-1 methylation data indicate enormous epigenomic diversity of individual colorectal cancers.

  19. Targeting metastatic colorectal cancer – present and emerging treatment options

    Directory of Open Access Journals (Sweden)

    Ciombor KK

    2014-07-01

    Full Text Available Kristen K Ciombor,1 Jordan Berlin21Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; 2Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USAAbstract: Metastatic colorectal cancer is a significant cause of morbidity and mortality in the US and around the world. While several novel cytotoxic and biologic therapies have been developed and proven efficacious in the past two decades, their optimal use in terms of patient selection, drug combinations, and regimen sequences has yet to be defined. Recent investigations regarding anti-epidermal growth factor receptor therapies include the comparison of single-agent panitumumab and cetuximab, the benefit of adding cetuximab to chemotherapy in the conversion therapy setting, the comparison of cetuximab and bevacizumab when added to first-line chemotherapy, and predictive biomarkers beyond KRAS exon 2 (codons 12 and 13 mutations. With respect to anti-vascular endothelial growth factor therapies, new data on continuing bevacizumab beyond disease progression on a bevacizumab-containing chemotherapy regimen, the addition of bevacizumab to triplet chemotherapy in the first-line setting, maintenance therapy with bevacizumab plus either capecitabine or erlotinib, the addition of aflibercept to chemotherapy, and regorafenib as monotherapy have emerged. Recent scientific and technologic advances in the field of metastatic colorectal cancer promise to elucidate the biological underpinnings of this disease and its therapies for the goal of improving personalized treatments for patients with metastatic colorectal cancer.Keywords: cetuximab, panitumumab, bevacizumab, aflibercept, regorafenib, biomarker

  20. The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study

    DEFF Research Database (Denmark)

    Andersen, V.; Agerstjerne, L.; Jensen, D.

    2009-01-01

    Background: Smoking, dietary factors, and alcohol consumption are known life style factors contributing to gastrointestinal carcinogenesis. Genetic variations in carcinogen handling may affect cancer risk. The multidrug resistance 1(MDR1/ABCB1) gene encodes the transport protein P-glycoprotein (a...... in inflammation, and may thereby affect the risk of malignity. Hence, genetic variations that modify the function of P-glycoprotein may be associated with the risk of colorectal cancer (CRC). We have previously found an association between the MDR1 intron 3 G-rs3789243-A polymorphism and the risk of CRC...... of colorectal carcinomas and adenomas in the Norwegian population was assessed in 167 carcinomas, 990 adenomas, and 400 controls. Genotypes were determined by allelic discrimination. Odds ratio (OR) and 95 confidence interval (95% CI) were estimated by binary logistic regression. Results: No association...

  1. Diagnostic Ultrasound in Colorectal Cancer

    DEFF Research Database (Denmark)

    Rafaelsen, Søren Rafael

    2014-01-01

    SUMMARYBackground and purpose Colorectal cancer is a common disease in Denmark with considerable morbidity and mortality. Although survival in recent years has improved, Denmark still has the lowest 5-year survival compared to the other Nordic countries. The treatment of patients depends on local...... the potential to contribute to the staging of colorectal cancer. The purpose of these studies was to determine the usefulness of ultrasound diagnostics in patients with colorectal cancer.The purpose of the TRUS studies was to compare staging of rectal carcinomas using digital rectal exploration...... of 295 patients with primary colorectal cancer we found a sensitivity of preoperative ultrasound, surgical exploration, and intraoperative ultrasound of 70%, 84%, and 97%, respectively, based on a patient-by-patient comparison (p

  2. Danish Colorectal Cancer Group Database

    DEFF Research Database (Denmark)

    Ingeholm, Peter; Gögenur, Ismail; Iversen, Lene H

    2016-01-01

    AIM OF DATABASE: The aim of the database, which has existed for registration of all patients with colorectal cancer in Denmark since 2001, is to improve the prognosis for this patient group. STUDY POPULATION: All Danish patients with newly diagnosed colorectal cancer who are either diagnosed......, and other pathological risk factors. DESCRIPTIVE DATA: The database has had >95% completeness in including patients with colorectal adenocarcinoma with >54,000 patients registered so far with approximately one-third rectal cancers and two-third colon cancers and an overrepresentation of men among rectal...... diagnosis, surgical interventions, and short-term outcomes. The database does not have high-resolution oncological data and does not register recurrences after primary surgery. The Danish Colorectal Cancer Group provides high-quality data and has been documenting an increase in short- and long...

  3. Colorectal Anastomotic Leakage: New perspectives

    NARCIS (Netherlands)

    F. Daams (Freek)

    2014-01-01

    markdownabstract__Abstract__ This thesis provides new perspectives on colorectal anastomotic leakages. In both experimental and clinical studies, aspects of prevention, early identification, treatment and consequences of anastomotic leakage are discussed.

  4. Obesity and colorectal cancer risk

    International Nuclear Information System (INIS)

    Hano Garcia, Olga Marina; Wood Rodriguez, Lisette; Villa Jimenez, Oscar Manuel

    2011-01-01

    Obesity is a chronic and multifactor disease characterized by presence of excess body fat harmful for health. Several studies have been conducted to assess the possible risk character of different factors for colorectal cancer including the following modifying factors: a diet rich in saturated fats, a diet low in vegetables, physical inactivity, alcohol consumption and obesity. A case-control study was conducted to include 276 adult patients (93 cases and 184 controls) consecutively seen from May, 2008 to May, 2009 in the Institute of Gastroenterology determining a possible association between obesity as risk factor and colorectal cancer. Variables measures included: sex, age, skin color, body mass index, hip-waist circumference and endoscopic location of cancer. We conclude that the colorectal cancer with predominance in female sex and in white people in both groups. Obesity according to a great relation hip-waist had an strong relation with colorectal cancer, which had predominance towards distal colon in both sexes

  5. Telomerase activity and telomere length in the colorectal polyp-carcinoma sequence Actividad de la telomerasa y longitud del telómero en la secuencia pólipo-carcinoma colorrectal

    OpenAIRE

    C. Valls Bautista; C. Piñol Felis; J. M. Reñe Espinet; J. Buenestado García; J. Viñas Salas

    2009-01-01

    Objective: the role of telomerase activity and telomere length in the adenoma-carcinoma sequence of colon carcinogenesis has not been well established. The objective of this study was to determine telomerase activity and telomere length patterns in patients with adenomatous polyps either associated or not with colorectal cancer, as well as the role of telomeric instability in the adenoma-carcinoma sequence. Patients and methods: we included in the study 14 patients who underwent surgery for c...

  6. Brain metastases from colorectal cancer

    DEFF Research Database (Denmark)

    Vagn-Hansen, Chris Aksel; Rafaelsen, Søren Rafael

    2001-01-01

    Brain metastases from colorectal cancer are rare. The prognosis for patients with even a single resectable brain metastasis is poor. A case of surgically treated cerebral metastasis from a rectal carcinoma is reported. The brain tumour was radically resected. However, cerebral, as well...... as extracerebral, disease recurred 12 months after diagnosis. Surgical removal of colorectal metastatic brain lesions in selected cases results in a longer survival time....

  7. Familial colorectal cancer type X

    DEFF Research Database (Denmark)

    Dominguez-Valentin, Mev; Therkildsen, Christina; Da Silva, Sabrina

    2015-01-01

    Heredity is a major cause of colorectal cancer, but although several rare high-risk syndromes have been linked to disease-predisposing mutations, the genetic mechanisms are undetermined in the majority of families suspected of hereditary cancer. We review the clinical presentation, histopathologic...... features, and the genetic and epigenetic profiles of the familial colorectal cancer type X (FCCTX) syndrome with the aim to delineate tumor characteristics that may contribute to refined diagnostics and optimized tumor prevention....

  8. EPIDEMIOLOGICAL EVALUATION OF COLORECTAL CANCER

    OpenAIRE

    B. Shafayan M. Keyhani

    2003-01-01

    This study was carried out to analyze certain epidemiological variations in Iranian patients with colorectal cancer. (CRC): From March 1981 up to March 1993, 103 patients were analyzed retrospectively for age, gender, marital state, job, nutritional habits, presenting symptoms and histopathological features. Most of the patients with colorectal cancer were male, age range 20-75 (mean 56), 25.4 percent were long-term smokers and bleeding was the most common symptom. The rectum was the most com...

  9. Cyclooxygenase as a target for chemoprevention in colorectal cancer: lost cause or a concept coming of age?

    LENUS (Irish Health Repository)

    Doherty, Glen A

    2009-02-01

    COX-2 is upregulated at an early stage in colorectal carcinogenesis and generates prostaglandins, which promote cancer cell proliferation, impair apoptosis and enhance angiogenesis, promoting tumour growth and metastasis. There are ample data from animal models and human studies to demonstrate enhanced tumour progression associated with COX-2 activity in cancer cells. Conversely, NSAIDs including aspirin inhibit COX-2 and, therefore, have anti-neoplastic properties. There has been sustained interest in COX-2 as a chemopreventive target in colorectal cancer (CRC) and although both aspirin and COX-2 selective NSAIDs have demonstrated efficacy, adverse effects have limited their widespread adoption. In particular, evidence of the cardiovascular effects of COX-2 selective inhibitors has led to questioning of the suitability of COX-2 as a target for chemoprevention. This review examines the basis for targeting COX-2 in CRC chemoprevention, evaluates the efficacy and safety of the approach and examines future strategies in this area.

  10. Alterations in mtDNA, gastric carcinogenesis and early diagnosis.

    Science.gov (United States)

    Rodrigues-Antunes, S; Borges, B N

    2018-05-26

    Gastric cancer remains one of the most prevalent cancers in the world. Due to this, efforts are being made to improve the diagnosis of this neoplasm and the search for molecular markers that may be involved in its genesis. Within this perspective, the mitochondrial DNA is considered as a potential candidate, since it has several well documented changes and is readily accessible. However, numerous alterations have been reported in mtDNA, not facilitating the visualization of which alterations and molecular markers are truly involved with gastric carcinogenesis. This review presents a compilation of the main known changes relating mtDNA to gastric cancer and their clinical significance.

  11. Perspectives in the paradigm of radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Sugakhara, T.; Vatanabe, M.; Niva, O.; Nikajdo, O.

    1995-01-01

    Carcinogenesis is analysed as a multistage process consisting of initiation, promotion and progression. This model includes the mutation of oncogenes and the loss of hetrezygosity by tumor-suppressor genes. The threshold concept of radiation cancerogenesis is proposed, under which ionizing radiation can induce in somatic cell genetic effects a s result of DNA damage and epigenetic changes as well. The epigenetic changes (through DNA or cytoplasma) can be stabilized as mutations observed in many cancer cells and play a dominant role in radiation cancerogenesis induction. The ration of epigenetic and genetic effects largely depends on radiation doses

  12. Bacterial infection increases risk of carcinogenesis by targeting mitochondria

    DEFF Research Database (Denmark)

    Strickertsson, Jesper A.B.; Desler, Claus; Rasmussen, Lene Juel

    2017-01-01

    pathways, and compares the impact of the bacterial alteration of mitochondrial function to that of cancer. Bacterial virulence factors have been demonstrated to induce mutations of mitochondrial DNA (mtDNA) and to modulate DNA repair pathways of the mitochondria. Furthermore, virulence factors can induce...... or impair the intrinsic apoptotic pathway. The effect of bacterial targeting of mitochondria is analogous to behavior of mitochondria in a wide array of tumours, and this strongly suggests that mitochondrial targeting of bacteria is a risk factor for carcinogenesis....

  13. The PTEN/NRF2 Axis Promotes Human Carcinogenesis

    DEFF Research Database (Denmark)

    Rojo, Ana I; Rada, Patricia; Mendiola, Marta

    2014-01-01

    and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1). INNOVATION: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3....../β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas. CONCLUSION: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514....

  14. Etiologic related studies of ultraviolet light-mediated carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Black, H S; Chan, J T

    1976-01-01

    Comparisons were made of cholesterol-5..cap alpha.. 6..cap alpha..-epoxide (CAE) levels in skin of hairless mice maintained on a regular or antioxidant supplemented diet and receiving chronic ultraviolet light (UVL) radiation over an 18-week period. Cholesterol-5..cap alpha.., 6..cap alpha..-epoxide levels in skin of animals on antioxidant supplemented diet, while reaching a peak four weeks after that of animals on regular diet, thereafter were consistently higher. Dietary antioxidants nevertheless had an inhibitory effect on UVL-induced tumors. These data are inconsistent with the theory of CAE involvement as an ultimate carcinogen in UVL-mediated carcinogenesis.

  15. Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients

    International Nuclear Information System (INIS)

    Diaz Rubio Garcia, E.

    2009-01-01

    The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the antiEGFR monoclonal antibodies (cetuximab and panitumumab) have emerged in combination with the standard cytotoxic chemotherapy (FOLFOX and FOLFIRI). However, the benefit from cetuximab and panitumumab is only confined to KRAS-wild type (KRAS-wt) colorectal tumors, while KRAS mutated tumors do not respond to these drugs. The 65 % of colorectal tumors are KRAS-wt tumors, but efficacy of antiEGFR therapies is detected only in 60-70 % of these KRAS-wt tumors. Other biomarkers and molecular pathways must be involved in the response of the antiEGFR therapies for the KRAS-wt colorectal tumors, such as the EGFR ligands, the EGFR-phosphorilated levels, the number of EGFR copies, the status of the KRAS effected B-RAF and the alternative intracellular signaling pathways PIK3CA/PTEN/AKT and JAK/STAT. A battery of these biomarkers is needed to select the most sensitive patients to the antiEGFR therapies. This pattern may represent a novel favorable cost-effectiveness tool to develop tailored treatments. A review of these biomarkers and molecular pathways, involved in the antiEGFR therapies response, is performed. (Author) 68 refs.

  16. MicroRNA7 expression in exhaled breath condensate of smokers with chronic obstructive pulmonary disease: A potential biomarker?

    OpenAIRE

    Nevine Abd Elfattah; R. Ali-Labib

    2017-01-01

    Rationale: The global burden of lung cancer is attributed to its poor outcome as it is usually discovered in an advanced stage therefore the constant search for screening protocols among the high risk groups like smokers and chronic obstructive pulmonary disease (COPD). Biomarker testing in exhaled breath condensate (EBC) samples is a simple inexpensive non invasive method. Many previous researches linked the dys-Regulation of microRNAs to the development of lung carcinogenesis. Consequently ...

  17. Prognostic biomarkers in osteoarthritis

    Science.gov (United States)

    Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan; Abramson, Steven B.

    2013-01-01

    Purpose of review Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. Recent findings The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Summary Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs). PMID:23169101

  18. Progastrin: a potential predictive marker of liver metastasis in colorectal cancer.

    Science.gov (United States)

    Westwood, David A; Patel, Oneel; Christophi, Christopher; Shulkes, Arthur; Baldwin, Graham S

    2017-07-01

    Staging of colorectal cancer often fails to discriminate outcomes of patients with morphologically similar tumours that exhibit different clinical behaviours. Data from several studies suggest that the gastrin family of growth factors potentiates colorectal cancer tumourigenesis. The aim of this study was to investigate whether progastrin expression may predict clinical outcome in colorectal cancer. Patients with colorectal adenocarcinoma of identical depth of invasion who had not received neoadjuvant therapy were included. The patients either had stage IIa disease with greater than 3-year disease-free survival without adjuvant therapy or stage IV disease with liver metastases on staging CT. Progastrin expression in tumour sections was scored with reference to the intensity and area of immunohistochemical staining. Progastrin expression by stage IV tumours was significantly greater than stage IIa tumours with mean progastrin immunopositivity scores of 2.1 ± 0.2 versus 0.5 ± 0.2, respectively (P colorectal cancer and supports its clinical relevance and potential use as a biomarker.

  19. The Genome-Wide Analysis of Carcinoembryonic Antigen Signaling by Colorectal Cancer Cells Using RNA Sequencing.

    Directory of Open Access Journals (Sweden)

    Olga Bajenova

    Full Text Available Сarcinoembryonic antigen (CEA, CEACAM5, CD66 is a promoter of metastasis in epithelial cancers that is widely used as a prognostic clinical marker of metastasis. The aim of this study is to identify the network of genes that are associated with CEA-induced colorectal cancer liver metastasis. We compared the genome-wide transcriptomic profiles of CEA positive (MIP101 clone 8 and CEA negative (MIP 101 colorectal cancer cell lines with different metastatic potential in vivo. The CEA-producing cells displayed quantitative changes in the level of expression for 100 genes (over-expressed or down-regulated. They were confirmed by quantitative RT-PCR. The KEGG pathway analysis identified 4 significantly enriched pathways: cytokine-cytokine receptor interaction, MAPK signaling pathway, TGF-beta signaling pathway and pyrimidine metabolism. Our results suggest that CEA production by colorectal cancer cells triggers colorectal cancer progression by inducing the epithelial- mesenchymal transition, increasing tumor cell invasiveness into the surrounding tissues and suppressing stress and apoptotic signaling. The novel gene expression distinctions establish the relationships between the existing cancer markers and implicate new potential biomarkers for colorectal cancer hepatic metastasis.

  20. Robotics in Colorectal Surgery

    Science.gov (United States)

    Weaver, Allison; Steele, Scott

    2016-01-01

    Over the past few decades, robotic surgery has developed from a futuristic dream to a real, widely used technology. Today, robotic platforms are used for a range of procedures and have added a new facet to the development and implementation of minimally invasive surgeries. The potential advantages are enormous, but the current progress is impeded by high costs and limited technology. However, recent advances in haptic feedback systems and single-port surgical techniques demonstrate a clear role for robotics and are likely to improve surgical outcomes. Although robotic surgeries have become the gold standard for a number of procedures, the research in colorectal surgery is not definitive and more work needs to be done to prove its safety and efficacy to both surgeons and patients. PMID:27746895

  1. Molecular genetics of colorectal cancer Genética molecular del cáncer colorrectal

    Directory of Open Access Journals (Sweden)

    D. Cruz-Bustillo Clarens

    2004-01-01

    Full Text Available Colorectal tumours constitute an excellent system to study carcinogenesis and the molecular events implicated in the development of cancer. Attending to the way it is transmitted, colorectal cancer may appear in one of three forms: sporadic, familial, and hereditary. The sporadic form is most common and has no familial or hereditary associated factor thus far, while familial and hereditary forms show the same inheritance pattern. Hereditary colorectal cancers develop by means of defined stages that go from lesions in the crypt of the colon through adenomas to manifest cancer. They are characterised by the accumulation of multiple mutations in tumour suppressor genes and oncogenes that affect the balance between cell proliferation and apoptosis. The colorectal carcinogenesis pathway is not unique and there are probably several ways for the initiation, development and progression of colorectal tumours.Los tumores colorrectales constituyen un excelente sistema para estudiar la carcinogénesis y los eventos moleculares involucrados en el desarrollo de un tumor. El cáncer colorrectal puede presentarse en tres formas, según su forma de transmisión: esporádico, familiar y hereditario. La forma esporádica que es la mayoritaria, no tiene hasta el momento ningún factor familiar o hereditario asociado, mientras que las formas familiares y hereditarias siguen un patrón de herencia en la propensión familiar a padecerlo. Los cánceres colorrectales hereditarios se desarrollan mediante etapas definidas que van desde lesiones en la cripta del colon a través de adenomas hasta manifestar el cáncer y se caracterizan por la acumulación de múltiples mutaciones en genes supresores de tumor y oncogenes que afectan el balance entre la proliferación celular y la apoptosis. La vía de carcinogénesis colorrectal no es una sola y probablemente existan varios caminos para el inicio, desarrollo y progresión de un tumor colorrectal.

  2. Polyyne-Enriched Extract from Oplopanax elatus Significantly Ameliorates the Progression of Colon Carcinogenesis in ApcMin/+ Mice

    Directory of Open Access Journals (Sweden)

    Xin Qiao

    2017-09-01

    Full Text Available Colorectal cancer (CRC is the third most common cancer in the world. Oplopanax elatus is widely used in traditional medicine. However, little is known about its pharmacological effects and bioactive compounds. We evaluated the effects of the polyyne-enriched extract from O. elatus (PEO on the progression of colon carcinogenesis in ApcMin/+ mice. In addition, these effects were also investigated in HCT116 and SW480 cells. After PEO oral administration (0.2% diet for 12 weeks, PEO significantly improved body weight changes and reduced the tumor burden and tumor multiplicity compared with the untreated mice. Meanwhile, western blot and immunohistochemistry results showed PEO significantly reduced the expression of β-catenin and cyclinD1 in both small intestine and the colon tissues compared with the untreated mice. In addition, PEO treatment significant decreased the cell viability in both HCT116 and SW480 cell lines. It also decreased the levels of β-catenin, cyclinD1, c-myc and p-GSK-3β in HCT116 and SW480 cells at 25 μM. These results indicate that PEO may have potential value in prevention of colon cancer by down-regulating Wnt-related protein.

  3. Colorectal Cancer: Prognostic Values

    Directory of Open Access Journals (Sweden)

    Suzana Manxhuka-Kerliu

    2009-02-01

    Full Text Available After lung cancer colorectal cancer (Cc is ranked the second, as a cause of cancer-related death. The purpose of this study was to analyze the Cc cases in our material with respect to all prognostic values including histological type and grade, vascular invasion, perineural invasion, and tumor border features. There were investigated 149 cases of resection specimen with colorectal cancer, which were fixed in buffered neutral formalin and embedded in paraffin. Tissue sections (4(µm thick were cut and stained with H&E. Adenocarcinoma was the most frequent histological type found in 85,90% of cases, in 60,94% of males and 39,06% of females; squamous cell carcinoma in 7,38%, in 63,63% of males and 36,36% of females; mucinous carcinoma in 4,68%, in 57,15% of males and 42,85% of females; while adenosquamous carcinoma, undifferentiated carcinoma and carcinoma in situ in 0,71% of cases each. Dukes' classification was used in order to define the depth of invasion. Dukes B was found in 68,45% of cases, whereas in 31,54% of cases Dukes C was found. As far as histological grading is concerned, Cc was mostly with moderate differentiation (75,16% with neither vascular nor perineural invasion. Resection margins were in all cases free of tumor. Our data indicate that the pathologic features of the resection specimen constitute the most powerful predictors of postoperative outcome in Cc. Dukes' stage and degree of differentiation provide independent prognostic information in Cc. However, differentiation should be assessed by the worst pattern.

  4. Identification of α(1,6)fucosylated proteins differentially expressed in human colorectal cancer

    International Nuclear Information System (INIS)

    Muinelo-Romay, Laura; Villar-Portela, Susana; Cuevas, Elisa; Gil-Martín, Emilio; Fernández-Briera, Almudena

    2011-01-01

    A universal hallmark of cancer cells is the change in their glycosylation phenotype. One of the most frequent alterations in the normal glycosylation pattern observed during carcinogenesis is the enhancement of α(1,6)linked fucose residues of glycoproteins, due to the up-regulation of the α(1,6)fucosyltransferase activity. Our previous results demonstrated the specific alteration of this enzyme activity and expression in colorectal cancer, suggesting its implication in tumour development and progression. In the current work we combined a LCA-affinity chromatography with SDS-PAGE and mass spectrometry in order to identify α(1,6)fucosylated proteins differentially expressed in colorectal cancer. This strategy allowed the identification of a group of α(1,6)fucosylated proteins candidates to be involved in CRC malignancy. The majority of the identified proteins take part in cell signaling and interaction processes as well as in modulation of the immunological response. Likewise, we confirmed the increased expression of GRP94 in colorectal cancer tissue and the significant down-regulation of the IgGFcBP expression in tumour cells. All these results validate the importance of core-fucosylated proteins profile analysis to understand the mechanisms which promote cancer onset and progression and to discover new tumour markers or therapeutic targets

  5. Expression profiling of colorectal cancer cells reveals inhibition of DNA replication licensing by extracellular calcium.

    Science.gov (United States)

    Aggarwal, Abhishek; Schulz, Herbert; Manhardt, Teresa; Bilban, Martin; Thakker, Rajesh V; Kallay, Enikö

    2017-06-01

    Colorectal cancer is one of the most common cancers in industrialised societies. Epidemiological studies, animal experiments, and randomized clinical trials have shown that dietary factors can influence all stages of colorectal carcinogenesis, from initiation through promotion to progression. Calcium is one of the factors with a chemoprophylactic effect in colorectal cancer. The aim of this study was to understand the molecular mechanisms of the anti-tumorigenic effects of extracellular calcium ([Ca 2+ ] o ) in colon cancer cells. Gene expression microarray analysis of colon cancer cells treated for 1, 4, and 24h with 2mM [Ca 2+ ] o identified significant changes in expression of 1571 probe sets (ANOVA, pcalcium-sensing receptor (CaSR), a G protein-coupled receptor is a mediator involved in this process. To test whether these results were physiologically relevant, we fed mice with a standard diet containing low (0.04%), intermediate (0.1%), or high (0.9%) levels of dietary calcium. The main molecules regulating replication licensing were inhibited also in vivo, in the colon of mice fed high calcium diet. We show that among the mechanisms behind the chemopreventive effect of [Ca 2+ ] o is inhibition of replication licensing, a process often deregulated in neoplastic transformation. Our data suggest that dietary calcium is effective in preventing replicative stress, one of the main drivers of cancer and this process is mediated by the calcium-sensing receptor. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Are there tumor suppressor genes on chromosome 4p in sporadic colorectal carcinoma?

    Science.gov (United States)

    Zheng, Hai-Tao; Jiang, Li-Xin; Lv, Zhong-Chuan; Li, Da-Peng; Zhou, Chong-Zhi; Gao, Jian-Jun; He, Lin; Peng, Zhi-Hai

    2008-01-07

    To study the candidate tumor suppressor genes (TSG) on chromosome 4p by detecting the high frequency of loss of heterozygosity (LOH) in sporadic colorectal carcinoma in Chinese patients. Seven fluorescent labeled polymorphic microsatellite markers were analyzed in 83 cases of colorectal carcinoma and matched normal tissue DNA by PCR. PCR products were electrophoresed on an ABI 377 DNA sequencer. Genescan 3.7 and Genotype 3.7 software were used for LOH scanning and analysis. The same procedure was performed by the other six microsatellite markers spanning D4S3013 locus to make further detailed deletion mapping. Comparison between LOH frequency and clinicopathological factors was performed by c2 test. Data were collected from all informative loci. The average LOH frequency on 4p was 24.25%, and 42.3% and 35.62% on D4S405 and D4S3013 locus, respectively. Adjacent markers of D4S3013 displayed a low LOH frequency (4p15.2) and D4S405 (4p14) locus are detected. Candidate TSG, which is involved in carcinogenesis and progression of sporadic colorectal carcinoma on chromosome 4p, may be located between D4S3017 and D4S2933 (about 1.7 cm).

  7. [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.

  8. Is radiation an appropriate model for chemical mutagenesis and carcinogenesis

    International Nuclear Information System (INIS)

    Bond, V.P.

    1982-01-01

    This chapter attempts to show why the quadratic, or ''linear quadratic,'' relationship holds for organ dose-single cell radiation effects, and to explore the extension of this relationship to chemical exposures in general. Demonstrates that although the ''αD + βD 2 relationship'' may be unexpected for normal pharmacologicalmedical dose-response relationships, a linear, no-threshold curve of this kind is expected for all stochastic-type (accidental or risk) situations with health consequences (e.g. all common accidents) including exposure to ''low-level radiation'' (LLR). Discusses the stochastic or risk approach, relevant radiobiology, and the stochastic for chemicals. Assumes that even though actual mutational rates cannot be expected to apply to the relevance of Tradescantia or any other single cell system as a predictor for mutagenesis and carcinogenesis in animals and man, the cardinal principles of genetics largely transcend species and the particular environment in which the cell is located. Concludes that with regard to LLR, the curve shapes and other relationships developed for Tradescantia would be expected to apply in principle to animal and human mutagenesis and carcinogenesis

  9. Etoricoxib in the Prevention of Rat Mammary Carcinogenesis

    Directory of Open Access Journals (Sweden)

    P. Orendáš

    2007-01-01

    Full Text Available Several experimental studies suggest that non-steroidal antiinflammatory drugs have chemopreventive effects in mammary carcinogenesis. In this study, tumour suppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2 etoricoxib in the prevention of N-methyl-Nnitrosourea (NMU-induced mammary carcinogenesis in Sprague-Dawley rats were evaluated. Etoricoxib was administered in the diet, at two concentrations: 1 0.01 mg/g (ETO 0.001% and 2 0.025 mg/g (ETO 0.0025%. Although the chemopreventive effects were not statistically significant, remarkable tumour suppressive effects with the concentration of ETO 0.0025% were recorded. The incidence decreased by 4.31% and tumour frequency per group decreased by 6.67% when compared to the control group. Latency (the period from carcinogen administration to the first tumour appearance increased by 7.28% in dose-dependent manner. The results of our experiments point to dose-dependent tumour suppressive effects of a higher concentration of etoricoxib (ETO 0.0025% when compared to the control group. They suggest that higher etoricoxib concentrations may enhance its tumour suppressive effects.

  10. Experimental photoimmunology: immunologic ramifications of UV-induced carcinogenesis

    International Nuclear Information System (INIS)

    Daynes, R.A.; Bernhard, E.J.; Gurish, M.F.; Lynch, D.H.

    1981-01-01

    The use of animal model systems to investigate the sequence of events which lead to the induction and progression of skin tumors following chronic ultraviolet light (UVL) exposure has clearly shown that the direct mutagenic effects of UVL is only one of the components involved in this process. In spite of the fact that overt carcinogenesis is only one of the many effects produced by UV light, most hypotheses as to the mechanism by which UVL can cause the mutations necessary to achieve the transformed phenotype have focused on the direct effects of UVL on DNA and the generation of carcinogenic compounds. Investigations during the last 5 yr, however, have clearly demonstrated that immunologic factors are also critically important in the pathogenesis of UV-induced skin cancers. A complete understanding of UV-carcinogenesis must therefore consider the mechanisms which allow the transformed cell to evade immunologic rejection by the host in addition to those aspects which deal with conversion of a normal cell to a cancer cell. It is the object of this review to provide both a historical account of the work which established the immunologic consequences of chronic UVL exposure and the results of recent experiments designed to investigate the kinetics and mechanisms by which UVL affects the immunologic apparatus. In addition, a hypothetical model is presented to explain the sequence of events which ultimately lead to the emergence of the suppressor T-cells which regulate antitumor immune responses

  11. Inherent aerobic capacity-dependent differences in breast carcinogenesis.

    Science.gov (United States)

    Thompson, Henry J; Jones, Lee W; Koch, Lauren G; Britton, Steven L; Neil, Elizabeth S; McGinley, John N

    2017-09-01

    Although regular physical activity is associated with improvement in aerobic capacity and lower breast cancer risk, there are heritable sets of traits that affect improvement in aerobic capacity in response to physical activity. Although aerobic capacity segregates risk for a number of chronic diseases, the effect of the heritable component on cancer risk has not been evaluated. Therefore, we investigated breast carcinogenesis in rodent models of heritable fitness in the absence of induced physical activity. Female offspring of N:NIH rats selectively bred for low (LIAC) or high (HIAC) inherent aerobic capacity were injected intraperitoneally with 1-methyl-1-nitrosurea (70 mg/kg body wt). At study termination 33 weeks post-carcinogen, cancer incidence (14.0 versus 47.3%; P < 0.001) and multiplicity (0.18 versus 0.85 cancers per rat; P < 0.0001) were significantly decreased in HIAC versus LIAC rats, respectively. HIAC had smaller visceral and subcutaneous body fat depots than LIAC and activity of two proteins that regulated the mammalian target of rapamycin, protein kinase B (Akt), and adenosine monophosphate-activated protein kinase were suppressed and activated, respectively, in HIAC. Although many factors distinguish between HIAC and LIAC, it appears that the protective effect of HIAC against breast carcinogenesis is mediated, at least in part, via alterations in core metabolic signaling pathways deregulated in the majority of human breast cancers. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Glutaminolysis and carcinogenesis of oral squamous cell carcinoma.

    Science.gov (United States)

    Cetindis, Marcel; Biegner, Thorsten; Munz, Adelheid; Teriete, Peter; Reinert, Siegmar; Grimm, Martin

    2016-02-01

    Glutaminolysis is a crucial factor for tumor metabolism in the carcinogenesis of several tumors but has not been clarified for oral squamous cell carcinoma (OSCC) yet. Expression of glutaminolysis-related solute carrier family 1, member 5 (SLC1A5)/neutral amino acid transporter (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLDH) was analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry. SLC1A5/ASCT2 and GLS were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue, while GLDH was weakly detected. Compared with SIN I-III SLC1A5/ASCT2 and GLS expression were significantly increased in OSCC. GLDH expression did not significantly differ from SIN I-III compared with OSCC. This study shows the first evidence of glutaminolysis-related SLC1A5/ASCT2, GLS, and GLDH expression in OSCC. The very weak GLDH expression indicates that glutamine metabolism is rather related to nucleotide or protein/hexosamine biosynthesis or to the function as an antioxidant (glutathione) than to energy production or generation of lactate through entering the tricarboxylic acid cycle. Overcoming glutaminolysis by targeting c-Myc oncogene (e.g. by natural compounds) and thereby cross-activation of mammalian target of rapamycin complex 1 or SLC1A5/ASCT2, GLS inhibitors may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

  13. 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

  14. Role of the chronic bacterial infection in urinary bladder carcinogenesis

    International Nuclear Information System (INIS)

    Higgy, N.A.

    1985-01-01

    The purpose of this thesis was to determine whether or not bacterial infection of the urinary bladder had a role in urinary bladder carcinogenesis. To investigate this proposition, four separate studies were conducted. The first study developed an experimental animal model where bacterial infection of the urinary bladder could be introduced and maintained for a period in excess of one year. The method of infection, inoculation of bacteria (Escherichia coli type 04) subserosally into the vesical wall, successfully caused persistent infection in the majority of animals. In the second study the temporal effects of bacterial infection on the induction of urothelial ornithine decarboxylase (ODC) and 3 H-thymidine uptake and DNA synthesis were examined. Bacterial infection of the urinary bladder induced urothelial ODC with a peak in enzyme activity 6 hr after infection. 3 H-Thymidine uptake and DNA synthesis peaked 48 hr after infection and coincided with the urothelial hyperplasia that occurred in response to the infection. In the third study the specific bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was given to rats concurrent with the urinary bacterial infection. In the fourth study rats were administered sodium nitrate and either dibutylamine or piperazine in the drinking water. The infected group developed bladder tumors while none were detected in the non-infected rats. From these studies it may be concluded that bacterial infection may have a significant role in the process of urinary bladder carcinogenesis

  15. International Activities in Radiation-Induced Carcinogenesis. Survey Paper

    Energy Technology Data Exchange (ETDEWEB)

    Komarov, E. [World Health Organization, Geneva (Switzerland)

    1969-11-15

    During the past 10 years special attention has been paid to the problem of late effects of radiation and in particular to radiation-induced carcinogenesis and leukaemogenesis. In the UNSCEAR report of 1958-1962 this.problem was mentioned as being of considerable importance from the point of view of estimation of risk to the population from environmental radiation. In 1964 a special report was prepared by UNSCEAR on radiation- induced carcinogenesis. In the ICRP publication No. 8, a chapter dealing with assessment of somatic risks discussed the problem of leukaemia and other neoplasms and particularly stressed the problem of thyroid carcinoma-and bone sarcoma. WHO panels of experts discussed the problem in 1960-1966 and made some recommendations for international activity in this field. In spite of the amount of scientific attention that has been given in recent years to experimental radiobiology in animals and lower forms, it has become abundantly clear that information directly applicable to humans is woefully inadequate and that there is a desperate need for carefully collected data from man on which to base public health planning and day to day work in radiation protection. This has long been recognized in the technical program of WHO in the emphasis given to the practical importance of epidemiology in human radiobiology and the degree to which it depends upon international collaboration.

  16. Colorectal Cancer: The Importance of Early Detection

    Science.gov (United States)

    ... of this page please turn JavaScript on. Feature: Colorectal Cancer The Importance of Early Detection Past Issues / Summer ... Cancer of the colon or rectum is called colorectal cancer. The colon and the rectum are part of ...

  17. Genetic Testing for Hereditary Colorectal Cancer

    Science.gov (United States)

    ... before 50). Dave has Lynch syndrome and had colorectal cancer at 28. Amy found out she has Lynch syndrome when she was diagnosed with colorectal cancer days after turning 47. Why is it Important ...

  18. Colorectal Cancer—Health Professional Version

    Science.gov (United States)

    Colorectal cancer studies often consider colon and rectal cancer together. Worldwide, colorectal cancer is the third most common form of cancer. Find evidence-based information on colon and rectal cancer treatment, causes and prevention, screening, research, genetics, and statistics.

  19. Colorectal Cancer: What You Should Know

    Science.gov (United States)

    ... Products For Consumers Home For Consumers Consumer Updates Colorectal Cancer: What You Should Know Share Tweet Linkedin Pin ... with—and more than 50,000 died from—colorectal cancer, according to the National Cancer Institute. It is ...

  20. Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Takashi Takeda

    2016-10-01

    Full Text Available Germline mutation of DNA mismatch repair (MMR genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1 and MutS homolog 2 (MSH2 has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP. Germline mutation of MMR genes, microsatellite instability (MSI, and immunohistochemistry (IHC were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%—1 out of 58 (1.72% with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H, loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.