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Sample records for cancer progression model

  1. Progress against Prostate Cancer

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Prostate Cancer Progress Against Prostate Cancer Past Issues / Winter 2010 Table of Contents ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  2. A Western-Type Diet Accelerates Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer

    OpenAIRE

    Llaverias, Gemma; Danilo, Christiane; Wang, Yu; Witkiewicz, Agnes K; Daumer, Kristin; Lisanti, Michael P; Frank, Philippe G

    2010-01-01

    Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model. Consumption of a Western-type diet—that is, enriched in both fat ...

  3. Zebrafish as a model to assess cancer heterogeneity, progression and relapse

    Directory of Open Access Journals (Sweden)

    Jessica S. Blackburn

    2014-07-01

    Full Text Available Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays.

  4. Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis.

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    Richard B Bankert

    Full Text Available Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2Rγ(null (NSG mice. This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues (including tumor cells, and tumor-associated lymphocytes and fibroblasts i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.

  5. In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone.

    Science.gov (United States)

    Arrigoni, Chiara; Bersini, Simone; Gilardi, Mara; Moretti, Matteo

    2016-01-01

    Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps. PMID:27571063

  6. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-01-01

    Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.

  7. Mathematical modeling of prostate cancer progression in response to androgen ablation therapy

    OpenAIRE

    Jain, Harsh Vardhan; Clinton, Steven K.; Bhinder, Arvinder; Friedman, Avner

    2011-01-01

    Prostate cancer progression depends in part on the complex interactions between testosterone, its active metabolite DHT, and androgen receptors. In a metastatic setting, the first line of treatment is the elimination of testosterone. However, such interventions are not curative because cancer cells evolve via multiple mechanisms to a castrate-resistant state, allowing progression to a lethal outcome. It is hypothesized that administration of antiandrogen therapy in an intermittent, as opposed...

  8. Glipizide suppresses prostate cancer progression in the TRAMP model by inhibiting angiogenesis

    OpenAIRE

    Cuiling Qi; Bin Li; Yang Yang; Yongxia Yang; Jialin Li; Qin Zhou; Yinxin Wen; Cuiling Zeng; Lingyun Zheng; Qianqian Zhang; Jiangchao Li; Xiaodong He; Jia Zhou; Chunkui Shao; Lijing Wang

    2016-01-01

    Drug repurposing of non-cancer drugs represents an attractive approach to develop new cancer therapy. Using the TRAMP transgenic mouse model, glipizide, a widely used drug for type 2 diabetes mellitus, has been identified to suppress prostate cancer (PC) growth and metastasis. Angiogenesis is intimately associated with various human cancer developments. Intriguingly, glipizide significantly reduces microvessel density in PC tumor tissues, while not inhibiting prostate cancer cell proliferatio...

  9. Inducing pluripotency and immortality in prostate tumor cells : a stem cell model of cancer progression

    OpenAIRE

    Fiñones, Rita Roces

    2009-01-01

    The progression from local prostate tumor to lethal prostate cancer is not well understood. Although current treatments cure a majority of patients, a significant minority (̃12 %) of people are diagnosed with late-stage, hormone-independent disease. As yet, the origin of the hormone-independent prostate cancer cells is unknown. In the present study, the transition to the lethal form of this disease is hypothesized to occur when a genetically- compromised tumor cell undergoes (1) an immortaliz...

  10. Preventing Breast Cancer: Making Progress

    Science.gov (United States)

    ... Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... 000 women will have been diagnosed with invasive breast cancer, and nearly 41,000 women will die from ...

  11. Targeting ECM Disrupts Cancer Progression

    DEFF Research Database (Denmark)

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T

    2015-01-01

    extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is...... summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression....

  12. Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model

    Directory of Open Access Journals (Sweden)

    Gopalakrishnan Velliyur K

    2005-03-01

    Full Text Available Abstract Background The changes in gene expression profile as prostate cancer progresses from an androgen-dependent disease to an androgen-independent disease are still largely unknown. Methods We examined the gene expression profile in the LNCaP prostate cancer progression model during chronic treatment with Casodex using cDNA microarrays consisting of 2305 randomly chosen genes. Results Our studies revealed a representative collection of genes whose expression was differentially regulated in LNCaP cells upon treatment with Casodex. A set of 15 genes were shown to be highly expressed in Casodex-treated LNCaP cells compared to the reference sample. This set of highly expressed genes represents a signature collection unique to prostate cancer since their expression was significantly greater than that of the collective pool of ten cancer cell lines of the reference sample. The highly expressed signature collection included the hypoxia-related genes membrane metallo-endopeptidase (MME, cyclin G2, and Bcl2/adenovirus E1B 19 kDa (BNIP3. Given the roles of these genes in angiogenesis, cell cycle regulation, and apoptosis, we further analyzed their expression and concluded that these genes may be involved in the molecular changes that lead to androgen-independence in prostate cancer. Conclusion Our data indicate that one of the mechanisms of Casodex action in prostate cancer cells is induction of hypoxic gene expression.

  13. Glipizide suppresses prostate cancer progression in the TRAMP model by inhibiting angiogenesis.

    Science.gov (United States)

    Qi, Cuiling; Bin Li; Yang, Yang; Yang, Yongxia; Li, Jialin; Zhou, Qin; Wen, Yinxin; Zeng, Cuiling; Zheng, Lingyun; Zhang, Qianqian; Li, Jiangchao; He, Xiaodong; Zhou, Jia; Shao, Chunkui; Wang, Lijing

    2016-01-01

    Drug repurposing of non-cancer drugs represents an attractive approach to develop new cancer therapy. Using the TRAMP transgenic mouse model, glipizide, a widely used drug for type 2 diabetes mellitus, has been identified to suppress prostate cancer (PC) growth and metastasis. Angiogenesis is intimately associated with various human cancer developments. Intriguingly, glipizide significantly reduces microvessel density in PC tumor tissues, while not inhibiting prostate cancer cell proliferation from the MTT assay and flow cytometry investigation. Moreover, glipizide inhibits the tubular structure formation of human umbilical vein endothelial cells by regulating the HMGIY/Angiopoietin-1 signaling pathway. Taken together, these results demonstrate that glipizide has the potential to be repurposed as an effective therapeutic for the treatment of PC by targeting tumor-induced angiogenesis. PMID:27292155

  14. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-04-26

    Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

  15. Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2⁺ breast cancer.

    Science.gov (United States)

    Doornebal, Chris W; Vrijland, Kim; Hau, Cheei-Sing; Coffelt, Seth B; Ciampricotti, Metamia; Jonkers, Jos; de Visser, Karin E; Hollmann, Markus W

    2015-08-01

    Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2 breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained. PMID:25734987

  16. Krüppel-like Factor 4 Inhibits Tumorigenic Progression and Metastasis in a Mouse Model of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jennifer L Yori

    2011-07-01

    Full Text Available Krüppel-like factor 4 (KLF4 is a zinc finger transcription factor that functions as an oncogene or tumor suppressor in a highly tissue-specific cell-dependent manner. However, its precise role in breast cancer and metastasis remains unclear. Here, we show that transient adenoviral expression of KLF4 in the 4T1 orthotopic mammary cancer model significantly attenuated primary tumor growth as well as micrometastases to the lungs and liver. These results can be attributed, in part, to decreased proliferation and increased apoptosis. Further supporting a tumor-suppressive role for KLF4 in the breast, we found that KLF4 expression is lost in a mouse model of HER2/NEU/ERBB2-positive breast cancer. To determine whether enforced KLF4 expression could alter tumor latency in these mice, we used a doxycycline-inducible expression model in the context of the MMTV-Neu transgene. Surprisingly, tumors that developed in this model also lost KLF4 expression, suggesting negative selection for sustained expression. We have previously reported that KLF4 inhibits epithelial-to-mesenchymal transition (EMT, a preliminary step in metastatic progression. Overexpression of KLF4 in 4T1 cells led to a significant reduction in the expression of Snail, a key mediator of EMT and metastasis. Conversely, KLF4 silencing increased Snail expression in the nontransformed MCF-10A cell line. Collectively, these data demonstrate the first functional, in vivo evidence for KLF4 as a tumor suppressor in breast cancer cells. Furthermore, our findings suggest an inhibitory role for KLF4 during breast cancer metastases that functions, in part, through repression of Snail.

  17. Declining death rates reflect progress against cancer.

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    Ahmedin Jemal

    Full Text Available BACKGROUND: The success of the "war on cancer" initiated in 1971 continues to be debated, with trends in cancer mortality variably presented as evidence of progress or failure. We examined temporal trends in death rates from all-cancer and the 19 most common cancers in the United States from 1970-2006. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed trends in age-standardized death rates (per 100,000 for all cancers combined, the four most common cancers, and 15 other sites from 1970-2006 in the United States using joinpoint regression model. The age-standardized death rate for all-cancers combined in men increased from 249.3 in 1970 to 279.8 in 1990, and then decreased to 221.1 in 2006, yielding a net decline of 21% and 11% from the 1990 and 1970 rates, respectively. Similarly, the all-cancer death rate in women increased from 163.0 in 1970 to 175.3 in 1991 and then decreased to 153.7 in 2006, a net decline of 12% and 6% from the 1991 and 1970 rates, respectively. These decreases since 1990/91 translate to preventing of 561,400 cancer deaths in men and 205,700 deaths in women. The decrease in death rates from all-cancers involved all ages and racial/ethnic groups. Death rates decreased for 15 of the 19 cancer sites, including the four major cancers, with lung, colorectum and prostate cancers in men and breast and colorectum cancers in women. CONCLUSIONS/SIGNIFICANCE: Progress in reducing cancer death rates is evident whether measured against baseline rates in 1970 or in 1990. The downturn in cancer death rates since 1990 result mostly from reductions in tobacco use, increased screening allowing early detection of several cancers, and modest to large improvements in treatment for specific cancers. Continued and increased investment in cancer prevention and control, access to high quality health care, and research could accelerate this progress.

  18. The Micro environmental Effect in the Progression, Metastasis, and Dormancy of Breast Cancer: A Model System within Bone Marrow

    International Nuclear Information System (INIS)

    Despite diagnostic advances, breast cancer remains the most prevalent cancer among women in the United States. The armamentarium of treatment options for metastatic disease is limited and mostly ineffective with regards to eradicating cancer. However, there have been novel findings in the recent literature that substantiate the function of the microenvironment in breast cancer progression and the support of metastasis to tertiary sites such as bone marrow. The uncovered significance of the microenvironment in the pathophysiology of breast cancer metastasis has served to challenge previously widespread theories and introduce new perspectives for the future research to eradicate breast cancer. This paper delineates the current understanding of the molecular mechanisms involved in the interactions between breast cancer cells and the microenvironment in progression, metastasis, and dormancy. The information, in addition to other mechanisms described in bone marrow, is discussed in the paper

  19. A multiscale and multiparametric approach for modeling the progression of oral cancer

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    Exarchos Konstantinos P

    2012-11-01

    Full Text Available Abstract Background In this work, we propose a multilevel and multiparametric approach in order to model the growth and progression of oral squamous cell carcinoma (OSCC after remission. OSCC constitutes the major neoplasm of the head and neck region, exhibiting a quite aggressive nature, often leading to unfavorable prognosis. Methods We formulate a Decision Support System assembling a multitude of heterogeneous data sources (clinical, imaging tissue and blood genomic, aiming to capture all manifestations of the disease. Our primary aim is to identify the factors that dictate OSCC progression and subsequently predict potential relapses of the disease. The discrimination potential of each source of data is initially explored separately, and afterwards the individual predictions are combined to yield a consensus decision achieving complete discrimination between patients with and without a disease relapse. Moreover, we collect and analyze gene expression data from circulating blood cells throughout the follow-up period in consecutive time-slices, in order to model the temporal dimension of the disease. For this purpose a Dynamic Bayesian Network (DBN is employed which is able to capture in a transparent manner the underlying mechanism dictating the disease evolvement, and employ it for monitoring the status and prognosis of the patients after remission. Results By feeding as input to the DBN data from the baseline visit we achieve accuracy of 86%, which is further improved to complete discrimination when data from the first follow-up visit are also employed. Conclusions Knowing in advance the progression of the disease, i.e. identifying groups of patients with higher/lower risk of reoccurrence, we are able to determine the subsequent treatment protocol in a more personalized manner.

  20. Portraits of breast cancer progression

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    Ganesan Shridar

    2007-08-01

    Full Text Available Abstract Background Clustering analysis of microarray data is often criticized for giving ambiguous results because of sensitivity to data perturbation or clustering techniques used. In this paper, we describe a new method based on principal component analysis and ensemble consensus clustering that avoids these problems. Results We illustrate the method on a public microarray dataset from 36 breast cancer patients of whom 31 were diagnosed with at least two of three pathological stages of disease (atypical ductal hyperplasia (ADH, ductal carcinoma in situ (DCIS and invasive ductal carcinoma (IDC. Our method identifies an optimum set of genes and divides the samples into stable clusters which correlate with clinical classification into Luminal, Basal-like and Her2+ subtypes. Our analysis reveals a hierarchical portrait of breast cancer progression and identifies genes and pathways for each stage, grade and subtype. An intriguing observation is that the disease phenotype is distinguishable in ADH and progresses along distinct pathways for each subtype. The genetic signature for disease heterogeneity across subtypes is greater than the heterogeneity of progression from DCIS to IDC within a subtype, suggesting that the disease subtypes have distinct progression pathways. Our method identifies six disease subtype and one normal clusters. The first split separates the normal samples from the cancer samples. Next, the cancer cluster splits into low grade (pathological grades 1 and 2 and high grade (pathological grades 2 and 3 while the normal cluster is unchanged. Further, the low grade cluster splits into two subclusters and the high grade cluster into four. The final six disease clusters are mapped into one Luminal A, three Luminal B, one Basal-like and one Her2+. Conclusion We confirm that the cancer phenotype can be identified in early stage because the genes altered in this stage progressively alter further as the disease progresses through DCIS

  1. Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

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    Eline Boghaert

    2014-12-01

    Full Text Available Ductal carcinoma in situ (DCIS is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo, but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

  2. Bitter melon extract impairs prostate cancer cell cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model

    OpenAIRE

    Ru, Peng; Steele, Robert; Nerurkar, Pratibha V.; Phillips, Nancy; Ray, Ratna

    2011-01-01

    Prostate cancer remains the second leading cause of cancer deaths among American men. Earlier diagnosis increases survival rate in patients. However, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment and prevention are necessary for inhibiting disease progression to a hormone refractory state. One of the approaches to control prostate cancer is prevention through diet, which inhibits one or more neoplastic events and...

  3. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model

    Science.gov (United States)

    A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene cou...

  4. Research Progress of Transgenic Animal Models of Lung Cancer%转基因肺癌动物模型研究进展

    Institute of Scientific and Technical Information of China (English)

    张修彦; 詹纯列

    2012-01-01

    Lung eaneer is one of the common malignant tumors in the world. Animal models of lung cancer have models of lung cancer are more similar to human lung cancer and are better for studies on the etiology and pathogenesis of lung cancer. This article is focused on the research progress of transgenic animal models of lung cancer in recent years.%肺癌是世界各国常见的恶性肿瘤,肺癌动物模型在人类肺癌病因、诊断、治疗等方面发挥重要的作用.其中转基因肺癌模型能够更好的模拟肺癌,更有利于肺癌病因及发病过程的研究.本文介绍了近年来转基因肺癌模型的研究进展.

  5. Dietary energy balance modulates ovarian cancer progression and metastasis

    OpenAIRE

    Al-Wahab, Zaid; Tebbe, Calvin; Chhina, Jasdeep; Dar, Sajad A.; Morris, Robert T.; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R.; Rattan, Ramandeep

    2014-01-01

    A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian ...

  6. Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model

    International Nuclear Information System (INIS)

    Tumour hypoxia is known to be a poor prognostic indicator, predictive of increased risk of metastatic disease and reduced survival. Genomic instability has been proposed as one of the potential mechanisms for hypoxic tumour progression. Both of these features are commonly found in many cancer types, but their relationship and association with tumour progression has not been examined in the same model. To address this issue, we determined the effects of 6 week in vivo acute hypoxic exposure on the levels of mutagenic lipid peroxidation product, malondialdehyde, and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA (8-oxo-dG) lesions in the transgenic polyomavirus middle T (PyMT) breast cancer mouse model. We observed significantly increased plasma lipid peroxidation and 8-oxo-dG lesion levels in the hypoxia-exposed mice. Consumption of malondialdehyde also induced a significant increase in the PyMT tumour DNA lesion levels, however, these increases did not translate into enhanced tumour progression. We further showed that the in vivo exposure to acute hypoxia induced accumulation of F4/80 positive tumour-associated macrophages (TAMs), demonstrating a relationship between hypoxia and macrophages in an experimental model. These data suggest that although exposure to acute hypoxia causes an increase in 8-oxo-dG lesions and TAMs in the PyMT tumours, these increases do not translate into significant changes in tumour progression at the primary or metastatic levels in this strong viral oncogene-driven breast cancer model

  7. Zinc finger proteins in cancer progression

    OpenAIRE

    Jen, Jayu; Wang, Yi-Ching

    2016-01-01

    Zinc finger proteins are the largest transcription factor family in human genome. The diverse combinations and functions of zinc finger motifs make zinc finger proteins versatile in biological processes, including development, differentiation, metabolism and autophagy. Over the last few decades, increasing evidence reveals the potential roles of zinc finger proteins in cancer progression. However, the underlying mechanisms of zinc finger proteins in cancer progression vary in different cancer...

  8. Association of Immunosuppression with DR6 Expression during the Development and Progression of Spontaneous Ovarian Cancer in Laying Hen Model

    Science.gov (United States)

    McNeal, Sa'Rah; Bitterman, Pincas; Bahr, Janice M.; Edassery, Seby L.; Abramowicz, Jacques S.; Basu, Sanjib

    2016-01-01

    Ovarian cancer (OVCA) mainly disseminates in the peritoneal cavity. Immune functions are important to prevent OVCA progression and recurrence. The mechanism of immunosuppression, a hallmark of tumor progression, is not well understood. The goal of this study was to determine the immune system's responses and its suppression during OVCA development and progression in hens. Frequencies of CD8+ T cells and IgY-containing cells and expression of immunosuppressors including IRG1 and DR6 in OVCA at early and late stages in hens were examined. Frequencies of stromal but not the intratumoral CD+8 T cells and IgY-containing cells increased significantly (P < 0.01) during OVCA development and progression. Tumor progression was associated with increased expression of IRG1 and DR6 and decreased infiltration of immune cells into the tumor. Frequency of stromal but not intratumoral immune cells increases during OVCA development and progression. Tumor-induced IRG1 and DR6 may prevent immune cells from invading the tumor.

  9. Effects of Surgery and Chemotherapy on Metastatic Progression of Prostate Cancer: Evidence from the Natural History of the Disease Reconstructed through Mathematical Modeling

    Directory of Open Access Journals (Sweden)

    Leonid Hanin

    2011-09-01

    Full Text Available This article brings mathematical modeling to bear on the reconstruction of the natural history of prostate cancer and assessment of the effects of treatment on metastatic progression. We present a comprehensive, entirely mechanistic mathematical model of cancer progression accounting for primary tumor latency, shedding of metastases, their dormancy and growth at secondary sites. Parameters of the model were estimated from the following data collected from 12 prostate cancer patients: (1 age and volume of the primary tumor at presentation; and (2 volumes of detectable bone metastases surveyed at a later time. This allowed us to estimate, for each patient, the age at cancer onset and inception of the first metastasis, the expected metastasis latency time and the rates of growth of the primary tumor and metastases before and after the start of treatment. We found that for all patients: (1 inception of the first metastasis occurred when the primary tumor was undetectable; (2 inception of all or most of the surveyed metastases occurred before the start of treatment; (3 the rate of metastasis shedding is essentially constant in time regardless of the size of the primary tumor and so it is only marginally affected by treatment; and most importantly, (4 surgery, chemotherapy and possibly radiation bring about a dramatic increase (by dozens or hundred times for most patients in the average rate of growth of metastases. Our analysis supports the notion of metastasis dormancy and the existence of prostate cancer stem cells. The model is applicable to all metastatic solid cancers, and our conclusions agree well with the results of a similar analysis based on a simpler model applied to a case of metastatic breast cancer.

  10. Effects of Surgery and Chemotherapy on Metastatic Progression of Prostate Cancer: Evidence from the Natural History of the Disease Reconstructed through Mathematical Modeling

    International Nuclear Information System (INIS)

    This article brings mathematical modeling to bear on the reconstruction of the natural history of prostate cancer and assessment of the effects of treatment on metastatic progression. We present a comprehensive, entirely mechanistic mathematical model of cancer progression accounting for primary tumor latency, shedding of metastases, their dormancy and growth at secondary sites. Parameters of the model were estimated from the following data collected from 12 prostate cancer patients: (1) age and volume of the primary tumor at presentation; and (2) volumes of detectable bone metastases surveyed at a later time. This allowed us to estimate, for each patient, the age at cancer onset and inception of the first metastasis, the expected metastasis latency time and the rates of growth of the primary tumor and metastases before and after the start of treatment. We found that for all patients: (1) inception of the first metastasis occurred when the primary tumor was undetectable; (2) inception of all or most of the surveyed metastases occurred before the start of treatment; (3) the rate of metastasis shedding is essentially constant in time regardless of the size of the primary tumor and so it is only marginally affected by treatment; and most importantly, (4) surgery, chemotherapy and possibly radiation bring about a dramatic increase (by dozens or hundred times for most patients) in the average rate of growth of metastases. Our analysis supports the notion of metastasis dormancy and the existence of prostate cancer stem cells. The model is applicable to all metastatic solid cancers, and our conclusions agree well with the results of a similar analysis based on a simpler model applied to a case of metastatic breast cancer

  11. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Mengmeng Lv

    Full Text Available The role of dietary restriction regimens such as caloric restriction, ketogenic diet and intermittent fasting in development of cancers has been detected via abundant preclinical experiments. However, the conclusions are controversial. We aim to review the relevant animal studies systematically and provide assistance for further clinical studies.Literatures on associations between dietary restriction and cancer published in PubMed in recent twenty years were comprehensively searched. Animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer were extracted from each eligible study. We analyzed the tumor incidence rates from 21 studies about caloric restriction.Fifty-nine studies were involved in our system review. The involved studies explored roles of dietary restriction during initiation, progression and metastasis of cancer. About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role, with the pooled OR (95%CI of 0.20 (0.12, 0.34 relative to controls. Ketogenic diet was also positively associated with cancer, which was indicated by eight of the nine studies. However, 37.5% of the related studies obtained a negative conclusion that intermittent fasting was not significantly preventive against cancer.Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated.

  12. Inferring Progression Models for CGH data

    OpenAIRE

    Liu, J.; N. Bandyopadhyay; Ranka, S; Baudis, M; Kahveci, T

    2009-01-01

    MOTIVATION: One of the mutational processes that has been monitored genome-wide is the occurrence of regional DNA Copy Number Alterations (CNAs), which may lead to deletion or over-expression of tumor suppressors or oncogenes, respectively. Understanding the relationship between CNAs and different cancer types is a fundamental problem in cancer studies. RESULTS: This paper develops an efficient method that can accurately model the progression of the cancer markers and reconstruct evolutionary...

  13. Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model

    Directory of Open Access Journals (Sweden)

    Lunt Sarah

    2008-05-01

    Full Text Available Abstract Background Tumour hypoxia is known to be a poor prognostic indicator, predictive of increased risk of metastatic disease and reduced survival. Genomic instability has been proposed as one of the potential mechanisms for hypoxic tumour progression. Both of these features are commonly found in many cancer types, but their relationship and association with tumour progression has not been examined in the same model. Methods To address this issue, we determined the effects of 6 week in vivo acute hypoxic exposure on the levels of mutagenic lipid peroxidation product, malondialdehyde, and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA (8-oxo-dG lesions in the transgenic polyomavirus middle T (PyMT breast cancer mouse model. Results We observed significantly increased plasma lipid peroxidation and 8-oxo-dG lesion levels in the hypoxia-exposed mice. Consumption of malondialdehyde also induced a significant increase in the PyMT tumour DNA lesion levels, however, these increases did not translate into enhanced tumour progression. We further showed that the in vivo exposure to acute hypoxia induced accumulation of F4/80 positive tumour-associated macrophages (TAMs, demonstrating a relationship between hypoxia and macrophages in an experimental model. Conclusion These data suggest that although exposure to acute hypoxia causes an increase in 8-oxo-dG lesions and TAMs in the PyMT tumours, these increases do not translate into significant changes in tumour progression at the primary or metastatic levels in this strong viral oncogene-driven breast cancer model.

  14. Antioxidants accelerate lung cancer progression in mice.

    Science.gov (United States)

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. PMID:24477002

  15. Psychological aspect of cancer: From stressor to cancer progression

    OpenAIRE

    Yuan, Aihua; Wang, Shukui; Li, Zongfang; Huang, Chen

    2010-01-01

    Substantial evidence indicates that psychological stress can influence the incidence and progression of cancers, and adequate psychotherapies are beneficial to cancer patients. Recently, the mechanisms responsible for the effects of psychological stress on cancer cells have been extensively investigated at the systemic, biochemical and molecular levels. Accumulating data indicate that the effects of psychological stress on cancer cells are mainly mediated by key stress-related mediators and t...

  16. Dysadherin: a new player in cancer progression.

    OpenAIRE

    Nam, Jeong-Seok; Hirohashi, Setsuo; Wakefield, Lalage M.

    2007-01-01

    Dysadherin is a cancer-associated cell membrane glycoprotein that promotes experimental cancer metastasis. Here we review recent work that has provided insights into possible mechanisms of action of this newly recognized player in the cancer progression process. Dysadherin modulates cell phenotype in a number of ways, including down-regulation of E-cadherin-mediated cell adhesion, and up-regulation of chemokine production. In this way, expression of dysadherin in a tumor can influence both th...

  17. Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

    Science.gov (United States)

    Ota, Shinichi; Geschwind, Jean-Francois H; Buijs, Manon; Wijlemans, Joost W; Kwak, Byung Kook; Ganapathy-Kanniappan, Shanmugasundaram

    2013-06-01

    Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer. PMID:23529644

  18. Muscarinic receptor signaling and colon cancer progression

    Institute of Scientific and Technical Information of China (English)

    Guofeng Xie; Jean-Pierre Raufman

    2016-01-01

    Due to the lack of effective treatments, advanced colorectal cancer (CRC) remains a leading cause of cancer death in the United States. Emerging evidence supports the observation that muscarinic receptor (MR) signaling plays a critical role in growth and progression of CRC. MR activation by acetylcholine and bile acids results in transactivation of epidermal growth factor receptors (EGFR) and post-EGFR signal transduction that enhances cell proliferation, migration, and invasion. Here, the authors review recent progress in understanding the molecular mechanisms underlying MR-mediated CRC progression and its therapeutic implications.

  19. Progress and controversies in developing cancer vaccines

    Directory of Open Access Journals (Sweden)

    Speiser Daniel E

    2005-04-01

    Full Text Available Abstract Immunotherapy has become a standard approach for cancer management, through the use of cytokines (eg: interleukin-2 and monoclonal antibodies. Cancer vaccines hold promise as another form of immunotherapy, and there has been substantial progress in identifying shared antigens recognized by T cells, in developing vaccine approaches that induce antigen-specific T cell responses in cancer patients, and in developing new technology for monitoring immune responses in various human tissue compartments. Dramatic clinical regressions of human solid tumors have occurred with some cancer vaccines, but the rate of those responses remains low. This article is part of a 2-part point:counterpoint series on peptide vaccines and adoptive therapy approaches for cancer. The current status of cancer vaccination, and associated challenges, are discussed. Emphasis is placed on the need to increase our knowledge of cancer immunobiology, as well as to improve monitoring of cellular immune function after vaccination. Progress in both areas will facilitate development of effective cancer vaccines, as well as of adoptive therapy. Effective cancer vaccines promise to be useful for treatment and prevention of cancer at low cost and with low morbidity.

  20. Preventing Breast Cancer: Making Progress

    Science.gov (United States)

    ... linking the development of this disease, in many cases, with exposure to the hormone estrogen. The focus of recent breast cancer prevention studies has been on testing the effectiveness of drugs called selective estrogen receptor modulators (SERMs). SERMs are ...

  1. Effects of flaxseed lignan secoisolariciresinol diglucoside on preneoplastic biomarkers of cancer progression in a model of simultaneous breast and ovarian cancer development

    Science.gov (United States)

    Delman, Devora M.; Fabian, Carol J.; Kimler, Bruce F.; Yeh, Henry; Petroff, Brian K.

    2016-01-01

    Breast cancer prevention efforts are focused increasingly on potentially beneficial dietary modifications due to their ease of implementation and wide acceptance. Secoisolariciresinol diglucoside (SDG) is a lignan found in high concentration in flaxseed that may have selective estrogen receptor modulator (SERM)-like effects resulting in antiestrogenic activity in a high estrogen environment. In parallel with a human phase II prevention trial, female ACI rats (n=8–10/group) received 0, 10 or 100 ppm SDG in the feed. The 100 ppm SDG treatment produced similar blood lignan levels as those observed in our human pilot study. Mammary and ovarian cancer progression were induced using local ovarian DMBA treatment and subcutaneous sustained release 17β-estradiol administered starting at 7 weeks of age. Mammary gland and ovarian tissues were collected at 3 months after initiation of treatment and examined for changes in epithelial cell proliferation (Ki-67, cell counts), histopathology and dysplasia scores as well as expression of selected genes involved in proliferation, estrogen signaling and cell adhesion. Treatment with SDG normalized several biomarkers in mammary gland tissue (dysplasia, cell number, and expression of several genes) that had been altered by carcinogen. There is no indication that SDG promotes pre-neoplastic progression in the ovarian epithelium. PMID:26010915

  2. The Cancer Stem Cell Concept in Progression of Head and Neck Cancer

    OpenAIRE

    Zhuo Chen

    2009-01-01

    Human head and neck cancer (HNC) is a highly heterogeneous disease. Understanding the biology of HNC progression is necessary for the development of novel approaches to its prevention, early detection, and treatment. A current evolutional progression model has limitations in explaining the heterogeneity observed in a single tumor nest. Accumulating evidence supports the existence of cancer stem cells (CSCs) as small subpopulations in solid tumors, including HNC. These CSCs can be selected by ...

  3. NGAL Expression Is Elevated in Both Colorectal Adenoma–Carcinoma Sequence and Cancer Progression and Enhances Tumorigenesis in Xenograft Mouse Models

    Science.gov (United States)

    Sun, Yan; Yokoi, Kenji; Li, Hui; Gao, Jun; Hu, Limei; Liu, Ben; Chen, Kexin; Hamilton, Stanley R.; Fan, Dominic; Sun, Baocun; Zhang, Wei

    2013-01-01

    Purpose There is growing evidence implicating that neutrophil gelatinase–associated lipocalin (NGAL) plays a role in the development and progression of cancers. However, the effect of NGAL in colorectal carcinoma (CRC) has not been clearly elucidated. In this study, we investigated the role of NGAL in the tumorigenesis and progression of CRC and evaluated the clinical value of NGAL expression. Experimental Design We examined NGAL expression in 526 colorectal tissue samples, including 53 sets of matched specimens (histologically normal mucosa, adenomas, and carcinomas) using immunohistochemical analysis. In CRCs, correlations between NGAL expression and clinicopathologic parameters were analyzed, and survival analysis was conducted. The role of NGAL was further tested using mouse xenograft models. Results NGAL expression was elevated during the colorectal adenoma–carcinoma sequence both among the 526 cases (rs = 0.66, P < 0.001) and in the 53 sets of matched specimens (rs = 0.60, P < 0.001). In CRCs, NGAL expression was associated with cancer stage (P = 0.041) and tumor recurrence in stage II patients (P = 0.037). Survival analysis revealed that NGAL expression was an independent prognostic factor for overall survival (HR = 1.84, P = 0.004) and for disease-free survival of stage II patients (HR = 5.88, P = 0.021). In mouse models, the xenografts in cecum and spleen were heavier and more numerous in the group injected with NGAL-overexpressing CRC cells (P < 0.05). Conclusions NGAL overexpression may promote the tumorigenesis and progression of CRC. Detecting NGAL expression in tumor tissues may be useful for evaluating prognosis of patients with CRC. PMID:21622717

  4. Cancer initiation and progression: an unsimplifiable complexity

    Directory of Open Access Journals (Sweden)

    Frezza Eldo E

    2006-10-01

    Full Text Available Abstract Background Cancer remains one of the most complex diseases affecting humans and, despite the impressive advances that have been made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still widely debated. Conclusion There is no doubt that human carcinogenesis is a dynamic process that depends on a large number of variables and is regulated at multiple spatial and temporal scales. Viewing cancer as a system that is dynamically complex in time and space will, however, probably reveal more about its underlying behavioural characteristics. It is encouraging that mathematicians, biologists and clinicians continue to contribute together towards a common quantitative understanding of cancer complexity. This way of thinking may further help to clarify concepts, interpret new and old experimental data, indicate alternative experiments and categorize the acquired knowledge on the basis of the similarities and/or shared behaviours of very different tumours.

  5. Parameterization of a disease progression simulation model for sequentially treated metastatic human epidermal growth factor receptor 2 positive breast cancer patients

    Science.gov (United States)

    Diaby, Vakaramoko; Ali, Askal A.; Adunlin, Georges; Kohn, Christine G.; Montero, Alberto J.

    2016-01-01

    Background The objective of this study is twofold: 1) to propose a simulation model for HER2+ metastatic breast cancer (mBC) which could further be used to assess the overall cost-effectiveness of the treatment sequences that would maximize survival of patients, and 2) to estimate transitional probabilities between treatment lines required to parameterize the simulation model, in the absence of individual patient data (IPD). Methods Individual patient data (IPD) were reconstructed for treatment lines composing four treatment sequences. Parametric models were tested to select the model that best fits the IPD. The transitional probability equations, used for disease progression modeling, were obtained by substituting the parameters of the general equation for transitional probabilities by the parameters estimated from fitted distributions. Results The log-logistic model best fitted the reconstructed data for progression-free and overall survival curves for each line of treatment. The shapes and scales of the log-logistic models were used to develop the transitional probability equations for the HER2+ mBC simulation model. Key limitations: The estimation of the transitional probabilities depends heavily on the accuracy of the IPD reconstruction. Nonetheless, analytical and graphical tests can be performed to check the face validity of the reconstructed data. Additionally, sensitivity analyses can be conducted to test the impact of uncertainty surrounding the estimated parameters defining equations for transitional probabilities. Conclusion The results of this study can be used as input in model-based economic evaluations of sequential therapy for HER2+ mBC. PMID:26824145

  6. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    Directory of Open Access Journals (Sweden)

    Sabrina Bimonte

    2015-01-01

    Full Text Available Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

  7. Heparin as an inhibitor of cancer progression

    OpenAIRE

    Borsig, L

    2010-01-01

    Heparin is frequently used for treatment of cancer-associated thromboembolism. Accumulating clinical evidence indicates that cancer patients treated with unfractionated and low-molecular weight heparin survives longer that patients treated by other anticoagulants, especially patients in the early stage of a disease. Experimental analysis from a number of animal models constantly provides evidence about the ability of heparin to attenuate metastasis. The non-anticoagulant activity of heparin o...

  8. Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer

    Science.gov (United States)

    Our previous report showed that concomitant supplementation of lycopene and eicosa-pentaenoic acid synergistically inhibited the proliferation of human colon cancer HT-29 cells in vitro. To validate our findings, the present study investigated whether consumption of lycopene and fish oil would help ...

  9. Microgravity alters cancer growth and progression.

    Science.gov (United States)

    Jhala, Dhwani V; Kale, Raosaheb K; Singh, Rana P

    2014-01-01

    Study of the process of cancer initiation, growth and progression in altered gravity is of utmost importance considering the health status of researchers visiting in space and future scope of space tourism. Microgravity affects various cells in the body differently; however, the mechanisms of such effects are not understood completely. Therefore, it is imperative to explore various physiological and biochemical processes, particularly those which can influence the process of carcinogenesis. If the changes in physiological or biochemical processes do not revert back to normalcy even after returning from the space to earth, it may lead to various aberrations and morphological changes during the life span. Such changes could lead to pathological conditions including cancer. For example, microgravity is observed to suppress the activity of immune cells, which itself increases the risk of cancer development. It is little known how the microgravity affects cellular and molecular events that determine physiological and biological responses. There is also a possibility of changes in epigenetic signatures during microgravity exposure which remains unexplored. Herein, we have reviewed the effect of microgravity on relevant molecular and biological processes, and how it could influence the course of cancer development. In this regard, we have also highlighted the areas of research that require more attention to bridge the gap of understanding for such biological processes. PMID:24720362

  10. 非人灵长类肿瘤模型研究进展%Progress of non-human primate animal models of cancers

    Institute of Scientific and Technical Information of China (English)

    夏厚军; 陈策实

    2011-01-01

    癌症是人类第二大致死的疾病.将体外细胞模型获得的癌症研究结果向临床转化过程中,动物活体实验是必不可少的一个环节.现在的肿瘤活体实验绝大部分采用啮齿类实验动物如小鼠和大鼠,这是因为它们具有个体小、繁殖迅速、遗传背景清楚、转基因技术成熟等优势.但是啮齿类和人的亲缘关系比较远,许多从啮齿类动物模型获得的研究结果不能在人体重现.非人灵长类动物在遗传进化、免疫、生理和代谢等诸多方面与人类高度近似,理论上更加适合癌症研究.本文对现有的非人灵长类肿瘤研究做一综述,主要集中介绍用化学和生物致癌剂在不同的非人灵长类动物诱导肿瘤的研究,为将来用非人灵长类动物研究人类癌症奠定基础.%Cancer is the second leading disease causing human death. Pre-clinical in vivo studies are essential for translating in vitro laboratory research results into the clinic. Rodents, including the mouse and rat, have been widely used for pre-clinical studies due to their small size, clear genetic backgrounds, rapid propagation, and mature transgenic technologies. However, because rodents are evolutionarily distinct from humans, many pre-clinical research results using rodent models cannot be reproduced in the clinic. Non-human primates (NHPs) may be better animal models than rodents for human cancer research because NHPs and humans share greater similarity in regards to their genetic evolution, immune system, physiology and metabolism. This article reviews the latest progress of cancer research in NHPs by focusing on the carcinogenesis of different NHPs induced by chemical and biological carcinogens. finally, future research directions for the use of NHPs in cancer research are discussed.

  11. Supramolecular nanofibrils inhibit cancer progression in vitro and in vivo

    Science.gov (United States)

    Kuang, Yi; Du, Xuewen; Zhou, Jie; Xu, Bing

    2014-01-01

    The recent discovery of the inverse comorbidity between cancer and Alzheimer’s disease implies that one may use amyloids to inhibit tumors. During the conversion of a dipeptide segment (Phe-Phe) in β-amyloid into a supramolecular hydrogelator, we obtained a small molecule (1) that can self-assembly into nanofibrils via multiple intermolecular hydrogen bonding and aromatic-aromatic interactions. Interestingly, while the monomers of 1 are innocuous, the nanofibrils formed by 1 can selectively inhibit the growth of glioblastoma cells over neuronal cells. To further assess the potential of this small molecular nanofibrils as anti-cancer agent, we exam the biological activity of the nanofibrils and demonstrate that the nanofibrils of 1 efficiently inhibit the progression of cancer cells (e.g., HeLa cells) both in cell assays and on xenograft mice model. This work suggests that nanofibrils derived from core motif of amyloid are effective agents for inhibiting cancer progression. Thus, this work contributes to a new approach that uses supramolecular nanofibrils as de novo molecular amyloids for inhibiting the growth of cancer cells. PMID:24574174

  12. Cancer stem cell targeted therapy: progress amid controversies

    OpenAIRE

    Wang, Tao; Shigdar, Sarah; Gantier, Michael P.; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; ZHOU, SHU-FENG; Zhao, Xinhan; Duan, Wei

    2015-01-01

    Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illu...

  13. Nuclear morphometry, nucleomics and prostate cancer progression

    Institute of Scientific and Technical Information of China (English)

    Robert W Veltri; Christhunesa S Christudass; Sumit Isharwal

    2012-01-01

    Prostate cancer (PCa) results from a multistep process.This process includes initiation,which occurs through various aging events and multiple insults (such as chronic infection,inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks),followed by a multistep process of progression.These steps include several genetic and epigenetic alterations,as well as alterations to the chmmatin structure,which occur in response to the carcinogenic stress-related events that sustain proliferative signaling.Events such as evading growth suppressors,resisting cell death,enabling replicative immortality,inducing angiogenesis,and activating invasion and metastasis are readily observed.In addition,in conjunction with these critical drivers of caminogenesis,other factors related to the etiopathogenesis of PCa,involving energy metabolism and evasion of the immune surveillance system,appear to be involved.In addition,when cancer spread and metastasis occur,the 'tumor microenvironment' in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a 'seed and soil' site where PCa proliferation and growth may occur over time.When PCa is initiated and progression ensues,significant alterations in nuclear size,shape and hetemchmmatin (DNA transcription) organization are found,and key nuclear transcriptional and structural proteins,as well as multiple nuclear bodies can lead to precancerous and malignant changes.These series of cellular and tissue-related malignancy-associated events can be quantified to assess disease progression and management.

  14. Interleukin-17: A Promoter in Colorectal Cancer Progression

    OpenAIRE

    Dang Wu; Pin Wu; Qi Huang; Yang Liu; Jun Ye; Jian Huang

    2013-01-01

    It is widely accepted that chronic inflammation plays an active role in cancer. Inflammatory immunocytes and related cytokines in the tumor microenvironment are supposed to be a “double-edged sword” in colorectal cancer (CRC) initiation and progression. Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, can promote cancer-elicited inflammation and prevent cancer cells from immune surveillance. Despite controversy, IL-17 is generally considered to be a promoter in CRC progression....

  15. Why is there no progress against cervical cancer?

    OpenAIRE

    Cohen, M M

    1996-01-01

    The author reflects on the disheartening report given by Dr. E. Jean Parboosingh and associates on Canadian screening programs for cervical cancer (see pages 1847 to 1853 of this issue). Although cancer of the cervix is one of the few preventable forms of cancer, little progress has been made toward the establishment of programs to control this disease. Barriers to progress include a lack of priority given to women's health issues, insufficient public awareness of cervical cancer, the absence...

  16. Motesanib diphosphate in progressive differentiated thyroid cancer

    DEFF Research Database (Denmark)

    Sherman, Steven I; Wirth, Lori J; Droz, Jean-Pierre;

    2008-01-01

    BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived gr......BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet......-derived growth-factor receptor, and KIT. METHODS: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end...... concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS: Motesanib diphosphate can induce partial responses in patients with advanced or...

  17. Global progress against cancer-challenges and oppor tunities

    Institute of Scientific and Technical Information of China (English)

    Frédéric Biemar; Margaret Foti

    2013-01-01

    The last ten years have seen remarkable progress in cancer research. However, despite significant breakthroughs in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Cancer’s complexity compounded with ifnancial, policy and regulatory roadblocks has slowed the rate of progress being made against cancer. In this paper, we review a few of the most recent breakthroughs that are fueling medical advances and bringing new hope for patients affected by this devastating disease. We also address the challenges facing us and the opportunities to accelerate future progress against cancer. The efforts of the American Association for Cancer Research (AACR) to address the cancer burden already extend beyond the borders of the United States of America. hTe AACR is committed to increasing its efforts to stem the tide of cancer worldwide by promoting innovative programs, strategies, and initiatives for cancer researchers and all those engaged in cancer-related biomedical sciences around the world.

  18. Mouse models of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

  19. The Cancer Stem Cell Concept in Progression of Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Zhuo (Georgia Chen

    2009-01-01

    Full Text Available Human head and neck cancer (HNC is a highly heterogeneous disease. Understanding the biology of HNC progression is necessary for the development of novel approaches to its prevention, early detection, and treatment. A current evolutional progression model has limitations in explaining the heterogeneity observed in a single tumor nest. Accumulating evidence supports the existence of cancer stem cells (CSCs as small subpopulations in solid tumors, including HNC. These CSCs can be selected by appropriate cell surface markers, which are cancer type specific and have been confirmed by unique in vitro and in vivo assays. Selected CSC populations maintain a self-renewal capability and show aggressive behaviors, such as chemoresistance and metastasis. In addition to introducing the CSC concept in solid tumors, this short review summarizes current publications in HNC CSC and the prospective development and application of the CSC concept to HNC in the clinic.

  20. 肝癌动物模型研究进展%Progress in research on animal models of liver cancer

    Institute of Scientific and Technical Information of China (English)

    黄佳飞; 周洪渊; 张倜

    2014-01-01

    肝癌动物模型的建立具有重要价值。动物模型的建立分为实验动物的选择和肿瘤的来源两部分。因肿瘤的来源不同又可以将模型分为不同的类型,不同类型的模型具有各自相应的特点和局限性。理想的肝癌动物模型应该在生物学习性、生化性质、病理学特征等方面与人类肝癌相类似,并且模型制作过程简便易行。%Asaresult,establishinganimalmodelsoflivercancerisofhighvalue.Therearetwoparts of the establishment of animal models-the selection of laboratory animals and the source of tumors.The animal models could be classified into different patterns due to difference sources of tumor,and these different patterns possess distinctive characters and limitations.The ideally animal models should satisfy the general requirements of biological habits,biochemical properties,and pathological features which are similar with human hepatocel-lular and easy to establish.

  1. 肝癌动物模型的研究及进展%Research Progress in Animal Models of Liver Cancer

    Institute of Scientific and Technical Information of China (English)

    申凤鸽

    2011-01-01

    [Objective]To establish good animal models of liver cancer and serve treatment of liver cancer in humans. [Method J Several common animal models of liver cancer were introduced briefly. [ Result] The commonly used animal models include C57BL/6J mouse model of or-thotopic liver cancer induced with Hepal-6 cells,nude mouse model of liver cancer established with Hep_G2 cell lines,rat liver cancer model established through direct transplantation or direct injection,HU-PBL-SCID mice model,and other transplanted liver cancer models or genetic liver cancer models. [ Conclusion] Animal model is an important means and platform for experimental studies. To establish animal models of liver cancer is of important significance for studies on pathogenesis, diagnosis and treatment of liver cancer.%[目的]建立良好的肝癌动物模型,为人类治疗肝癌服务.[方法]简单介绍几种比较常见的肝癌动物模型.[结果]目前比较常用的动物模型有:Hepal-6细胞诱发C57BL /6J小鼠原位肝癌模型、采用Hep_G2细胞株建立裸鼠肝癌模型、直接移植法建立大鼠肝癌模型、直接注入法建立大鼠肝癌模型、免疫重建荷人高转移肝癌SCD鼠模型、其他移植性肝癌模型和基因性肝癌模型.[结论]动物模型是进行试验研究的重要手段和平台,建立肝癌动物模型对肝癌发生机制、诊断与治疗研究有很重要的意义.

  2. Role of ADAMs in cancer formation and progression.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

    The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. One of their best-established roles is the release of biologically important ligands, such as tumor necrosis factor-alpha, epidermal growth factor, transforming growth factor-alpha, and amphiregulin. Because these ligands have been implicated in the formation and progression of tumors, it might be expected that the specific ADAMs involved in their release would also be involved in malignancy. Consistent with this hypothesis, emerging data from model systems suggest that ADAMs, such as ADAM-9, ADAM-12, ADAM-15, and ADAM-17, are causally involved in tumor formation\\/progression. In human cancer, specific ADAMs are up-regulated, with levels generally correlating with parameters of tumor progression and poor outcome. In preclinical models, selective ADAM inhibitors against ADAM-10 and ADAM-17 have been shown to synergize with existing therapies in decreasing tumor growth. The ADAMs are thus a new family of potential targets for the treatment of cancer, especially malignancies that are dependent on human epidermal growth factor receptor ligands or tumor necrosis factor-alpha.

  3. Is human cytomegalovirus associated with breast cancer progression?

    OpenAIRE

    Utrera-Barillas, Dolores; Valdez-Salazar, Hilda-Alicia; Gómez-Rangel, David; Alvarado-Cabrero, Isabel; Aguilera, Penélope; Gómez-Delgado, Alejandro; Ruiz-Tachiquin, Martha-Eugenia

    2013-01-01

    Background It has been hypothesized that human cytomegalovirus (HCMV) may be associated with breast cancer progression. However, the role of HCMV infection in breast cancer remains controversial. We aimed to assess whether HCMV genes (UL122 and UL83) could be detected in breast carcinomas and reinvestigated their possible association with breast cancer progression. DNA from paraffin-embedded tissues was analyzed by real-time PCR. We investigated 20 fibroadenomas and 27 primary breast carcinom...

  4. Expression of p53, p21(CIP1/WAF1) and eIF4E in the adjacent tissues of oral squamous cell carcinoma: establishing the molecular boundary and a cancer progression model.

    Science.gov (United States)

    Li, Yi; Li, Bo; Xu, Bo; Han, Bo; Xia, Hui; Chen, Qian-Ming; Li, Long-Jiang

    2015-09-01

    The present study evaluated the expression of key molecules and the status of DNA in both oral squamous cell carcinoma (OSCC) and adjacent tissues to establish a molecular surgical boundary and provide a cancer progression model. Biopsy samples from 50 OSCC patients were divided into T (cancer), P1 (0-0.5 cm), P2 (0.5-1 cm), P3 (1-1.5 cm) and P4 (1.5-2 cm) groups based on the distances from the visible boundary of the primary focus. Twenty samples of normal mucosa were used as controls. We used immunohistochemical staining and flow cytometry to evaluate p53, p21(CIP1/WAF1), eIF4E and Ki-67 expression and to determine DNA status, respectively. Sub-mucosal invasion was present in the P1 and P2 groups as determined by haematoxylin and eosin staining. Mutant p53 expression decreased gradually from cancerous to normal mucosae, whereas p21(CIP1/WAF1) expression displayed an opposite trend. eIF4E expression decreased from cancerous to normal mucosae. Ki-67 expression, the heteroploidy ratio, S-phase fraction and proliferative index decreased gradually with the distance from the tumour centre. Based on these results, we suggest that the resection boundary in OSCC surgery should be beyond 2 cm from the tumour. Additionally, the adjacent tissues of the primary focus could be used as a model for assessing cancer progression. PMID:25835715

  5. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    International Nuclear Information System (INIS)

    Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients

  6. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    Energy Technology Data Exchange (ETDEWEB)

    Juratli, Mazen A.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A. [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Melerzanov, Alexander V. [Moscow Institute of Physics and Technology (MIPT), Moscow Region, 141700 (Russian Federation); Zharov, Vladimir P. [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moscow Institute of Physics and Technology (MIPT), Moscow Region, 141700 (Russian Federation); Galanzha, Ekaterina I., E-mail: egalanzha@uams.edu [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2014-01-15

    Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.

  7. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    Directory of Open Access Journals (Sweden)

    Mazen A. Juratli

    2014-01-01

    Full Text Available Circulating tumor cells (CTCs are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min. These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.

  8. Parameter estimates for invasive breast cancer progression in the Canadian National Breast Screening Study

    OpenAIRE

    Taghipour, S.; Banjevic, D; Miller, A.B.; Montgomery, N; A K S Jardine; Harvey, B. J.

    2013-01-01

    Background: The aim of screening is to detect a cancer in the preclinical state. However, a false-positive or a false-negative test result is a real possibility. Methods: We describe invasive breast cancer progression in the Canadian National Breast Screening Study and construct progression models with and without covariates. The effect of risk factors on transition intensities and false-negative probability is investigated. We estimate the transition rates, the sojourn time and sensitivity o...

  9. Progress in Gene Therapy for Prostate Cancer

    OpenAIRE

    KamranAliAhmed; BrianJamesDavis; TorrenceMWilson; GregoryAWiseman; MarkJFederspiel; JohnCMorris

    2012-01-01

    Gene therapy has held promise to correct various disease processes. Prostate cancer represents the second leading cause of cancer death in American men. A number of clinical trials involving gene therapy for the treatment of prostate cancer have been reported. The ability to efficiently transduce tumors with effective levels of therapeutic genes has been identified as a fundamental barrier to effective cancer gene therapy. The approach utilizing gene therapy in prostate cancer patients at our...

  10. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective.

    Science.gov (United States)

    Betof, Allison S; Dewhirst, Mark W; Jones, Lee W

    2013-03-01

    Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of 'exercise - oncology' has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examining the association between exercise behavior, functional capacity/exercise capacity, and cancer-specific recurrence and mortality as well as all-cause mortality individuals following a cancer diagnosis. We also evaluate evidence from clinical studies investigating the effects of structured exercise on blood-based biomarkers associated with cancer progression/metastasis as well findings from preclinical investigations examining the effects and molecular mechanisms of exercise in mouse models of cancer. Current gaps in knowledge are also discussed. PMID:22610066

  11. Triumph or tragedy: progress in cancer

    OpenAIRE

    ERENLER, Ayşe Şebnem; GEÇKİL, Hikmet

    2014-01-01

    Cancer is probably the number one research area among all human endeavors, receiving the largest portion of science funding in most countries. This is because cancer remains one of the oldest conundrums among all human maladies. Although we now have a greater understanding of the biological and molecular basis of cancer, its diagnosis and therapy still pose great challenges. In this review, our aim is not to establish a comprehensive understanding of cancer, which is essentially impossible, b...

  12. FGF Signaling in Prostate Cancer Progression

    Institute of Scientific and Technical Information of China (English)

    Nora M. NAVONE

    2009-01-01

    @@ Objective: prostate cancer is the second leading cause of cancer death in men in the United States. Localized prostate cancer can be cured by andro-gen ablation, but when the disease escapes the confines of the gland, the prospects for cure decrease drastically and the disease becomes "castrate resistant.

  13. Targeting the extracellular matrix to disrupt cancer progression

    Directory of Open Access Journals (Sweden)

    Freja Albjerg Venning

    2015-10-01

    Full Text Available Metastatic complications are responsible for more than 90% of cancer related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multi-step process, with each step involving intricate cross-talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM. Many ECM proteins are significantly de-regulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.

  14. Depth-resolved nanoscale nuclear architecture mapping for early prediction of cancer progression

    Science.gov (United States)

    Uttam, Shikhar; Pham, Hoa V.; LaFace, Justin; Hartman, Douglas J.; Liu, Yang

    2016-03-01

    Effective management of patients who are at risk of developing invasive cancer is a primary challenge in early cancer detection. Techniques that can help establish clear-cut protocols for successful triaging of at-risk patients have the potential of providing critical help in improving patient care while simultaneously reducing patient cost. We have developed such a technique for early prediction of cancer progression that uses unstained tissue sections to provide depth-resolved nanoscale nuclear architecture mapping (nanoNAM) of heterogeneity in optical density alterations manifested in precancerous lesions during cancer progression. We present nanoNAM and its application to predicting cancer progression in a well-established mouse model of spontaneous carcinogenesis: ApcMin/+ mice.

  15. Progress in neutron capture therapy for cancer

    International Nuclear Information System (INIS)

    Prognosis for some cancers is good, but for others, few patients will survive 12 months. This latter group of cancers is characterised by a proclivity to disseminate malignant cells in the host organ. In some cases systemic metastases occur, but in other cases, failure to achieve local control results in death. First among these cancers are the high grade brain tumours, astrocytoma 3,4 and glioblastoma multiforme. Local control of these tumors should lead to cure. Other cancers melanoma metastatic to the brain, for which a useful palliative therapy is not yet available, and pancreatic cancer for which localised control at an early stage could bring about improved prognosis. Patients with these cancers have little grounds for hope. Our primary objective is to reverse this situation with Neutron Capture Therapy (NCT). The purpose of this fourth symposium is to hasten the day whereby patients with these cancers can reasonably hope for substantial remissions

  16. Ovarian cancer immunotherapy: opportunities, progresses and challenges.

    Science.gov (United States)

    Liu, Bei; Nash, John; Runowicz, Carolyn; Swede, Helen; Stevens, Richard; Li, Zihai

    2010-01-01

    Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer. PMID:20146807

  17. Ovarian cancer immunotherapy: opportunities, progresses and challenges

    Directory of Open Access Journals (Sweden)

    Stevens Richard

    2010-02-01

    Full Text Available Abstract Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer.

  18. STAT3 activation in monocytes accelerates liver cancer progression

    International Nuclear Information System (INIS)

    Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor

  19. STAT3 activation in monocytes accelerates liver cancer progression

    Directory of Open Access Journals (Sweden)

    Wu Wen-Yong

    2011-12-01

    Full Text Available Abstract Background Signal transducer and activator of transcription 3 (STAT3 is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. Methods Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN, which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. Results Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. Conclusion Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical

  20. Recent Progress in Light-Triggered Nanotheranostics for Cancer Treatment

    Science.gov (United States)

    Zhang, Pengcheng; Hu, Chunhua; Ran, Wei; Meng, Jia; Yin, Qi; Li, Yaping

    2016-01-01

    Treatments of high specificity are desirable for cancer therapy. Light-triggered nanotheranostics (LTN) mediated cancer therapy could be one such treatment, as they make it possible to visualize and treat the tumor specifically in a light-controlled manner with a single injection. Because of their great potential in cancer therapy, many novel and powerful LTNs have been developed, and are mainly prepared from photosensitizers (PSs) ranging from small organic dyes such as porphyrin- and cyanine-based dyes, semiconducting polymers, to inorganic nanomaterials such as gold nanoparticles, transition metal chalcogenides, carbon nanotubes and graphene. Using LTNs and localized irradiation in combination, complete tumor ablation could be achieved in tumor-bearing animal models without causing significant toxicity. Given their great advances and promising future, we herein review LTNs that have been tested in vivo with a highlight on progress that has been made in the past a couple of years. The current challenges faced by these LTNs are also briefly discussed. PMID:27217830

  1. Progress of cervical cancer genetic-radiotherapy

    International Nuclear Information System (INIS)

    Although cervical cancer gene therapy has a distance to clinical use due to some problems, the combinating of irradiation and gene therapy holds much promise in cancer therapy based on the traditional radiotherapy, chemotherapy and surgery. This review focuses on the group of radiogenic therapy that are either. (authors)

  2. Progress in gene therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    KamranAliAhmed

    2012-11-01

    Full Text Available Gene therapy has held promise to correct various disease processes. Prostate cancer represents the second leading cause of cancer death in American men. A number of clinical trials involving gene therapy for the treatment of prostate cancer have been reported. The ability to efficiently transduce tumors with effective levels of therapeutic genes has been identified as a fundamental barrier to effective cancer gene therapy. The approach utilizing gene therapy in prostate cancer patients at our institution attempts to address this deficiency. The sodium-iodide symporter (NIS is responsible for the ability of the thyroid gland to transport and concentrate iodide. The characteristics of the NIS gene suggest that it could represent an ideal therapeutic gene for cancer therapy. Published results from Mayo Clinic researchers have indicated several important successes with the use of the NIS gene and prostate gene therapy. Studies have demonstrated that transfer of the human NIS gene into prostate cancer using adenovirus vectors in vitro and in vivo results in efficient uptake of radioactive iodine and significant tumor growth delay with prolongation of survival. Preclinical successes have culminated in the opening of a phase I trial for patients with advanced prostate disease which is currently accruing patients. Further study will reveal the clinical promise of NIS gene therapy in the treatment of prostate as well as other malignancies.

  3. Comprehensive cancer control: progress and accomplishments.

    Science.gov (United States)

    Rochester, Phyllis W; Townsend, Julie S; Given, Leslie; Krebill, Hope; Balderrama, Sandra; Vinson, Cynthia

    2010-12-01

    The potential for Comprehensive Cancer Control (CCC) across the nation has been realized in the last decade with 69 Coalitions developing and implementing CCC plans. Many partners at all levels--national, state, jurisdictional, tribal and communities--have contributed to this success. This article details the contribution of these partners across these various levels, with a selection of the many activities contributing to this success. Consequently the cancer burden, although still of major importance, continues to be addressed in significant ways. Although there are future challenges, CCC coalitions continue to play an important role in addressing the cancer burden. PMID:21069448

  4. PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis

    OpenAIRE

    Su, Zao-Zhong; Goldstein, Neil I.; Jiang, Hongping; Wang, Mei-Nai; Duigou, Gregory J.; Young, Charles S. H.; Fisher, Paul B.

    1999-01-01

    Cancer is a progressive disease culminating in acquisition of metastatic potential by a subset of evolving tumor cells. Generation of an adequate blood supply in tumors by production of new blood vessels, angiogenesis, is a defining element in this process. Although extensively investigated, the precise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a genetic element, progression elevated gene-3 (PEG-3),...

  5. High-throughput genomic technology in research and clinical management of breast cancer. Molecular signatures of progression from benign epithelium to metastatic breast cancer

    OpenAIRE

    Rennstam, Karin; Hedenfalk, Ingrid

    2006-01-01

    It is generally accepted that early detection of breast cancer has great impact on patient survival, emphasizing the importance of early diagnosis. In a widely recognized model of breast cancer development, tumor cells progress through chronological and well defined stages. However, the molecular basis of disease progression in breast cancer remains poorly understood. High-throughput molecular profiling techniques are excellent tools for the study of complex molecular alterations. By accurate...

  6. Molecular genetics of breast cancer progression

    OpenAIRE

    Sigurður Ingvarsson 1956

    1999-01-01

    Somatic changes in the genome of breast cancer cells include amplifications, deletions and gene mutations. Several chromosome regions harboring known oncogenes are found amplified in breast tumors. Despite the high number of chromosome regions deleted in breast tumors the functional relationship to known genes at these locations and cancer growth is mainly undiscovered. Mutations in two tumor suppressor genes (TSG) have been described in a subset of breast carcinomas. These TSG are the TP53, ...

  7. Regulation of prostate cancer progression by the tumor microenvironment.

    Science.gov (United States)

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  8. Formal Modeling and Analysis of Pancreatic Cancer Microenvironment

    OpenAIRE

    Wang, Qinsi; Miskov-Zivanov, Natasa; Liu, Bing; Faeder, James R.; Lotze, Michael; Clarke, Edmund M

    2016-01-01

    The focus of pancreatic cancer research has been shifted from pancreatic cancer cells towards their microenvironment, involving pancreatic stellate cells that interact with cancer cells and influence tumor progression. To quantitatively understand the pancreatic cancer microenvironment, we construct a computational model for intracellular signaling networks of cancer cells and stellate cells as well as their intercellular communication. We extend the rule-based BioNetGen language to depict in...

  9. Metabolic, autophagic, and mitophagic activities in cancer initiation and progression.

    Science.gov (United States)

    Hjelmeland, Anita; Zhang, Jianhua

    2016-04-01

    Cancer is a complex disease marked by uncontrolled cell growth and invasion. These processes are driven by the accumulation of genetic and epigenetic alterations that promote cancer initiation and progression. Contributing to genome changes are the regulation of oxidative stress and reactive species-induced damage to molecules and organelles. Redox regulation, metabolic plasticity, autophagy, and mitophagy play important and interactive roles in cancer hallmarks including sustained proliferation, activated invasion, and replicative immortality. However, the impact of these processes can differ depending on the signaling pathways altered in cancer, tumor type, tumor stage, and/or the differentiation state. Here, we highlight some of the representative studies on the impact of oxidative and nitrosative activities, mitochondrial bioenergetics, metabolism, and autophagy and mitophagy in the context of tumorigenesis. We discuss the implications of these processes for cellular activities in cancer for anti-cancer-based therapeutics. PMID:27372165

  10. Relaxin/RXFP1 Signaling in Prostate Cancer Progression

    OpenAIRE

    Feng, Shu; Agoulnik, Irina U; Li, Zhen; Han, Hee Dong; Lopez-Berestein, Gabriel; Sood, Anil; Ittmann, Michael M.; Agoulnik, Alexander I.

    2009-01-01

    We have shown that relaxin peptide expression was significantly elevated in recurrent human prostate cancer. Stimulation with relaxin increased migration, invasiveness, proliferation, and adhesion of LNCaP and PC3 cells in vitro. Opposite effects on cellular phenotype were observed after suppression of endogenous relaxin/RXFP1 expression or signaling. We showed an accelerated progression of prostate cancer in TRAMP males with transgenic relaxin overexpression and a longer survival of TRAMP, R...

  11. Cabozantinib for progressive metastatic medullary thyroid cancer: a review

    OpenAIRE

    Colombo JR; Wein RO

    2014-01-01

    Joshua R Colombo, Richard O Wein Department of Otolaryngology, Head and Neck Surgery, Tufts Medical Center, Boston, MA, USA Abstract: Medullary thyroid cancer is uncommon and patients typically present with advanced disease. Treatment options for patients with progressive, metastatic medullary thyroid cancer had been limited until recently. Tyrosine kinase inhibitors have garnered increasing interest in this subset of patients. The US Food and Drug Administration recently approved cabozantin...

  12. A computational approach to resolve cell level contributions to early glandular epithelial cancer progression

    OpenAIRE

    Park Sunwoo; Mostov Keith; Debnath Jayanta; Kim Sean HJ; Hunt C Anthony

    2009-01-01

    Abstract Background Three-dimensional (3D) embedded cell cultures provide an appropriate physiological environment to reconstruct features of early glandular epithelial cancer. Although these are orders of magnitude simpler than tissues, they too are complex systems that have proven challenging to understand. We used agent-based, discrete event simulation modeling methods to build working hypotheses of mechanisms of epithelial 3D culture phenotype and early cancer progression. Starting with a...

  13. Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mehta, Kapil, E-mail: kmehta@mdanderson.org; Han, Amy [Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030 (United States); Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030 (United States)

    2011-02-25

    Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer.

  14. Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer

  15. The physics of cancer: The role of epigenetics and chromosome conformation in cancer progression

    Science.gov (United States)

    Naimark, Oleg B.; Nikitiuk, Aleksandr S.; Baudement, Marie-Odile; Forné, Thierry; Lesne, Annick

    2016-08-01

    Cancer progression is generally described in terms of accumulated genetic alterations and ensuing changes in cell properties. However, intermediary modifications are involved in the establishment of cancer cell phenotypes, at different levels of nuclear organization: DNA damages and their structural consequences, epigenetic modifications and their impact on chromatin architecture, changes in chromosome 3D organization. We review some of these alterations with a focus on their physical aspects. The challenge is to understand the multiscale interplay between generic physical mechanisms and specific biological factors in cancer cells. We argue that such an interdisciplinary perspective offers a novel viewpoint on cancer progression, early diagnosis and possibly therapeutic targets.

  16. Radioimmunoimaging progress and its value of pancreatic cancer

    International Nuclear Information System (INIS)

    Radioimmunoimaging (RII) used radiolabeled antibodies for diagnostic imaging of neoplasms. It is based on the Specific binding of antibodies and tumor antigen. Genetic engineering technology promoted the development of a variety of antibodies and derivatives as well as stimulated a in-depth study of radioimmunoimaging. RII plays certain role in tumor diagnosis. Pancreatic cancer high degree of malignan, which arises hiding and progress rapidly. The treatment is difficulty. With development and improvement of monoclonal antibody and application of pre-localization technology and radioimmunoguided surgery, pancreatic cancer RII expected to become an important diagnostic method of the pancreatic cancer. (authors)

  17. Lineage factors and differentiation states in lung cancer progression.

    Science.gov (United States)

    Cheung, W K C; Nguyen, D X

    2015-11-19

    Lung cancer encompasses a heterogeneous group of malignancies. Here we discuss how the remarkable diversity of major lung cancer subtypes is manifested in their transforming cell of origin, oncogenic dependencies, phenotypic plasticity, metastatic competence and response to therapy. More specifically, we review the increasing evidence that links this biological heterogeneity to the deregulation of cell lineage-specific pathways and the transcription factors that ultimately control them. As determinants of pulmonary epithelial differentiation, these poorly characterized transcriptional networks may underlie the etiology and biological progression of distinct lung cancers, while providing insight into innovative therapeutic strategies. PMID:25823023

  18. Genome evolution during progression to breast cancer

    KAUST Repository

    Newburger, D. E.

    2013-04-08

    Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.

  19. Mouse models of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Yunguang Tong; Wancai Yang; H. Phillip Koeffler

    2011-01-01

    Colorectal cancer is one of the most common malignancies in the world. Many mouse models have been developed to evaluate features of colorectal cancer in humans. These can be grouped into genetically-engineered, chemically-induced, and inoculated models. However, none recapitulates all of the characteristics of human colorectal cancer. It is critical to use a specific mouse model to address a particular research question. Here, we review commonly used mouse models for human colorectal cancer.

  20. A superstatistical model of metastasis and cancer survival

    CERN Document Server

    Chen, L Leon

    2007-01-01

    We introduce a superstatistical model for the progression statistics of malignant cancer cells. The metastatic cascade is modeled as a complex nonequilibrium system with several macroscopic pathways and inverse-chi-square distributed parameters of the underlying Poisson processes. The predictions of the model are in excellent agreement with observed survival time probability distributions of breast cancer patients.

  1. Integrin-mediated function of Rab GTPases in cancer progression

    Directory of Open Access Journals (Sweden)

    Alahari Suresh K

    2010-12-01

    Full Text Available Abstract The RAS (rat sarcoma superfamily of small GTPases is broadly subdivided into five groups: Ras, Rho, Rab, Ran, and Arf. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, proliferation, vesicle transport, nuclear assembly, and cytoskeleton formation. However, some Rab proteins have been reported to be necessary for the adhesion and migration of cancer cells. Although Ras and Rho family members have been strongly implicated in cancer progression, knowledge of Rabs action in this regard is limited. Some reports have also linked Rab GTPases with cancer cell migration and invasiveness. This review discusses the implications of the involvement of Rabs in malignant transformation and cancer therapy through integrin-mediated signaling events, with particular emphasis on breast cancer.

  2. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    Directory of Open Access Journals (Sweden)

    MartinTenniswood

    2014-05-01

    Full Text Available Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.

  3. Alterations in Cell-Extracellular Matrix Interactions during Progression of Cancers

    Directory of Open Access Journals (Sweden)

    Rajeswari Jinka

    2012-01-01

    Full Text Available Cancer progression is a multistep process during which normal cells exhibit molecular changes that culminate into the highly malignant and metastatic phenotype, observed in cancerous tissues. The initiation of cell transformation is generally associated with genetic alterations in normal cells that lead to the loss of intercellular- and/or extracellular-matrix- (ECM- mediated cell adhesion. Transformed cells undergo rapid multiplication and generate more modifications in adhesion and motility-related molecules which allow them to escape from the original site and acquire invasive characteristics. Integrins, which are multifunctional adhesion receptors, and are present, on normal as well as transformed cells, assist the cells undergoing tumor progression in creating the appropriate environment for their survival, growth, and invasion. In this paper, we have briefly discussed the role of ECM proteins and integrins during cancer progression and described some unique conditions where adhesion-related changes could induce genetic mutations in anchorage-independent tumor model systems.

  4. Onionin A inhibits ovarian cancer progression by suppressing cancer cell proliferation and the protumour function of macrophages.

    Science.gov (United States)

    Tsuboki, Junko; Fujiwara, Yukio; Horlad, Hasita; Shiraishi, Daisuke; Nohara, Toshihiro; Tayama, Shingo; Motohara, Takeshi; Saito, Yoichi; Ikeda, Tsuyoshi; Takaishi, Kiyomi; Tashiro, Hironori; Yonemoto, Yukihiro; Katabuchi, Hidetaka; Takeya, Motohiro; Komohara, Yoshihiro

    2016-01-01

    It is well known that tumour-associated macrophages (TAMs) play an important role in tumour development by modulating the tumour microenvironment, and targeting of protumour activation or the M2 polarization of TAMs is expected to be an effective therapy for cancer patients. We previously demonstrated that onionin A (ONA), a natural low molecular weight compound isolated from onions, has an inhibitory effect on M2 macrophage polarization. In the present study, we investigated whether ONA had a therapeutic anti-ovarian cancer effect using in vitro and in vivo studies. We found that ONA reduced the extent of ovarian cancer cell proliferation induced by co-culture with human macrophages. In addition, we also found that ONA directly suppressed cancer cell proliferation. A combinatorial effect with ONA and anti-cancer drugs was also observed. The activation of signal transducer and activator of transcription 3 (STAT3), which is involved in cell proliferation and chemo-resistance, was significantly abrogated by ONA in ovarian cancer cells. Furthermore, the administration of ONA suppressed cancer progression and prolonged the survival time in a murine ovarian cancer model under single and combined treatment conditions. Thus, ONA is considered useful for the additional treatment of patients with ovarian cancer owing to its suppression of the protumour activation of TAMs and direct cytotoxicity against cancer cells. PMID:27404320

  5. Epigenetic reduction of DNA repair in progression togastrointestinal cancer

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Deficiencies in DNA repair due to inherited germ-linemutations in DNA repair genes cause increased risk ofgastrointestinal (GI) cancer. In sporadic GI cancers,mutations in DNA repair genes are relatively rare.However, epigenetic alterations that reduce expressionof DNA repair genes are frequent in sporadic GI cancers.These epigenetic reductions are also found in fielddefects that give rise to cancers. Reduced DNA repairlikely allows excessive DNA damages to accumulatein somatic cells. Then either inaccurate translesionsynthesis past the un-repaired DNA damages or errorproneDNA repair can cause mutations. ErroneousDNA repair can also cause epigenetic alterations (i.e. ,epimutations, transmitted through multiple replicationcycles). Some of these mutations and epimutations maycause progression to cancer. Thus, deficient or absentDNA repair is likely an important underlying cause ofcancer. Whole genome sequencing of GI cancers showthat between thousands to hundreds of thousands ofmutations occur in these cancers. Epimutations thatreduce DNA repair gene expression and occur early inprogression to GI cancers are a likely source of this highgenomic instability. Cancer cells deficient in DNA repairare more vulnerable than normal cells to inactivation byDNA damaging agents. Thus, some of the most clinicallyeffective chemotherapeutic agents in cancer treatmentare DNA damaging agents, and their effectivenessoften depends on deficient DNA repair in cancer cells.Recently, at least 18 DNA repair proteins, each activein one of six DNA repair pathways, were found to besubject to epigenetic reduction of expression in GIcancers. Different DNA repair pathways repair differenttypes of DNA damage. Evaluation of which DNA repairpathway(s) are deficient in particular types of GI cancerand/or particular patients may prove useful in guidingchoice of therapeutic agents in cancer therapy.

  6. Cancer care. Cancer plan--progress report: must try even harder.

    Science.gov (United States)

    Coombes, Rebecca

    2004-11-25

    Despite progress in some areas, major obstacle achieving a uniformly good service for cancer patients remain. PCTs' lack of expertise is holding back progress ending delays in diagnosis and treatment. SHAs need to be clearer with PCTs about the importance of meeting national targets. PMID:15597927

  7. CD4+ lymphocytes modulate prostate cancer progression in mice

    OpenAIRE

    Poutahidis, Theofilos; Rao, Varada P.; Olipitz, Werner; Taylor, Christie L.; Jackson, Erin A.; Levkovich, Tatiana; Lee, Chung Wei; Fox, James G.; Ge, Zhongming; Erdman, Susan E

    2009-01-01

    Chronic inflammation contributes to the development of prostate cancer in humans. Here, we show that male ApcMin/+ mice also develop prostate carcinoma with increasing age, mimicking that seen in humans in their 5th or 6th decade of life. Proinflammatory cytokines were significantly linked with cancer and increasing age in our mouse model; however, prostate and bowel tissues lacked evidence of inflammatory cell infiltrates other than mast cells. Lymphocytes protected against cancer, and prote...

  8. Animal Models of Colorectal Cancer

    Science.gov (United States)

    Johnson, Robert L.; Fleet, James C.

    2012-01-01

    Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the United States. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist. PMID:23076650

  9. Hypoxia in models of lung cancer

    DEFF Research Database (Denmark)

    Graves, Edward E; Vilalta, Marta; Cecic, Ivana K;

    2010-01-01

    PURPOSE: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to...... establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. EXPERIMENTAL DESIGN: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or......H2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. RESULTS: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping...

  10. Prolyl-4-hydroxylase α subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition

    International Nuclear Information System (INIS)

    metastasis to lungs in xenograft models. These results suggest the critical role of P4HA2 in breast cancer progression and identify P4HA2 as a potential therapeutic target and biomarker for breast cancer progression

  11. Surgical treatment for progressive prostate cancer: A clinical case

    Directory of Open Access Journals (Sweden)

    E. I. Veliev

    2014-11-01

    Full Text Available In spite of its existing standards, the treatment of patients with progressive prostate cancer (PC remains a matter of debate. Ensuring that the patients have good quality of life is also relevant. The paper describes a clinical case of a patient with progressive PC after hormone therapy, brachytherapy, salvage prostatectomy, enucleation of the testicular parenchyma, and salvage lymphadenectomy. A phallic prosthesis and an artificial urinary sphincter have been implanted to improve quality of life. The results of preoperative examination and the technological features of surgical interventions are given.

  12. Tristetraprolin inhibits gastric cancer progression through suppression of IL-33

    OpenAIRE

    Kaiyuan Deng; Hao Wang; Ting Shan; Yigang Chen; Hong Zhou; Qin Zhao; Jiazeng Xia

    2016-01-01

    Tristetraprolin (TTP) is an adenine/uridine (AU)-rich element (ARE)-binding protein that can induce degradation of mRNAs. In this study, we report that TTP suppresses the expression of interleukin-33 (IL-33), a tumor-promoting inflammatory cytokine, and thereby inhibits the progression of gastric cancer (GC). Overexpression of TTP decreased the level of IL-33, whereas knockdown of TTP increased IL-33 levels. We also discovered that TTP inhibited the proliferation, migration, and invasion of G...

  13. ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer.

    Directory of Open Access Journals (Sweden)

    Guadalupe Lorenzatti Hiles

    Full Text Available ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable

  14. Engineered Swine Models of Cancer.

    Science.gov (United States)

    Watson, Adrienne L; Carlson, Daniel F; Largaespada, David A; Hackett, Perry B; Fahrenkrug, Scott C

    2016-01-01

    Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications. PMID:27242889

  15. Engineered Swine Models of Cancer

    Science.gov (United States)

    Watson, Adrienne L.; Carlson, Daniel F.; Largaespada, David A.; Hackett, Perry B.; Fahrenkrug, Scott C.

    2016-01-01

    Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications.

  16. Engineered Swine Models of Cancer

    Directory of Open Access Journals (Sweden)

    Adrienne L. Watson

    2016-05-01

    Full Text Available Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications.

  17. Mathematical models of breast and ovarian cancers.

    Science.gov (United States)

    Botesteanu, Dana-Adriana; Lipkowitz, Stanley; Lee, Jung-Min; Levy, Doron

    2016-07-01

    Women constitute the majority of the aging United States (US) population, and this has substantial implications on cancer population patterns and management practices. Breast cancer is the most common women's malignancy, while ovarian cancer is the most fatal gynecological malignancy in the US. In this review, we focus on these subsets of women's cancers, seen more commonly in postmenopausal and elderly women. In order to systematically investigate the complexity of cancer progression and response to treatment in breast and ovarian malignancies, we assert that integrated mathematical modeling frameworks viewed from a systems biology perspective are needed. Such integrated frameworks could offer innovative contributions to the clinical women's cancers community, as answers to clinical questions cannot always be reached with contemporary clinical and experimental tools. Here, we recapitulate clinically known data regarding the progression and treatment of the breast and ovarian cancers. We compare and contrast the two malignancies whenever possible in order to emphasize areas where substantial contributions could be made by clinically inspired and validated mathematical modeling. We show how current paradigms in the mathematical oncology community focusing on the two malignancies do not make comprehensive use of, nor substantially reflect existing clinical data, and we highlight the modeling areas in most critical need of clinical data integration. We emphasize that the primary goal of any mathematical study of women's cancers should be to address clinically relevant questions. WIREs Syst Biol Med 2016, 8:337-362. doi: 10.1002/wsbm.1343 For further resources related to this article, please visit the WIREs website. PMID:27259061

  18. Molecular sampling of prostate cancer: a dilemma for predicting disease progression

    Directory of Open Access Journals (Sweden)

    Mucci Lorelei A

    2010-03-01

    Full Text Available Abstract Background Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. Methods We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively. Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Results Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. Conclusions The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.

  19. Contribution of Epithelial-Mesenchymal Transition to Pancreatic Cancer Progression

    Directory of Open Access Journals (Sweden)

    Hidayatullah G. Munshi

    2010-12-01

    Full Text Available Pancreatic adenocarcinoma (PDAC is one of the most lethal human malignancies, with median survival of less than one year and overall five-year survival of less than 5%. There is increasing evidence demonstrating that epithelial-mesenchymal transition (EMT contributes to pancreatic cancer metastasis and to treatment resistance. In this review, we will examine the data demonstrating the role and regulation of EMT in pancreatic cancer progression, focusing particularly on the transcription factors and microRNAs involved in EMT. We will examine how EMT is involved in the generation and maintenance of stem cells, and the role of EMT in modulating resistance of PDAC cells to drug therapies. We will also identify putative EMT-targeting agents that may help to reduce the morbidity and mortality associated with pancreatic cancer.

  20. Oct-4 is associated with gastric cancer progression and prognosis

    Directory of Open Access Journals (Sweden)

    Jiang WL

    2016-01-01

    Full Text Available Wen-Li Jiang,1 Peng-Fei Zhang,2 Guo-Feng Li,1 Jian-Hua Dong,1 Xue-Song Wang,1 Yuan-Yu Wang3 1Department of Surgery, Juxian People’s Hospital, 2Department of Surgery, Rizhao People’s Hospital of Traditional Chinese Medicine, Rizhao, 3Department of Gastrointestinal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China Aim: To investigate the clinical significance of Oct-4 in the development and progression of gastric cancer.Methods: Immunohistochemistry was used to analyze Oct-4 expression in 412 gastric cancer cases. Oct-4 protein levels were upregulated in gastric cancer tissues compared with adjacent noncancerous tissues.Results: Positive expression of Oct-4 correlated with age, depth of invasion, Lauren classification, lymph node metastasis, distant metastasis, and TNM stage. In stages I, II, and III, the 5-year survival rate of patients with high expression of Oct-4 was significantly lower than that in patients with low expression of Oct-4. In stage IV, Oct-4 expression did not correlate with the 5-year survival rate. Furthermore, multivariate analysis suggested that the depth of invasion, lymph node metastasis, distant metastasis, TNM stage, and upregulation of Oct-4 were independent prognostic factors of gastric cancer.Conclusion: Oct-4 protein is a useful marker in predicting tumor progression and prognosis. Keywords: gastric carcinoma, invasion, metastasis, survival rate

  1. Tpl2 induces castration resistant prostate cancer progression and metastasis.

    Science.gov (United States)

    Lee, Hye Won; Cho, Hyun Jung; Lee, Se Jeong; Song, Hye Jin; Cho, Hee Jin; Park, Min Chul; Seol, Ho Jun; Lee, Jung-Il; Kim, Sunghoon; Lee, Hyun Moo; Choi, Han Yong; Nam, Do-Hyun; Joo, Kyeung Min

    2015-05-01

    Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC. PMID:25274482

  2. On an orthotropic model for progressive degradation

    DEFF Research Database (Denmark)

    Hammer, Velaja B.; Pedersen, Pauli

    1999-01-01

    Progressive degradation in orthotropic materials is modelled from a smear-out point of view, and physical measurable quantities are used as the describing parameters. Evolution of stiffness and evolution of strength are kept uncoupled. For plane problems the stiffness evolution is modelled by the...

  3. MicroRNA-17~92 inhibits colorectal cancer progression by targeting angiogenesis.

    Science.gov (United States)

    Ma, Huabin; Pan, Jin-Shui; Jin, Li-Xin; Wu, Jianfeng; Ren, Yan-Dan; Chen, Pengda; Xiao, Changchun; Han, Jiahuai

    2016-07-01

    The miR-17~92 microRNA (miRNA) cluster host gene is upregulated in a broad spectrum of human cancers including colorectal cancer (CRC). Previous studies have shown that miR-17~92 promotes tumorigenesis and cancer angiogenesis in some tumor models. However, its role in the initiation and progression of CRC remains unknown. In this study, we found that transgenic mice overexpressing miR-17~92 specifically in epithelial cells of the small and large intestines exhibited decreased tumor size and tumor angiogenesis in azoxymethane and dextran sulfate sodium salt (AOM-DSS)-induced CRC model as compared to their littermates control. Further study showed that miR-17~92 inhibited the progression of CRC via suppressing tumor angiogenesis through targeting multiple tumor angiogenesis-inducing genes, TGFBR2, HIF1α, and VEGFA in vivo and in vitro. Collectively, we demonstrated that miR-17~92 suppressed tumor progression by inhibiting tumor angiogenesis in a genetically engineered mouse model, indicating the presence of cellular context-dependent pro- and anti-cancer effects of miR-17~92. PMID:27080303

  4. Mouse models for cancer research

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Lynette Moore; Ping Ji

    2011-01-01

    Mouse models of cancer enable researchers to leamn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Joumnal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue.

  5. Chitosan oligosaccharide suppresses tumor progression in a mouse model of colitis-associated colorectal cancer through AMPK activation and suppression of NF-κB and mTOR signaling.

    Science.gov (United States)

    Mattaveewong, Tharinee; Wongkrasant, Preedajit; Chanchai, Sumalee; Pichyangkura, Rath; Chatsudthipong, Varanuj; Muanprasat, Chatchai

    2016-07-10

    Novel, effective and safe agents are needed for the chemoprevention of colorectal cancer (CRC). This study investigated the effects of chitosan oligosaccharides (COS) on CRC progression and their underlying mechanisms and safety profiles in mice. Using a mouse model of colitis-associated CRC, we found that oral administration of COS (500mg/kg/day) resulted in a ∼60% reduction of tumor size and tumor numbers/sectioning. In addition, COS treatment increased AMPK activity, suppressed the NF-κB-mediated inflammatory response and reduced the expressions of cyclin D1, phosphorylated ribosomal protein S6, and MMP-9 in the colon tissues of these mice. Importantly, administration of COS (500mg/kg/day; 50 days) had no adverse effects on renal or liver functions. Our results indicate that COS suppressed CRC progression via AMPK activation and the suppression of NF-κB and mTOR signaling. COS may be of potential utility in the chemoprevention of CRC. PMID:27106148

  6. Quantification of mouse pulmonary cancer models by microcomputed tomography imaging

    International Nuclear Information System (INIS)

    The advances in preclinical cancer models, including orthotopic implantation models or genetically engineered mouse models of cancer, enable pursuing the molecular mechanism of cancer disease that might mimic genetic and biological processes in humans. Lung cancer is the major cause of cancer deaths; therefore, the treatment and prevention of lung cancer are expected to be improved by a better understanding of the complex mechanism of disease. In this study, we have examined the quantification of two distinct mouse lung cancer models by utilizing imaging modalities for monitoring tumor progression and drug efficacy evaluation. The utility of microcomputed tomography (micro-CT) for real-time/non-invasive monitoring of lung cancer progression has been confirmed by combining bioluminescent imaging and histopathological analyses. Further, we have developed a more clinically relevant lung cancer model by utilizing K-rasLSL-G12D/p53LSL-R270H mutant mice. Using micro-CT imaging, we monitored the development and progression of solitary lung tumor in K-rasLSL-G12D/p53LSL-R270H mutant mouse, and further demonstrated tumor growth inhibition by anticancer drug treatment. These results clearly indicate that imaging-guided evaluation of more clinically relevant tumor models would improve the process of new drug discovery and increase the probability of success in subsequent clinical studies. (author)

  7. Antiangiogenic cancer drug using the zebrafish model.

    Science.gov (United States)

    Santoro, Massimo M

    2014-09-01

    The process of de novo vessel formation, called angiogenesis, is essential for tumor progression and spreading. Targeting of molecular pathways involved in such tumor angiogenetic processes by using specific drugs or inhibitors is important for developing new anticancer therapies. Drug discovery remains to be the main focus for biomedical research and represents the essence of antiangiogenesis cancer research. To pursue these molecular and pharmacological goals, researchers need to use animal models that facilitate the elucidation of tumor angiogenesis mechanisms and the testing of antiangiogenic therapies. The past few years have seen the zebrafish system emerge as a valid model organism to study developmental angiogenesis and, more recently, as an alternative vertebrate model for cancer research. In this review, we will discuss why the zebrafish model system has the advantage of being a vertebrate model equipped with easy and powerful transgenesis as well as imaging tools to investigate not only physiological angiogenesis but also tumor angiogenesis. We will also highlight the potential of zebrafish for identifying antitumor angiogenesis drugs to block tumor development and progression. We foresee the zebrafish model as an important system that can possibly complement well-established mouse models in cancer research to generate novel insights into the molecular mechanism of the tumor angiogenesis. PMID:24903092

  8. Cancer Metabolism: A Modeling Perspective

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    . Cancer cells present in complex tumor tissues communicate with the surrounding microenvironment and develop traits which promote their growth, survival, and metastasis. Decoding the full scope and targeting dysregulated metabolic pathways that support neoplastic transformations and their preservation...... suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells...... requires both the advancement of experimental technologies for more comprehensive measurement of omics as well as the advancement of robust computational methods for accurate analysis of the generated data. Here, we review cancer-associated reprogramming of metabolism and highlight the capability of genome...

  9. Modeling Disease Progression with Longitudinal Markers

    OpenAIRE

    Inoue, Lurdes Y.T.; Etzioni, Ruth; Morrell, Christopher; Müller, Peter

    2008-01-01

    In this paper we propose a Bayesian natural history model for disease progression based on the joint modeling of longitudinal biomarker levels, age at clinical detection of disease and disease status at diagnosis. We establish a link between the longitudinal responses and the natural history of the disease by using an underlying latent disease process which describes the onset of the disease and models the transition to an advanced stage of the disease as dependent on the biomarker levels. We...

  10. The role of S100 genes in breast cancer progression.

    LENUS (Irish Health Repository)

    McKiernan, Eadaoin

    2011-06-01

    The S100 gene family encode low molecular weight proteins implicated in cancer progression. In this study, we analyzed the expression of four S100 genes in one cohort of patients with breast cancer and 16 S100 genes in a second cohort. In both cohorts, the expression of S100A8 and S1009 mRNA level was elevated in high-grade compared to low-grade tumors and in estrogen receptor-negative compared to estrogen receptor-positive tumors. None of the S100 transcripts investigated were significantly associated with the presence of lymph node metastasis. Notably, multiple S100 genes, including S100A1, S100A2, S100A4, S100A6, S100A8, S100A9, S100A10, S100A11, and S100A14 were upregulated in basal-type breast cancers compared to non-basal types. Using Spearman\\'s correlation analysis, several S100 transcripts correlated significantly with each other, the strongest correlation has been found between S100A8 and S100A9 (r = 0.889, P < 0.001, n = 295). Of the 16 S100 transcripts investigated, only S100A11 and S100A14 were significantly associated with patient outcome. Indeed, these two transcripts predicted outcome in the cohort of patients that did not receive systemic adjuvant therapy. Based on our findings, we conclude that the different S100 genes play varying roles in breast cancer progression. Specific S100 genes are potential targets for the treatment of basal-type breast cancers.

  11. The role of S100 genes in breast cancer progression.

    LENUS (Irish Health Repository)

    McKiernan, Eadaoin

    2012-02-01

    The S100 gene family encode low molecular weight proteins implicated in cancer progression. In this study, we analyzed the expression of four S100 genes in one cohort of patients with breast cancer and 16 S100 genes in a second cohort. In both cohorts, the expression of S100A8 and S1009 mRNA level was elevated in high-grade compared to low-grade tumors and in estrogen receptor-negative compared to estrogen receptor-positive tumors. None of the S100 transcripts investigated were significantly associated with the presence of lymph node metastasis. Notably, multiple S100 genes, including S100A1, S100A2, S100A4, S100A6, S100A8, S100A9, S100A10, S100A11, and S100A14 were upregulated in basal-type breast cancers compared to non-basal types. Using Spearman\\'s correlation analysis, several S100 transcripts correlated significantly with each other, the strongest correlation has been found between S100A8 and S100A9 (r = 0.889, P < 0.001, n = 295). Of the 16 S100 transcripts investigated, only S100A11 and S100A14 were significantly associated with patient outcome. Indeed, these two transcripts predicted outcome in the cohort of patients that did not receive systemic adjuvant therapy. Based on our findings, we conclude that the different S100 genes play varying roles in breast cancer progression. Specific S100 genes are potential targets for the treatment of basal-type breast cancers.

  12. Cyr61 promotes breast tumorigenesis and cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, Miaw-Sheue; Bogart, Daphne F.; Castaneda, Jessica M.; Li, Patricia; Lupu, Ruth

    2002-01-16

    Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the ''normal'' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and anti-E2 resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.

  13. Progress With Nonhuman Animal Models of Addiction.

    Science.gov (United States)

    Crabbe, John C

    2016-09-01

    Nonhuman animals have been major contributors to the science of the genetics of addiction. Given the explosion of interest in genetics, it is fair to ask, are we making reasonable progress toward our goals with animal models? I will argue that our goals are changing and that overall progress has been steady and seems likely to continue apace. Genetics tools have developed almost incredibly rapidly, enabling both more reductionist and more synthetic or integrative approaches. I believe that these approaches to making progress have been unbalanced in biomedical science, favoring reductionism, particularly in animal genetics. I argue that substantial, novel progress is also likely to come in the other direction, toward synthesis and abstraction. Another area in which future progress with genetic animal models seems poised to contribute more is the reconciliation of human and animal phenotypes, or consilience. The inherent power of the genetic animal models could be more profitably exploited. In the end, animal research has continued to provide novel insights about how genes influence individual differences in addiction risk and consequences. The rules of the genetics game are changing so fast that it is hard to remember how comparatively little we knew even a generation ago. Rather than worry about whether we have been wasting time and resources asking the questions we have been, we should look to the future and see if we can come up with some new ones. The valuable findings from the past will endure, and the sidetracks will be forgotten. PMID:27588527

  14. Algorithmic methods to infer the evolutionary trajectories in cancer progression

    OpenAIRE

    Caravagna, Giulio; Graudenzi, Alex; Ramazzotti, Daniele; Sanz-Pamplona, Rebeca; De Sano, Luca; Mauri, Giancarlo; Moreno, Victor; Antoniotti, Marco; Mishra, Bud

    2016-01-01

    The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next generation sequencing (NGS) data, and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the di...

  15. Entropy, complexity, and Markov diagrams for random walk cancer models

    Science.gov (United States)

    Newton, Paul K.; Mason, Jeremy; Hurt, Brian; Bethel, Kelly; Bazhenova, Lyudmila; Nieva, Jorge; Kuhn, Peter

    2014-12-01

    The notion of entropy is used to compare the complexity associated with 12 common cancers based on metastatic tumor distribution autopsy data. We characterize power-law distributions, entropy, and Kullback-Liebler divergence associated with each primary cancer as compared with data for all cancer types aggregated. We then correlate entropy values with other measures of complexity associated with Markov chain dynamical systems models of progression. The Markov transition matrix associated with each cancer is associated with a directed graph model where nodes are anatomical locations where a metastatic tumor could develop, and edge weightings are transition probabilities of progression from site to site. The steady-state distribution corresponds to the autopsy data distribution. Entropy correlates well with the overall complexity of the reduced directed graph structure for each cancer and with a measure of systemic interconnectedness of the graph, called graph conductance. The models suggest that grouping cancers according to their entropy values, with skin, breast, kidney, and lung cancers being prototypical high entropy cancers, stomach, uterine, pancreatic and ovarian being mid-level entropy cancers, and colorectal, cervical, bladder, and prostate cancers being prototypical low entropy cancers, provides a potentially useful framework for viewing metastatic cancer in terms of predictability, complexity, and metastatic potential.

  16. Hypothermia activates adipose tissue to promote malignant lung cancer progression.

    Directory of Open Access Journals (Sweden)

    Gangjun Du

    Full Text Available Microenvironment has been increasingly recognized as a critical regulator of cancer progression. In this study, we identified early changes in the microenvironment that contribute to malignant progression. Exposure of human bronchial epithelial cells (BEAS-2B to methylnitrosourea (MNU caused a reduction in cell toxicity and an increase in clonogenic capacity when the temperature was lowered from 37°C to 28°C. Hypothermia-incubated adipocyte media promoted proliferation in A549 cells. Although a hypothermic environment could increase urethane-induced tumor counts and Lewis lung cancer (LLC metastasis in lungs of three breeds of mice, an increase in tumor size could be discerned only in obese mice housed in hypothermia. Similarly, coinjections using differentiated adipocytes and A549 cells promoted tumor development in athymic nude mice when adipocytes were cultured at 28°C. Conversely, fat removal suppressed tumor growth in obese C57BL/6 mice inoculated with LLC cells. Further studies show hypothermia promotes a MNU-induced epithelial-mesenchymal transition (EMT and protects the tumor cell against immune control by TGF-β1 upregulation. We also found that activated adipocytes trigger tumor cell proliferation by increasing either TNF-α or VEGF levels. These results suggest that hypothermia activates adipocytes to stimulate tumor boost and play critical determinant roles in malignant progression.

  17. Clonal selection for transcriptionally active viral oncogenes during progression to cancer.

    OpenAIRE

    Tine, BA Van; Kappes, JC; Banerjee, NS; Knops, J.; Lai, L; Steenbergen, R D M; Meijer, C J L M; Snijders, P J F; Chatis, P; Broker, TR; Moen, PTJr; Chow, L T

    2004-01-01

    Primary keratinocytes immortalized by human papillomaviruses (HPVs), along with HPV-induced cervical carcinoma cell lines, are excellent models for investigating neoplastic progression to cancer. By simultaneously visualizing viral DNA and nascent viral transcripts in interphase nuclei, we demonstrated for the first time a selection for a single dominant papillomavirus transcription center or domain (PVTD) independent of integrated viral DNA copy numbers or loci. The PVTD did not associate wi...

  18. Immunological network signatures of cancer progression and survival

    Directory of Open Access Journals (Sweden)

    Lavelle Timothy J

    2011-03-01

    Full Text Available Abstract Background The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. Methods To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. Results The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. Conclusions The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding

  19. Research Progress of Lung Cancer with Leptomeningeal Metastasis

    Directory of Open Access Journals (Sweden)

    Chunhua MA

    2014-09-01

    Full Text Available Leptomeningeal metastases is one of the most serious complications of lung cancer, the patients with poor prognosis. Leptomeningeal metastasis in patients with lack specificity of clinical manifestations. The main clinical performance are the damage of cerebral symptoms, cranial nerve and spinal nerve. The diagnosis primarily based on the history of tumor, clinical symptoms, enhance magnetic resnance image (MRI scan and cerebrospinal fluid cytology. In recent years, new ways of detecting clinically, significantly increase the rate of early detection of leptomeningeal metastases. The effect of comprehensive treatments are still sad. The paper make a review of research progress in pathologic physiology, clinical manifestations, diagnosis methods and treatments of lung cancer with leptomeningeal metastases.

  20. S100A7 and the progression of breast cancer

    International Nuclear Information System (INIS)

    The S100 gene family comprises more than 20 members whose protein sequences encompass at least one EF-hand Ca2+ binding motif. The expression of individual family members is not ubiquitous for all tissues and there appears to be an element of tissue-specific expression. Molecular analysis of breast tumors has revealed that several S100s, including S100A2, S100A4 and S100A7, exhibit altered expression levels during breast tumorigenesis and/or progression. Subsequent studies have started to describe a functional role for these S100 proteins as well as their mechanism of action and the biochemical pathways they modify. The present review outlines what is known about S100A7 in breast cancer and summarizes the need to better understand the importance of this protein in breast cancer

  1. Checkpoint inhibition for colorectal cancer: progress and possibilities.

    Science.gov (United States)

    Paul, Barry; O'Neil, Bert H; McRee, Autumn J

    2016-06-01

    Colorectal cancer (CRC) remains the third most common cause of cancer death in the USA. Despite an increase in the repertoire of treatment options available for CRC, median overall survival has plateaued at approximately 2.5 years. Strategies that engage the patient's native immune system to overcome checkpoint inhibition have proven to be promising in subsets of CRCs, specifically those with mismatch repair deficiency. Further studies are required to determine combinations of standard therapies with immunotherapy drugs and to discover the best biomarkers to predict response. This review provides insight into the progress made in treating patients with advanced CRC with immunotherapeutics and the areas that demand further research to make these drugs more effective in this patient population. PMID:27197538

  2. Towards Laser Driven Hadron Cancer Radiotherapy: A Review of Progress

    CERN Document Server

    Ledingham, K W D; Shikazono, N; Ma, C-M

    2014-01-01

    It has been known for about sixty years that proton and heavy ion therapy is a very powerful radiation procedure for treating tumours. It has an innate ability to irradiate tumours with greater doses and spatial selectivity compared with electron and photon therapy and hence is a tissue sparing procedure. For more than twenty years powerful lasers have generated high energy beams of protons and heavy ions and hence it has been frequently speculated that lasers could be used as an alternative to RF accelerators to produce the particle beams necessary for cancer therapy. The present paper reviews the progress made towards laser driven hadron cancer therapy and what has still to be accomplished to realise its inherent enormous potential.

  3. Towards Laser Driven Hadron Cancer Radiotherapy: A Review of Progress

    Directory of Open Access Journals (Sweden)

    Ken W. D. Ledingham

    2014-09-01

    Full Text Available It has been known for about sixty years that proton and heavy ion therapy is a very powerful radiation procedure for treating tumors. It has an innate ability to irradiate tumors with greater doses and spatial selectivity compared with electron and photon therapy and, hence, is a tissue sparing procedure. For more than twenty years, powerful lasers have generated high energy beams of protons and heavy ions and it has, therefore, frequently been speculated that lasers could be used as an alternative to radiofrequency (RF accelerators to produce the particle beams necessary for cancer therapy. The present paper reviews the progress made towards laser driven hadron cancer therapy and what has still to be accomplished to realize its inherent enormous potential.

  4. Oct-4 is associated with gastric cancer progression and prognosis

    OpenAIRE

    Jiang WL; Zhang PF; Li GF; Dong JH; Wang XS; Wang YY

    2016-01-01

    Wen-Li Jiang,1 Peng-Fei Zhang,2 Guo-Feng Li,1 Jian-Hua Dong,1 Xue-Song Wang,1 Yuan-Yu Wang3 1Department of Surgery, Juxian People’s Hospital, 2Department of Surgery, Rizhao People’s Hospital of Traditional Chinese Medicine, Rizhao, 3Department of Gastrointestinal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China Aim: To investigate the clinical significance of Oct-4 in the development and progression of gastric cancer.Meth...

  5. Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression

    International Nuclear Information System (INIS)

    It is well recognized that colorectal cancer does not frequently metastasize to bone. The aim of this retrospective study was to establish whether colorectal cancer ever bypasses other organs and metastasizes directly to bone and whether the presence of lung lesions is superior to liver as a better predictor of the likelihood and timing of bone metastasis. We performed a retrospective analysis on patients with a clinical diagnosis of colon cancer referred for staging using whole-body 18F-FDG PET and CT or PET/CT. We combined PET and CT reports from 252 individuals with information concerning patient history, other imaging modalities, and treatments to analyze disease progression. No patient had isolated osseous metastasis at the time of diagnosis, and none developed isolated bone metastasis without other organ involvement during our survey period. It took significantly longer for colorectal cancer patients to develop metastasis to the lungs (23.3 months) or to bone (21.2 months) than to the liver (9.8 months). Conclusion: Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare, perhaps more rare than we previously thought. Our findings suggest that resistant metastasis to the lungs predicts potential disease progression to bone in the colorectal cancer population better than liver metastasis does

  6. Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression

    Directory of Open Access Journals (Sweden)

    Gayed Isis W

    2009-08-01

    Full Text Available Abstract Background It is well recognized that colorectal cancer does not frequently metastasize to bone. The aim of this retrospective study was to establish whether colorectal cancer ever bypasses other organs and metastasizes directly to bone and whether the presence of lung lesions is superior to liver as a better predictor of the likelihood and timing of bone metastasis. Methods We performed a retrospective analysis on patients with a clinical diagnosis of colon cancer referred for staging using whole-body 18F-FDG PET and CT or PET/CT. We combined PET and CT reports from 252 individuals with information concerning patient history, other imaging modalities, and treatments to analyze disease progression. Results No patient had isolated osseous metastasis at the time of diagnosis, and none developed isolated bone metastasis without other organ involvement during our survey period. It took significantly longer for colorectal cancer patients to develop metastasis to the lungs (23.3 months or to bone (21.2 months than to the liver (9.8 months. Conclusion: Metastasis only to bone without other organ involvement in colorectal cancer patients is extremely rare, perhaps more rare than we previously thought. Our findings suggest that resistant metastasis to the lungs predicts potential disease progression to bone in the colorectal cancer population better than liver metastasis does.

  7. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression.

    Science.gov (United States)

    Feinberg, Andrew P; Koldobskiy, Michael A; Göndör, Anita

    2016-05-01

    This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer. PMID:26972587

  8. Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression.

    Science.gov (United States)

    Linn, Douglas E; Penney, Kathryn L; Bronson, Roderick T; Mucci, Lorelei A; Li, Zhe

    2016-04-01

    TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency. We found that only the mice that lacked the interstitial region developed prostate adenocarcinomas marked by poor differentiation and epithelial-to-mesenchymal transition. Mechanistic investigations identified several interstitial genes, including Ets2 and Bace2, whose reduced expression correlated in the gene homologs in human prostate cancer with biochemical relapse and lethal disease. Accordingly, PTEN-deficient mice with prostate-specific knockout of Ets2 exhibited marked progression of prostate adenocarcinomas that was partly attributed to activation of MAPK signaling. Collectively, our findings established that Ets2 is a tumor suppressor gene in prostate cancer, and its loss along with other genes within the TMPRSS2-ERG interstitial region contributes to disease progression. Cancer Res; 76(7); 1869-81. ©2016 AACR. PMID:26880803

  9. Lung Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing lung cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  10. Prostate Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing prostate cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  11. Breast Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing breast cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  12. Ovarian Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  13. Cervical Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing cervical cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  14. Liver Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing liver cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  15. Pancreatic Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing pancreatic cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  16. Colorectal Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing colorectal cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  17. Intakes of meat, fish, poultry, and eggs and risk of prostate cancer progression1234

    OpenAIRE

    Richman, Erin L; Stampfer, Meir J.; Paciorek, Alan; Broering, Jeanette M; Carroll, Peter R.; Chan, June M.

    2009-01-01

    Background: Processed meat and fish have been shown to be associated with the risk of advanced prostate cancer, but few studies have examined diet after prostate cancer diagnosis and risk of its progression.

  18. Plac8 Links Oncogenic Mutations to Regulation of Autophagy and Is Critical to Pancreatic Cancer Progression

    Directory of Open Access Journals (Sweden)

    Conan Kinsey

    2014-05-01

    Full Text Available Mutations in p53 and RAS potently cooperate in oncogenic transformation, and correspondingly, these genetic alterations frequently coexist in pancreatic ductal adenocarcinoma (PDA and other human cancers. Previously, we identified a set of genes synergistically activated by combined RAS and p53 mutations as frequent downstream mediators of tumorigenesis. Here, we show that the synergistically activated gene Plac8 is critical for pancreatic cancer growth. Silencing of Plac8 in cell lines suppresses tumor formation by blocking autophagy, a process essential for maintaining metabolic homeostasis in PDA, and genetic inactivation in an engineered mouse model inhibits PDA progression. We show that Plac8 is a critical regulator of the autophagic machinery, localizing to the lysosomal compartment and facilitating lysosome-autophagosome fusion. Plac8 thus provides a mechanistic link between primary oncogenic mutations and the induction of autophagy, a central mechanism of metabolic reprogramming, during PDA progression.

  19. Tumor-derived exosomes in cancer progression and treatment failure.

    Science.gov (United States)

    Yu, Shaorong; Cao, Haixia; Shen, Bo; Feng, Jifeng

    2015-11-10

    Exosomes have diameter within the range of 30-100 nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  20. Desmoglein 3: A Help or a Hindrance in Cancer Progression?

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Louise [Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Center for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Blizard Building, London E1 2AT (United Kingdom); Department of Cellular and Molecular Physiology, University of Liverpool, Institute of Translational Medicine, Liverpool L69 3BX (United Kingdom); Wan, Hong, E-mail: h.wan@qmul.ac.uk [Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Center for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Blizard Building, London E1 2AT (United Kingdom)

    2015-01-26

    Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and structural integrity. Like adherens junctions, desmosomes function as tumour suppressors and are down regulated in the process of epithelial-mesenchymal transition and in tumour cell invasion and metastasis. However, recently several studies have shown that various desmosomal components, including desmoglein 3, are up-regulated in cancer with increased levels of expression correlating with the clinical stage of malignancy, implicating their potentiality to serve as a diagnostic and prognostic marker. Furthermore, in vitro studies have demonstrated that overexpression of desmoglein 3 in cancer cell lines activates several signal pathways that have an impact on cell morphology, adhesion and locomotion. These additional signalling roles of desmoglein 3 may not be associated to its adhesive function in desmosomes but rather function outside of the junctions, acting as a key regulator in the control of actin based cellular processes. This review will discuss recent advances which support the role of desmoglein 3 in cancer progression.

  1. Desmoglein 3: A Help or a Hindrance in Cancer Progression?

    International Nuclear Information System (INIS)

    Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and structural integrity. Like adherens junctions, desmosomes function as tumour suppressors and are down regulated in the process of epithelial-mesenchymal transition and in tumour cell invasion and metastasis. However, recently several studies have shown that various desmosomal components, including desmoglein 3, are up-regulated in cancer with increased levels of expression correlating with the clinical stage of malignancy, implicating their potentiality to serve as a diagnostic and prognostic marker. Furthermore, in vitro studies have demonstrated that overexpression of desmoglein 3 in cancer cell lines activates several signal pathways that have an impact on cell morphology, adhesion and locomotion. These additional signalling roles of desmoglein 3 may not be associated to its adhesive function in desmosomes but rather function outside of the junctions, acting as a key regulator in the control of actin based cellular processes. This review will discuss recent advances which support the role of desmoglein 3 in cancer progression

  2. Engineered Swine Models of Cancer

    OpenAIRE

    Watson, Adrienne L; Carlson, Daniel F.; Largaespada, David A; Hackett, Perry B; Fahrenkrug, Scott C.

    2016-01-01

    Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs...

  3. A computational approach to resolve cell level contributions to early glandular epithelial cancer progression

    Directory of Open Access Journals (Sweden)

    Park Sunwoo

    2009-12-01

    Full Text Available Abstract Background Three-dimensional (3D embedded cell cultures provide an appropriate physiological environment to reconstruct features of early glandular epithelial cancer. Although these are orders of magnitude simpler than tissues, they too are complex systems that have proven challenging to understand. We used agent-based, discrete event simulation modeling methods to build working hypotheses of mechanisms of epithelial 3D culture phenotype and early cancer progression. Starting with an earlier software analogue, we validated an improved in silico epithelial analogue (ISEA for cardinal features of a normally developed MDCK cyst. A set of axiomatic operating principles defined simulated cell actions. We explored selective disruption of individual simulated cell actions. New framework features enabled recording detailed measures of ISEA cell activities and morphology. Results Enabled by a small set of cell operating principles, ISEA cells multiplied and self-organized into cyst-like structures that mimicked those of MDCK cells in a 3D embedded cell culture. Selective disruption of "anoikis" or directional cell division caused the ISEA to develop phenotypic features resembling those of in vitro tumor reconstruction models and cancerous tissues in vivo. Disrupting either process, or both, altered cell activity patterns that resulted in morphologically similar outcomes. Increased disruption led to a prolonged presence of intraluminal cells. Conclusions ISEA mechanisms, behaviors, and morphological properties may have biological counterparts. To the extent that in silico-to-in vitro mappings are valid, the results suggest plausible, additional mechanisms of in vitro cancer reconstruction or reversion, and raise potentially significant implications for early cancer diagnosis based on histology. Further ISEA development and use are expected to provide a viable platform to complement in vitro methods for unraveling the mechanistic basis of

  4. Progression of Diabetic Capillary Occlusion: A Model.

    Directory of Open Access Journals (Sweden)

    Xiao Fu

    2016-06-01

    Full Text Available An explanatory computational model is developed of the contiguous areas of retinal capillary loss which play a large role in diabetic maculapathy and diabetic retinal neovascularization. Strictly random leukocyte mediated capillary occlusion cannot explain the occurrence of large contiguous areas of retinal ischemia. Therefore occlusion of an individual capillary must increase the probability of occlusion of surrounding capillaries. A retinal perifoveal vascular sector as well as a peripheral retinal capillary network and a deleted hexagonal capillary network are modelled using Compucell3D. The perifoveal modelling produces a pattern of spreading capillary loss with associated macular edema. In the peripheral network, spreading ischemia results from the progressive loss of the ladder capillaries which connect peripheral arterioles and venules. System blood flow was elevated in the macular model before a later reduction in flow in cases with progression of capillary occlusions. Simulations differing only in initial vascular network structures but with identical dynamics for oxygen, growth factors and vascular occlusions, replicate key clinical observations of ischemia and macular edema in the posterior pole and ischemia in the retinal periphery. The simulation results also seem consistent with quantitative data on macular blood flow and qualitative data on venous oxygenation. One computational model applied to distinct capillary networks in different retinal regions yielded results comparable to clinical observations in those regions.

  5. The Multifunctional Protein Kinase C-ε in Cancer Development and Progression

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Kirti; Basu, Alakananda, E-mail: alakananda.basu@unthsc.edu [Department of Molecular and Medical Genetics, University of North Texas Health Science Center, Institute for Cancer Research, and Focused on Resources for her Health Education and Research, Fort Worth, TX 76107 (United States)

    2014-04-10

    The protein kinase C (PKC) family proteins are important signal transducers and have long been the focus of cancer research. PKCε, a member of this family, is overexpressed in most solid tumors and plays critical roles in different processes that lead to cancer development. Studies using cell lines and animal models demonstrated the transforming potential of PKCε. While earlier research established the survival functions of PKCε, recent studies revealed its role in cell migration, invasion and cancer metastasis. PKCε has also been implicated in epithelial to mesenchymal transition (EMT), which may be the underlying mechanism by which it contributes to cell motility. In addition, PKCε affects cell-extracellular matrix (ECM) interactions by direct regulation of the cytoskeletal elements. Recent studies have also linked PKCε signaling to cancer stem cell functioning. This review focuses on the role of PKCε in different processes that lead to cancer development and progression. We also discussed current literatures on the pursuit of PKCε as a target for cancer therapy.

  6. The Multifunctional Protein Kinase C-ε in Cancer Development and Progression

    International Nuclear Information System (INIS)

    The protein kinase C (PKC) family proteins are important signal transducers and have long been the focus of cancer research. PKCε, a member of this family, is overexpressed in most solid tumors and plays critical roles in different processes that lead to cancer development. Studies using cell lines and animal models demonstrated the transforming potential of PKCε. While earlier research established the survival functions of PKCε, recent studies revealed its role in cell migration, invasion and cancer metastasis. PKCε has also been implicated in epithelial to mesenchymal transition (EMT), which may be the underlying mechanism by which it contributes to cell motility. In addition, PKCε affects cell-extracellular matrix (ECM) interactions by direct regulation of the cytoskeletal elements. Recent studies have also linked PKCε signaling to cancer stem cell functioning. This review focuses on the role of PKCε in different processes that lead to cancer development and progression. We also discussed current literatures on the pursuit of PKCε as a target for cancer therapy.

  7. The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression

    International Nuclear Information System (INIS)

    E-cadherin is a cell–cell adhesion protein fulfilling a prominent role in epithelial differentiation. Data from model systems suggest that E-cadherin is a potent invasion/tumor suppressor of breast cancer. Consistent with this role in breast cancer progression, partial or complete loss of E-cadherin expression has been found to correlate with poor prognosis in breast cancer patients. The E-cadherin gene (CDH1) is located on human chromosome 16q22.1, a region frequently affected with loss of heterozygosity in sporadic breast cancer. Invasive lobular breast carcinomas, which are typically completely E-cadherin-negative, often show inactivating mutations in combination with loss of heterozygosity of the wild-type CDH1 allele. Mutations were found at early noninvasive stages, thus associating E-cadherin mutations with loss of cell growth control and defining CDH1 as the tumor suppressor for the lobular breast cancer subtype. Ductal breast cancers in general show heterogeneous loss of E-cadherin expression, associated with epigenetic transcriptional downregulation. It is proposed that the microenvironment at the invasive front is transiently downregulating E-cadherin transcription. This can be associated with induction of nonepithelial cadherins

  8. Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression.

    Science.gov (United States)

    Mir, R; Pradhan, S J; Patil, P; Mulherkar, R; Galande, S

    2016-03-31

    The chromatin organizer SATB1 has been implicated in the development and progression of multiple cancers including breast and colorectal cancers. However, the regulation and role of SATB1 in colorectal cancers is poorly understood. Here, we demonstrate that expression of SATB1 is induced upon hyperactivation of Wnt/β-catenin signaling and repressed upon depletion of TCF7L2 (TCF4) and β-catenin. Using several colorectal cancer cell line models and the APC min mutant zebrafish in vivo model, we established that SATB1 is a novel target of Wnt/β-catenin signaling. We show that direct binding of TCF7L2/β-catenin complex on Satb1 promoter is required for the regulation of SATB1. Moreover, SATB1 is sufficient to regulate the expression of β-catenin, members of TCF family, multiple downstream effectors and mediators of Wnt pathway. SATB1 potentiates the cellular changes and expression of key cancer-associated genes in non-aggressive colorectal cells, promotes their aggressive phenotype and tumorigenesis in vivo. Conversely, depletion of SATB1 from aggressive cells reprograms the expression of cancer-associated genes, reverses their cancer phenotype and reduces the potential of these cells to develop tumors in vivo. We also show that SATB1 and β-catenin bind to the promoters of TCF7L2 and the downstream targets of Wnt signaling and regulate their expression. Our findings suggest that SATB1 shares a feedback regulatory network with TCF7L2/β-catenin signaling and is required for Wnt signaling-dependent regulation of β-catenin. Collectively, these results provide unequivocal evidence to establish that SATB1 reprograms the expression of tumor growth- and metastasis-associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling critical for colorectal cancer tumorigenesis. PMID:26165840

  9. Mouse models of intestinal inflammation and cancer.

    Science.gov (United States)

    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With

  10. Paracrine effects of stem cells in wound healing and cancer progression

    OpenAIRE

    DITTMER, JÜRGEN; Leyh, Benjamin

    2014-01-01

    Stem cells play an important role in tissue repair and cancer development. The capacity to self-renew and to differentiate to specialized cells allows tissue-specific stem cells to rebuild damaged tissue and cancer stem cells to initiate and promote cancer. Mesenchymal stem cells, attracted to wounds and cancer, facilitate wound healing and support cancer progression primarily by secreting bioactive factors. There is now growing evidence that, like mesenchymal stem cells, also tissue-specific...

  11. Dual roles of PARP-1 promote cancer growth and progression

    OpenAIRE

    Schiewer, Matthew J.; Goodwin, Jonathan F.; Han, Sumin; Brenner, J. Chad; Augello, Michael A.; Dean, Jeffry L.; Liu, Fengzhi; Planck, Jamie L.; Ravindranathan, Preethi; Chinnaiyan, Arul M.; McCue, Peter; Gomella, Leonard G.; Raj, Ganesh V; Dicker, Adam P.; Brody, Jonathan R

    2012-01-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair, and also functions as a context-specific regulator of transcription factors. Using multiple models, data demonstrate that PARP-1 elicits pro-tumorigenic effects in androgen receptor (AR)-positive prostate cancer (PCa) cells, both in the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited ...

  12. Alterations in mechanical properties are associated with prostate cancer progression.

    Science.gov (United States)

    Wang, Xuejian; Wang, Jianbo; Liu, Yingxi; Zong, Huafeng; Che, Xiangyu; Zheng, Wei; Chen, Feng; Zhu, Zheng; Yang, Deyong; Song, Xishuang

    2014-03-01

    Cancer progression and metastasis have been shown to be accompanied by alterations in the mechanical properties of tissues, but the relationship between the mechanical properties and malignant behavior in prostate cancer (Pca) is less clear. The aims of this study were to detect the mechanical properties of benign prostatic hyperplasia (BPH) and Pca tissues on both the macro- and micro-scales, to explore the relationships between mechanical properties and malignant behavior and, finally, to identify the important molecules in the mechanotransduction signaling pathway. We demonstrated that the strain index of Pca tissue was significantly higher than that of BPH tissue on the macro-scale but the Young's modulus of the Pca tissues, especially in advanced Pca, was lower than that of BPH tissues on the micro-scale. These two seemingly contradictory results can be explained by the excessive proliferation of tumor cells (Ki-67) and the degradation of scaffold proteins (collagens). These data indicate that alterations of the macro- and micro-mechanical properties of Pca tissues with malignant behavior are contradictory. The mechanical properties of tissues might be useful as a new risk factor for malignancy and metastasis in Pca. Furthermore, collagens, matrix metalloproteinase, fibronectin, and integrins might be the important molecules in the mechanotransduction signaling pathway. PMID:24504844

  13. Role of Proprotein Convertases in Prostate Cancer Progression

    Directory of Open Access Journals (Sweden)

    Frédéric Couture

    2012-11-01

    Full Text Available Better understanding of the distinct and redundant functions of the proprotein convertase (PC enzyme family within pathophysiological states has a great importance for potential therapeutic strategies. In this study, we investigated the functional redundancy of PCs in prostate cancer in the commonly used androgen-sensitive LNCaP and the androgen-independent DU145 human cell lines. Using a lentiviral-based shRNA delivery system, we examined in vitro and in vivo cell proliferation characteristics of knockdown cell lines for the endogenous PCs furin, PACE4, and PC7 in both cell lines. Of the three PCs, only PACE4 was essential to maintain a high-proliferative status, as determined in vitro using XTT proliferation assays and in vivo using tumor xenografts in nude mice. Furin knockdowns in both cell lines had no effects on cell proliferation or tumor xenograft growth. Paradoxically, PC7 knockdowns reduced in vitro cellular proliferation but had no effect in vivo. Because PCs act within secretion pathways, we showed that conditioned media derived from PACE4 knockdown cells had very poor cell growth-stimulating effects in vitro. Immunohistochemistry of PACE4 knockdown tumors revealed reduced Ki67 and higher p27KIP levels (proliferation and cell cycle arrest markers, respectively. Interestingly, we determined that the epidermal growth factor receptor signaling pathway was activated in PC7 knockdown tumors only, providing some explanations of the paradoxical effects of PC7 silencing in prostate cancer cell lines. We conclude that PACE4 has a distinct role in maintaining proliferation and tumor progression in prostate cancer and this positions PACE4 as a relevant therapeutic target for this disease.

  14. Effect of Proton Beam on Cancer Progressive and Metastatic Enzymes

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate the effect of proton beam on enzymes for promotion/progression of carcinogenesis and metastasis of malignant tumor cells to clarify proton beam-specific biological effects. The changes of cancer chemopreventive enzymes in human colorectal adenocarcinoma HT-29 cells irradiated with proton beams were tested by measuring the activities of quinine reductase (QR), glutathione S-transferase (GST), and ornithine decarboxylase (ODC), glutathione (GSH) levels, and expression of cyclooxygenase-2 (COX-2). We also examined the effect of proton beam on the ODC activity and expression of COX-2 in human breast cancer cell. We then assessed the metastatic capabilities of HT-29 and MDA-MB-231 cells irradiated with proton beam by measuring the invasiveness of cells through Matrigel-coated membrane and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP activity in MDA-MB-231 and HT-29 cells. QR activity of irradiated HT-29 cells was slightly increased. Proton irradiation at dose of 32 Gy in HT-29 cells increased GST activity by 1.23-fold. In addition GSH levels in HT-29 cells was significantly increased 1.23- (p<0.05), 1.32- (p<0.01) and 1.34-fold (p<0.01) with the proton irradiation at doses of 8, 16 and 32 Gy, respectively. These results suggest that colon cancer chemopreventive activity was increased with the proton irradiation by increasing QR and GST activities and GSH levels and inhibiting ODC activity. Proton ion irradiation decreased the invasiveness of TPA-treated HT-29 cells and MDA-MB-231 cells through Matrigel-coated membrane. Proton ion irradiation pretreatment decreased TPA-induced MMP activity in MDA-MB-231 and HT-29 cells. Further studies are necessary to investigate if these findings could be translated to in vivo situations

  15. Syndecans as modulators and potential pharmacological targets in cancer progression

    Directory of Open Access Journals (Sweden)

    NikosKaramanos

    2014-02-01

    Full Text Available Extracellular matrix (ECM components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs, a family of transmembrane heparan sulfate proteoglycans (HSPGs. Specifically, heparan sulfate (HS chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases (MMPs, ADAM as well as ADΑMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble syndecans “shed syndecans” in the extracellular matrix interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed syndecans, upon binding to several matrix effectors, such as growth factors, chemokines and cytokines, have the ability to act as competitive inhibitors for membrane PGs, and modulate the inflammatory microenvironment of cancer cells. It is notable that syndecans and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of syndecans in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.

  16. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

    Science.gov (United States)

    Paschall, Amy V; Liu, Kebin

    2016-01-01

    Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo. PMID:27584043

  17. Mouse models for colorectal cancer

    OpenAIRE

    KARIM, BAKTIAR O.; Huso, David L.

    2013-01-01

    Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with the number of affected people increasing. There are many risk factors that increase CRC risk, including family or personal history of CRC, smoking, consumption of red meat, obesity, and alcohol consumption. Conversely, increased screening, maintaining healthy body weight, not smoking, and limiting intake of red meat are all associated with reduced CRC morbidity and mortality. Mouse models of ...

  18. Establishing of the Transplanted Animal Models for Human Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Xingli Zhang; Jinchang Wu

    2009-01-01

    Lung cancer is the leading cause of cancer mortality worldwide.Even with the applications of excision,radiotherapy,chemotherapy,and gene therapy,the 5 year survival rate is only 15% in the USA.Clinically relevant laboratory animal models of the disease could greatly facilitate understanding of the pathogenesis of lung cancer,its progression,invasion and metastasis.Transplanted lung cancer models are of special interest and are widely used today.Such models are essential tools in accelerating development of new therapies for lung cancer.In this communication we will present a brief overview of the hosts,sites and pathways used to establish transplanted animal lung tumor models.

  19. MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer.

    Science.gov (United States)

    Valeri, Nicola; Braconi, Chiara; Gasparini, Pierluigi; Murgia, Claudio; Lampis, Andrea; Paulus-Hock, Viola; Hart, Jonathan R; Ueno, Lynn; Grivennikov, Sergei I; Lovat, Francesca; Paone, Alessio; Cascione, Luciano; Sumani, Khlea M; Veronese, Angelo; Fabbri, Muller; Carasi, Stefania; Alder, Hansjuerg; Lanza, Giovanni; Gafa', Roberta; Moyer, Mary P; Ridgway, Rachel A; Cordero, Julia; Nuovo, Gerard J; Frankel, Wendy L; Rugge, Massimo; Fassan, Matteo; Groden, Joanna; Vogt, Peter K; Karin, Michael; Sansom, Owen J; Croce, Carlo M

    2014-04-14

    MicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment. PMID:24735923

  20. An iPSC Line from Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression

    Directory of Open Access Journals (Sweden)

    Jungsun Kim

    2013-06-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC carries a dismal prognosis and lacks a human cell model of early disease progression. When human PDAC cells are injected into immunodeficient mice, they generate advanced-stage cancer. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC lines were not of the expected cancer genotype, one PDAC line, 10–22 cells, when injected into immunodeficient mice, generated pancreatic intraepithelial neoplasia (PanIN precursors to PDAC that progressed to the invasive stage. The PanIN-like cells secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4α network in intermediate-stage lesions. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression.

  1. Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer.

    Science.gov (United States)

    Fu, De-Yuan; Tan, Hao-Sheng; Wei, Jin-Li; Zhu, Chang-Ren; Jiang, Ji-Xin; Zhu, Yu-Xiang; Cai, Feng-Lin; Chong, Mei-Hong; Ren, Chuan-Li

    2015-09-01

    The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer. PMID:25971583

  2. Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression

    OpenAIRE

    2015-01-01

    Transforming growth factor-beta (TGF-β) and oxidative stress/Reactive Oxygen Species (ROS) both have pivotal roles in health and disease. In this review we are analyzing the interplay between TGF-β and ROS in tumorigenesis and cancer progression. They have contradictory roles in cancer progression since both can have antitumor effects, through the induction of cell death, senescence and cell cycle arrest, and protumor effects by contributing to cancer cell spreading, proliferation, survival, ...

  3. Fasting inhibits human cancer progression via the epithelial-mesenchymal transition process: Important evidence unraveled

    OpenAIRE

    Ala-Eddin Al Moustafa

    2012-01-01

    Metastatic cancer disease is responsible for the majority of cancer-related deaths in human cancer patients. In parallel, recently it was pointed-out that fasting could play an important role during cancer treatment and progression via the deregulation of insulin-like growth factor-1 (IGF-1) as well as others growth factors and genes. Meanwhile, it is established that the epithelial-mesenchymal transition (EMT) is a major process for the progression of cancer cells from non-invasive to invasi...

  4. DIONISIO Progress Report and Code Models

    International Nuclear Information System (INIS)

    The extension of the DIONISIO code to the high burnup range requires the incorporation of some specific models to represent the main phenomena that take place in the external pellet ring. The development of a different structure in the pellet periphery composed by small grains and large pores, the deterioration of the thermal conductivity, the development of a burnup profile that reaches high values in the pellet rim, among other related phenomena, are nowadays accepted to be consequences of the progressive accumulation of fissile Pu that takes place particularly in the outer pellet ring. Models to represent these phenomena, which were taken from the open literature, are presently under evaluation or were already included in DIONISIO

  5. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    Energy Technology Data Exchange (ETDEWEB)

    Schaal, Courtney [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States); Padmanabhan, Jaya [Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave., Tampa, FL 33612 (United States); Chellappan, Srikumar, E-mail: Srikumar.Chellappan@moffitt.org [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States)

    2015-07-31

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer.

  6. Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Liu, Zijuan; Bharadwaj, Uddalak; Wang, Hao; Wang, Xinwen; Zhang, Sheng; Liuzzi, Juan P; Chang, Shou-Mei; Cousins, Robert J; Fisher, William E; Brunicardi, F Charles; Logsdon, Craig D; Chen, Changyi; Yao, Qizhi

    2007-11-20

    Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth. PMID:18003899

  7. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

    International Nuclear Information System (INIS)

    Highlights: ► A novel FAK inhibitor TAE226 suppressed FAK activity in HCT116 colon cancer cells. ► TAE226 suppressed proliferation and migration, with a modest effect on adhesion. ► Silencing of FAK by siRNA made no obvious difference on cancer cell attachment. ► TAE226 treatment suppressed the progression of peritoneal dissemination. ► Oral administration of TAE226 prolonged the survival of tumor-bearing mice. -- Abstract: Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable

  8. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Hui-fang [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Takaoka, Munenori [Department of General Surgery, Kawasaki Medical School, 2-1-80 Nakasange, Kita-ku, Okayama 700-8505 (Japan); Bao, Xiao-hong [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Wang, Zhi-gang [College of Life Science, Inner Mongolia University, The Key Laboratory of Mammal Reproductive Biology and Biotechnology, Ministry of Education, Hohhot 010021 (China); Tomono, Yasuko [Division of Molecular and Cell Biology, Shigei Medical Research Institute, 2117 Yamada, Okayama 700-0202 (Japan); Sakurama, Kazufumi; Ohara, Toshiaki [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Fukazawa, Takuya; Yamatsuji, Tomoki [Department of General Surgery, Kawasaki Medical School, 2-1-80 Nakasange, Kita-ku, Okayama 700-8505 (Japan); Fujiwara, Toshiyoshi [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Naomoto, Yoshio, E-mail: ynaomoto@med.kawasaki-m.ac.jp [Department of General Surgery, Kawasaki Medical School, 2-1-80 Nakasange, Kita-ku, Okayama 700-8505 (Japan)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer A novel FAK inhibitor TAE226 suppressed FAK activity in HCT116 colon cancer cells. Black-Right-Pointing-Pointer TAE226 suppressed proliferation and migration, with a modest effect on adhesion. Black-Right-Pointing-Pointer Silencing of FAK by siRNA made no obvious difference on cancer cell attachment. Black-Right-Pointing-Pointer TAE226 treatment suppressed the progression of peritoneal dissemination. Black-Right-Pointing-Pointer Oral administration of TAE226 prolonged the survival of tumor-bearing mice. -- Abstract: Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken

  9. A microengineered pathophysiological model of early-stage breast cancer.

    Science.gov (United States)

    Choi, Yoonseok; Hyun, Eunjeh; Seo, Jeongyun; Blundell, Cassidy; Kim, Hee Chan; Lee, Eunhee; Lee, Su Hyun; Moon, Aree; Moon, Woo Kyung; Huh, Dongeun

    2015-08-21

    A mounting body of evidence in cancer research suggests that the local microenvironment of tumor cells has a profound influence on cancer progression and metastasis. In vitro studies on the tumor microenvironment and its pharmacological modulation, however, are often hampered by the technical challenges associated with creating physiological cell culture environments that integrate cancer cells with the key components of their native niche such as neighboring cells and extracellular matrix (ECM) to mimic complex microarchitecture of cancerous tissue. Using early-stage breast cancer as a model disease, here we describe a biomimetic microengineering strategy to reconstitute three-dimensional (3D) structural organization and microenvironment of breast tumors in human cell-based in vitro models. Specifically, we developed a microsystem that enabled co-culture of breast tumor spheroids with human mammary ductal epithelial cells and mammary fibroblasts in a compartmentalized 3D microfluidic device to replicate microarchitecture of breast ductal carcinoma in situ (DCIS). We also explored the potential of this breast cancer-on-a-chip system as a drug screening platform by evaluating the efficacy and toxicity of an anticancer drug (paclitaxel). Our microengineered disease model represents the first critical step towards recapitulating pathophysiological complexity of breast cancer, and may serve as an enabling tool to systematically examine the contribution of the breast cancer microenvironment to the progression of DCIS to an invasive form of the disease. PMID:26158500

  10. The reverse transcriptase encoded by LINE-1 retrotransposons in the genesis, progression and therapy of cancer

    Directory of Open Access Journals (Sweden)

    Ilaria eSciamanna

    2016-02-01

    Full Text Available In higher eukaryotic genomes, Long Interspersed Nuclear Element 1 (LINE-1 retrotransposons represent a large family of repeated genomic elements. They transpose using a reverse transcriptase (RT, which they encode as part of the ORF2p product. RT inhibition in cancer cells, either via RNA interference-dependent silencing of active LINE-1 elements, or using RT inhibitory drugs, reduces cancer cell proliferation, promotes their differentiation and antagonizes tumor progression in animal models. Indeed, the nonnucleoside RT inhibitor efavirenz has recently been tested in a phase II clinical trial with metastatic prostate cancer patients. An in-depth analysis of ORF2p in a mouse model of breast cancer showed ORF2p to be precociously expressed in precancerous lesions and highly abundant in advanced cancer stages, while being barely detectable in normal breast tissue, providing a rationale for the finding that RT-expressing tumours are therapeutically sensitive to RT inhibitors. We summarise mechanistic and gene profiling studies indicating that highly abundant LINE-1-derived RT can sequester RNA substrates for reverse transcription in tumor cells, entailing the formation of RNA:DNA hybrid molecules and impairing the overall production of regulatory miRNAs, with a global impact on the cell transcriptome. Based on these data, LINE-1-ORF2 encoded RT has a tumor-promoting potential that is exerted at an epigenetic level. We propose a model whereby LINE1-RT drives a previously unrecognized global regulatory process, the deregulation of which drives cell transformation and tumorigenesis and possibly implicated in cancer cell heterogeneity.

  11. The reverse transcriptase encoded by LINE-1 retrotransposons in the genesis, progression and therapy of cancer

    Science.gov (United States)

    Sciamanna, Ilaria; De Luca, Chiara; Spadafora, Corrado

    2016-02-01

    In higher eukaryotic genomes, Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons represent a large family of repeated genomic elements. They transpose using a reverse transcriptase (RT), which they encode as part of the ORF2p product. RT inhibition in cancer cells, either via RNA interference-dependent silencing of active LINE-1 elements, or using RT inhibitory drugs, reduces cancer cell proliferation, promotes their differentiation and antagonizes tumor progression in animal models. Indeed, the nonnucleoside RT inhibitor efavirenz has recently been tested in a phase II clinical trial with metastatic prostate cancer patients. An in-depth analysis of ORF2p in a mouse model of breast cancer showed ORF2p to be precociously expressed in precancerous lesions and highly abundant in advanced cancer stages, while being barely detectable in normal breast tissue, providing a rationale for the finding that RT-expressing tumours are therapeutically sensitive to RT inhibitors. We summarise mechanistic and gene profiling studies indicating that highly abundant LINE-1-derived RT can “sequester” RNA substrates for reverse transcription in tumor cells, entailing the formation of RNA:DNA hybrid molecules and impairing the overall production of regulatory miRNAs, with a global impact on the cell transcriptome. Based on these data, LINE-1-ORF2 encoded RT has a tumor-promoting potential that is exerted at an epigenetic level. We propose a model whereby LINE1-RT drives a previously unrecognized global regulatory process, the deregulation of which drives cell transformation and tumorigenesis and possibly implicated in cancer cell heterogeneity.

  12. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

    OpenAIRE

    Abiko, K; Matsumura, N; Hamanishi, J; Horikawa, N.(Nagoya University, Nagoya, 464, Japan); Murakami, R; K. Yamaguchi; Yoshioka, Y; Baba, T; Konishi, I; Mandai, M

    2015-01-01

    Background: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. Methods: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse...

  13. Using the MCF10A/MCF10CA1a Breast Cancer Progression Cell Line Model to Investigate the Effect of Active, Mutant Forms of EGFR in Breast Cancer Development and Treatment Using Gefitinib.

    Directory of Open Access Journals (Sweden)

    Darrell C Bessette

    Full Text Available Basal-like and triple negative breast cancer (TNBC share common molecular features, poor prognosis and a propensity for metastasis to the brain. Amplification of epidermal growth factor receptor (EGFR occurs in ~50% of basal-like breast cancer, and mutations in the epidermal growth factor receptor (EGFR have been reported in up to ~ 10% of Asian TNBC patients. In non-small cell lung cancer several different mutations in the EGFR tyrosine kinase domain confer sensitivity to receptor tyrosine kinase inhibitors, but the tumourigenic potential of EGFR mutations in breast cells and their potential for targeted therapy is unknown.Constructs containing wild type, G719S or E746-A750 deletion mutant forms of EGFR were transfected into the MCF10A breast cells and their tumorigenic derivative, MCF10CA1a. The effects of EGFR over-expression and mutation on proliferation, migration, invasion, response to gefitinib, and tumour formation in vivo was investigated. Copy number analysis and whole exome sequencing of the MCF10A and MCF10CA1a cell lines were also performed.Mutant EGFR increased MCF10A and MCF10CA1a proliferation and MCF10A gefitinib sensitivity. The EGFR-E746-A750 deletion increased MCF10CA1a cell migration and invasion, and greatly increased MCF10CA1a xenograft tumour formation and growth. Compared to MCF10A cells, MCF10CA1a cells exhibited large regions of gain on chromosomes 3 and 9, deletion on chromosome 7, and mutations in many genes implicated in cancer.Mutant EGFR enhances the oncogenic properties of MCF10A cell line, and increases sensitivity to gefitinib. Although the addition of EGFR E746-A750 renders the MCF10CA1a cells more tumourigenic in vivo it is not accompanied by increased gefitinib sensitivity, perhaps due to additional mutations, including the PIK3CA H1047R mutation, that the MCF10CA1a cell line has acquired. Screening TNBC/basal-like breast cancer for EGFR mutations may prove useful for directing therapy but, as in non

  14. Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer.

    Directory of Open Access Journals (Sweden)

    Hisae Nakamura

    Full Text Available Genistein is an isoflavone found in soy, and its chemo-preventive and -therapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. To clarify in vivo effects of genistein in advanced prostate cancer patients, we developed a patient-derived prostate cancer xenograft model, in which a clinical prostatectomy sample was grafted into immune deficient mice. Our results showed an increased lymph node (LN and secondary organ metastases in genistein-treated mice compared to untreated controls. Interestingly, invasive malignant cells aggregated to form islands/micrometastasis only in the secondary organs of the genistein-treated groups, not in the untreated control group. To understand the underlying mechanism for metastatic progression, we examined cell proliferation and apoptosis on paraffin-sections. Immunohistological data show that tumors of genistein-treated groups have more proliferating and fewer apoptotic cancer cells than those of the untreated group. Our immunoblotting data suggest that increased proliferation and metastasis are linked to enhanced activities of tyrosine kinases, EGFR and its downstream Src, in genistein-treated groups. Despite the chemopreventive effects proposed by earlier in vitro studies, the cancer promoting effect of genistein observed here suggests the need for careful selection of patients and safer planning of clinical trials.

  15. The Valuable Role of Measuring Serum Lipid Profile in Cancer Progression

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    Farahnaz Ghahremanfard

    2015-09-01

    Full Text Available Objective: Serum lipid levels are not only associated with etiology, but also with prognosis in cancer. To investigate this issue further, we aimed to evaluate the serum levels of lipids in association with the most important prognostic indicators in cancer patients at the start of chemotherapy. Methods: In a retrospective cross-sectional study, using existing medical records obtained from 2009–2014, the data of all incident cancer cases in Iranian patients referred to the Semnan oncology clinic for chemotherapy were analyzed. Data on demographics, cancer type, prognostic indicators (e.g. lymph node involvement, metastasis, and stage of disease, as well as the patient’s lipid profile were collected. We used multiple logistic regression models to show the relationship between prognosis indicators and lipid profile adjusting for age, gender, and type of cancer. Results: The data of 205 patients was gathered. We found a significant difference in the lipid profile between different types of cancers (breast, colon, gastric, and ovarian. With the exception of high-density lipoprotein levels in women, which were higher than in men, the means of other lipid profiles were similar between the genders. There was a significant association between higher levels of low-density lipoprotein (LDL >110mg/dL in the serum and metastasis (adjusted odds ratio=2.4, 95% CI 1.2–3.5. No significant association was reported between lipid profile and lymph nodes involvement and stage of the disease. Conclusion: Our study suggested a benefit of measuring serum levels of lipids for predicting cancer progression. Increased LDL levels can be considered a predictive factor for increasing the risk of metastasis.

  16. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

    Science.gov (United States)

    Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

    2016-06-30

    Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  17. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment

    OpenAIRE

    Li, Kang; Dan, Zeng; Nie, Yu-Qiang

    2014-01-01

    In recent decades, the study of the mechanism of tumorigenesis has brought much progress to cancer treatment. However, cancer stem cell (CSC) theory has changed previous views of tumors, and has provided a new method for treatment of cancer. The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development, resulting in a new effective strategy for cancer treatment. Gastric CSCs (GCSCs) are the basis for the onset of gas...

  18. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Loomans, Holli A. [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Andl, Claudia D., E-mail: claudia.andl@vanderbilt.edu [Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Digestive Disease Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Vanderbilt Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2014-12-30

    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion.

  19. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

    International Nuclear Information System (INIS)

    In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFβ and highlights how its dysregulation contributes to cancer progression and cell invasion

  20. Exosomes from the tumor microenvironment as reciprocal regulators that enhance prostate cancer progression.

    Science.gov (United States)

    Liu, Che-Ming; Hsieh, Chia-Ling; Shen, Chia-Ning; Lin, Cheng-Chieh; Shigemura, Katsumi; Sung, Shian-Ying

    2016-09-01

    Distant organ metastasis of prostate cancer is a puzzle, and various theories have successively arisen to explain the mechanism of lethal cancer progression. While perhaps agreeable to many cancer biologists, the very statement of "seed and soil" proposed by Stephan Paget in 1881 is arguably still the major statement for organ-specific cancer metastasis. Since recent studies showed important correlations of regulation of cancer cells and the microenvironment, exosomes from cancer and stromal cells seem to create another important niche for metastasis. Stromal cells pretreated with exosomes from metastatic cancer cells increase the potential of change stromal cells. The poorly metastatic cancer cells could also enhance malignancy through transfer of proteins, microribonucleic acid and messenger ribonucleic acid to recipient cancer cells. Herein, we reviewed extracellular exosomes as a factor involved in cross-talk between stromal and prostate cancer epithelial cells. PMID:27397852

  1. The fundamental role of mechanical properties in the progression of cancer disease and inflammation

    Science.gov (United States)

    Mierke, Claudia Tanja

    2014-07-01

    The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in

  2. A risk evaluation model of cervical cancer based on etiology and human leukocyte antigen allele susceptibility

    OpenAIRE

    Bicheng Hu; Ning Tao; Fanyu Zeng; Min Zhao; Lixin Qiu; Wen Chen; Yun Tan; Yun Wei; Xufeng Wu; Xinxing Wu

    2014-01-01

    Background: There are no reliable risk factors to accurately predict progression to cervical cancer in patients with chronic cervicitis infected with human papillomavirus (HPV). The aim of this study was to create a validated predictive model based on the risk factors for cervical cancer. A model to estimate the risk of cervical cancer may help select patients for intervention therapy in order to reduce the occurrence of cervical cancer after HPV infection. Methods: This retrospective anal...

  3. ANIMAL MODELS OF CANCER: A REVIEW

    OpenAIRE

    Archana M Navale

    2013-01-01

    Cancer is the second leading cause of death worldwide. In USA three persons out of five will develop some type of cancer. Beyond these statistics of mortality, the morbidity due to cancer presents a real scary picture. Last 50 years of research has rendered some types of cancer curable, but still the major fear factor associated with this disease is unchanged. Animal models are classified according to the method of induction of cancer in the animal. Spontaneous tumor models are the most primi...

  4. MUC1 Regulates PDGFA Expression During Pancreatic Cancer Progression

    Science.gov (United States)

    Sahraei, Mahnaz; Roy, Lopamudra Das; Curry, Jennifer M; Teresa, Tinder L; Nath, Sritama; Besmer, Dahlia; Kidiyoor, Amritha; Dalia, Ritu; Gendler, Sandra J; Mukherjee, Pinku

    2012-01-01

    Pancreatic Ductal Adenocarcinoma (PDA) has one of the worst prognoses of all cancers. Mucin 1 (MUC1), a transmembrane mucin glycoprotein, is a key modulator of several signaling pathways that affect oncogenesis, motility, and metastasis. Its expression is known to be associated with poor prognosis in patients. However, the precise mechanism remains elusive. We report a novel association of MUC1 with Platelet-Derived Growth Factor-A (PDGFA). PDGFA is one of the many drivers of tumor growth, angiogenesis, and metastasis in PDA. Using mouse PDA models as well as human samples, we show clear evidence that MUC1 regulates the expression and secretion of PDGFA. This, in turn, influences proliferation and invasion of pancreatic cancer cells leading to higher tumor burden in vivo. In addition, we reveal that MUC1 over expressing cells are heavily dependent on PDGFA both for proliferation and invasion while MUC1-null cells are not. Moreover, PDGFA and MUC1 are critical for translocation of βcatenin to the nucleus for oncogenesis to ensue. Finally, we elucidate the underlying mechanism by which MUC1 regulates PDGFA expression and secretion in pancreatic cancer cells. We show that MUC1 associates with Hif1-α, a known transcription factor involved in controlling PDGFA expression. Furthermore, MUC1 facilitates Hif1-α translocation to the nucleus. In summary, we have demonstrated that MUC1-induced invasion and proliferation occurs via increased exogenous production of PDGFA. Thus, impeding MUC1 regulation of PDGFA signaling may be therapeutically beneficial for patients with PDA. PMID:22266848

  5. Systemic Chemotherapy for Progression of Brain Metastases in Extensive-Stage Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Nagla Abdel Karim

    2015-01-01

    Full Text Available Lung cancer is the most common cause of cancer related mortality in men and women. Approximately 15% of lung cancers are small cell type. Chemotherapy and radiation are the mainstay treatments. Currently, the standard chemotherapy regimen includes platinum/etoposide. For extensive small cell lung cancer, irinotecan and cisplatin have also been used. Patients with relapsed small cell lung cancer have a very poor prognosis, and the morbidity increases with brain metastases. Approximately 10%–14% of small cell lung cancer patients exhibit brain metastases at the time of diagnosis, which increases to 50%–80% as the disease progresses. Mean survival with brain metastases is reported to be less than six months, thus calling for improved regimens. Here we present a case series of patients treated with irinotecan for progressive brain metastases in small cell lung cancer, which serves as a reminder of the role of systemic chemotherapy in this setting.

  6. Network analysis of breast cancer progression and reversal using a tree-evolving network algorithm.

    Directory of Open Access Journals (Sweden)

    Ankur P Parikh

    2014-07-01

    Full Text Available The HMT3522 progression series of human breast cells have been used to discover how tissue architecture, microenvironment and signaling molecules affect breast cell growth and behaviors. However, much remains to be elucidated about malignant and phenotypic reversion behaviors of the HMT3522-T4-2 cells of this series. We employed a "pan-cell-state" strategy, and analyzed jointly microarray profiles obtained from different state-specific cell populations from this progression and reversion model of the breast cells using a tree-lineage multi-network inference algorithm, Treegl. We found that different breast cell states contain distinct gene networks. The network specific to non-malignant HMT3522-S1 cells is dominated by genes involved in normal processes, whereas the T4-2-specific network is enriched with cancer-related genes. The networks specific to various conditions of the reverted T4-2 cells are enriched with pathways suggestive of compensatory effects, consistent with clinical data showing patient resistance to anticancer drugs. We validated the findings using an external dataset, and showed that aberrant expression values of certain hubs in the identified networks are associated with poor clinical outcomes. Thus, analysis of various reversion conditions (including non-reverted of HMT3522 cells using Treegl can be a good model system to study drug effects on breast cancer.

  7. The Role of Mitochondria in Cancer Induction, Progression and Changes in Metabolism.

    Science.gov (United States)

    Rogalinska, Malgorzata

    2016-01-01

    Mitochondria play important roles as energetic centers. Mutations in mitochondrial DNA (mtDNA) were found in several diseases, including cancers. Studies on cytoplasmic hybrids (cybrids) confirm that directed mutation introduced into mtDNA could be a reason for cancer induction. Mitochondria could also be a factor linking cancer transformation and progression. The importance of mitochondria in cancer also confirms their involvement in the resistance to treatment. Resistance to treatment of cancer cells can frequently be a reason for glycolysis acceleration. It could be explained by cancer cells' high proliferation index and high energy request. The involvement of mitochondria in metabolic disturbances of several metabolic diseases, including cancers, was reported. These data confirm that cancer induction, as well as cancer progression, could have metabolic roots. The aberrant products observed in prostate cells involved in the Krebs cycle could promote cancer progression. These multiple relationships between alterations on a genetic level translated into disturbances in cellular metabolism and their potential relation with epigenetic control of gene expression make cancerogenesis more complicated and prognoses' success in studies on cancer etiology more distant in time. PMID:26471969

  8. Effects of clusterin over-expression on metastatic progression and therapy in breast cancer

    Directory of Open Access Journals (Sweden)

    Chatterjee Namita

    2010-03-01

    Full Text Available Abstract Background Clusterin is a secreted glycoprotein that is upregulated in a variety of cell lines in response to stress, and enhances cell survival. A second nuclear isoform of clusterin that is associated with cell death has also been identified. The aim of this study was to determine the role(s of the secretory isoform in breast tumor progression and metastasis. Methods To investigate the role of secretory clusterin in the biology of breast cancer tumor growth and resistance to therapy we have engineered an MCF-7 cell line (MCF-7CLU that over-expresses clusterin. We have measured the in vitro effects of clusterin over-expression on cell cycle, cell death, and sensitivity to TNFalpha and tamoxifen. Using an orthotopic model of breast cancer, we have also determined the effects of over-expression of clusterin on tumor growth and metastatic progression. Results In vitro, over-expression of secretory clusterin alters the cell cycle kinetics and decreases the rate of cell death, resulting in the enhancement of cell growth. Over-expression of secretory clusterin also blocks the TNFalpha-mediated induction of p21 and abrogates the cleavage of Bax to t-Bax, rendering the MCF-7CLU cells significantly more resistant to the cytokine than the parental cells. Orthotopic primary tumors derived from MCF-7CLU cells grow significantly more rapidly than tumors derived from parental MCF-7 cells and, unlike the parental cells, metastasize frequently to the lungs. Conclusions These data suggest that secretory clusterin, which is frequently up-regulated in breast cancers by common therapies, including anti-estrogens, may play a significant role in tumor growth, metastatic progression and subsequent drug resistance in surviving cells.

  9. 13A. Integrative Cancer Care: The Life Over Cancer Model

    OpenAIRE

    Block, Keith; Block, Penny; Gyllenhaal, Charlotte; Shoham, Jacob

    2013-01-01

    Focus Areas: Integrative Algorithms of Care Integrative cancer treatment fully blends conventional cancer treatment with integrative therapies such as diet, supplements, exercise and biobehavioral approaches. The Life Over Cancer model comprises three spheres of intervention: improving lifestyle, improving biochemical environment (terrain), and improving tolerance of conventional treatment. These levels are applied within the context of a life-affirming approach to cancer patients and treatme...

  10. Progress through Collaboration - Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The National Cancer Institute (NCI), through the Office of Cancer Clinical Proteomics Research (OCCPR), has signed two Memorandums of Understanding (MOUs) in the areas of sharing proteomics reagents and protocols and also in regulatory science.

  11. Cancer statistics for African Americans, 2016: Progress and opportunities in reducing racial disparities.

    Science.gov (United States)

    DeSantis, Carol E; Siegel, Rebecca L; Sauer, Ann Goding; Miller, Kimberly D; Fedewa, Stacey A; Alcaraz, Kassandra I; Jemal, Ahmedin

    2016-07-01

    In this article, the American Cancer Society provides the estimated number of new cancer cases and deaths for blacks in the United States and the most recent data on cancer incidence, mortality, survival, screening, and risk factors for cancer. Incidence data are from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries, and mortality data are from the National Center for Health Statistics. Approximately 189,910 new cases of cancer and 69,410 cancer deaths will occur among blacks in 2016. Although blacks continue to have higher cancer death rates than whites, the disparity has narrowed for all cancers combined in men and women and for lung and prostate cancers in men. In contrast, the racial gap in death rates has widened for breast cancer in women and remained level for colorectal cancer in men. The reduction in overall cancer death rates since the early 1990s translates to the avoidance of more than 300,000 deaths among blacks. In men, incidence rates from 2003 to 2012 decreased for all cancers combined (by 2.0% per year) as well as for the top 3 cancer sites (prostate, lung, and colorectal). In women, overall rates during the corresponding time period remained unchanged, reflecting increasing trends in breast cancer combined with decreasing trends in lung and colorectal cancer rates. Five-year relative survival is lower for blacks than whites for most cancers at each stage of diagnosis. The extent to which these disparities reflect unequal access to health care versus other factors remains an active area of research. Progress in reducing cancer death rates could be accelerated by ensuring equitable access to prevention, early detection, and high-quality treatment. CA Cancer J Clin 2016;66:290-308. © 2016 American Cancer Society. PMID:26910411

  12. Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, Platelet Factor-4

    International Nuclear Information System (INIS)

    Longstanding evidence implicates an inadequate diet as a key factor in the onset and progression of prostate cancer. The purpose herein was to discover, validate and characterize functional biomarkers of dietary supplementation capable of suppressing the course of prostate cancer in vivo. The Lady transgenic mouse model that spontaneously develops prostate cancer received a diet supplemented with a micronutrient cocktail of vitamin E, selenium and lycopene ad libitum. A proteomic analysis was conducted to screen for serum biomarkers of this dietary supplementation. Candidate peptides were validated and identified by sequencing and analyzed for their presence within the prostates of all mice by immunohistochemistry. Dietary supplementation with the combined micronutrients significantly induced the expression of the megakaryocyte-specific inhibitor of angiogenesis, platelet factor-4 (P = 0.0025). This observation was made predominantly in mice lacking tumors and any manifestations associated with progressive disease beyond 37 weeks of life, at which time no survivors remained in the control group (P < 0.0001). While prostates of mice receiving standard chow were enlarged and burdened with poorly differentiated carcinoma, those of mice on the supplemented diet appeared normal. Immunohistochemical analysis revealed marked amplifications of both platelet binding and platelet factor-4 within the blood vessels of prostates from mice receiving micronutrients only. We present unprecedented data whereby these combined micronutrients effectively promotes tumor dormancy in early prostate cancer, following initiation mutations that may drive the angiogenesis-dependent response of the tumor, by inducing platelet factor-4 expression and concentrating it at the tumor endothelium through enhanced platelet binding

  13. Recent Progress on Nutraceutical Research in Prostate Cancer

    OpenAIRE

    Li, Yiwei; Ahmad, Aamir; Kong, Dejuan; Bao, Bin; Sarkar, Fazlul H.

    2014-01-01

    Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy. Prostate Cancer (PCa) is most frequently diagnosed cancer and second leading cause of cancer-related death in men in US. Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa. Several nutraceuticals includi...

  14. Molecular markers′ progress of breast cancer treatment efficacy

    OpenAIRE

    Dan Wang; Jingwei Xu; Guang Shi; Guanghao Yin

    2015-01-01

    Breast cancer is a famous malignant tumor which is caused by varieties of mutation in multiple genes. In order to detect breast cancer in an earlier time and take appropriate treatment which includes  predicting treatment efficacy, we need a more accurate method of discovering the occurrence of breast cancer. With the development of molecular biology and biological detection technologies continue to emerge, molecular markers of breast cancer have gaining more and more widespread attention, an...

  15. Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology-Genomic Integration Analysis.

    Directory of Open Access Journals (Sweden)

    Rachael Natrajan

    2016-02-01

    Full Text Available The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters.We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D in solid tumors, termed the tumor ecosystem diversity index (EDI, using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3 breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2 breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10-4, hazard ratio = 1.47, 95% CI 1.17-1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26-2.52. Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size.To our knowledge, this is the first

  16. Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

    Science.gov (United States)

    Natrajan, Rachael; Sailem, Heba; Mardakheh, Faraz K.; Arias Garcia, Mar; Tape, Christopher J.; Dowsett, Mitch; Bakal, Chris; Yuan, Yinyin

    2016-01-01

    Background The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters. Methods and Findings We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10−4, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size. Conclusions To

  17. The microenvironment in breast cancer progression: biology and implications for treatment

    OpenAIRE

    Place, Andrew Elliott; Polyak, Kornelia; Huh, Sung Jin

    2011-01-01

    Breast cancer comprises a heterogeneous group of malignancies derived from the ductal epithelium. The microenvironment of these cancers is now recognized as a critical participant in tumor progression and therapeutic responses. Recent data demonstrate significant gene expression and epigenetic alterations in cells composing the microenvironment during disease progression, which can be explored as biomarkers and targets for therapy. Indeed, gene expression signatures derived from tumor stroma ...

  18. Defining Aggressive Prostate Cancer Using a 12-Gene Model

    Directory of Open Access Journals (Sweden)

    Tarek A. Bismar

    2006-01-01

    Full Text Available The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015. This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process.

  19. Progress in diagnosis of breast cancer: Advances in radiology technology

    OpenAIRE

    J Mari Beth Linder; Alan D Schiska

    2015-01-01

    Breast cancer is the leading cause of cancer in females between the ages of 15 and 54, and the second leading cause of cancer death in women in the United States. Diagnosis begins with detection by breast examination (clinical breast exam or breast self-exam) or by radiologic studies, like mammography. Many advances in the diagnosis of breast cancer have taken place in recent years. This article will review the history of radiologic advances in the diagnosis of breast cancer. Use of technolog...

  20. Progress in diagnosis of breast cancer: Advances in radiology technology

    Directory of Open Access Journals (Sweden)

    J Mari Beth Linder

    2015-01-01

    Full Text Available Breast cancer is the leading cause of cancer in females between the ages of 15 and 54, and the second leading cause of cancer death in women in the United States. Diagnosis begins with detection by breast examination (clinical breast exam or breast self-exam or by radiologic studies, like mammography. Many advances in the diagnosis of breast cancer have taken place in recent years. This article will review the history of radiologic advances in the diagnosis of breast cancer. Use of technological advancements in digital breast tomosynthesis, magnetic resonance imaging, and ultrasound in breast cancer diagnosis will be presented. Advantages and disadvantages of these diagnostic interventions when compared to older, traditional X-ray films will be discussed. It is important for all nurses, including radiology and oncology nurses, to be well informed about these varied diagnostic modalities, and appreciate the fact that advances in radiologic imaging technologies can yield improved outcomes for breast cancer patients.

  1. iTRAQ identification of candidate serum biomarkers associated with metastatic progression of human prostate cancer.

    Science.gov (United States)

    Rehman, Ishtiaq; Evans, Caroline A; Glen, Adam; Cross, Simon S; Eaton, Colby L; Down, Jenny; Pesce, Giancarlo; Phillips, Joshua T; Yen, Ow Saw; Thalmann, George N; Wright, Phillip C; Hamdy, Freddie C

    2012-01-01

    A major challenge in the management of patients with prostate cancer is identifying those individuals at risk of developing metastatic disease, as in most cases the disease will remain indolent. We analyzed pooled serum samples from 4 groups of patients (n = 5 samples/group), collected prospectively and actively monitored for a minimum of 5 yrs. Patients groups were (i) histological diagnosis of benign prostatic hyperplasia with no evidence of cancer 'BPH', (ii) localised cancer with no evidence of progression, 'non-progressing' (iii) localised cancer with evidence of biochemical progression, 'progressing', and (iv) bone metastasis at presentation 'metastatic'. Pooled samples were immuno-depleted of the 14 most highly abundant proteins and analysed using a 4-plex iTRAQ approach. Overall 122 proteins were identified and relatively quantified. Comparisons of progressing versus non-progressing groups identified the significant differential expression of 25 proteins (pfactor 1 alpha 1 (eEF1A1), one of the candidates identified, was significantly higher in osteoblasts in close proximity to metastatic tumour cells compared with osteoblasts in control bone (p = 0.0353, Mann Whitney U). Our proteomic approach has identified leads for potentially useful serum biomarkers associated with the metastatic progression of prostate cancer. The panels identified, including eEF1A1 warrant further investigation and validation. PMID:22355332

  2. Targeted serum metabolite profiling and sequential metabolite ratio analysis for colorectal cancer progression monitoring.

    Science.gov (United States)

    Zhu, Jiangjiang; Djukovic, Danijel; Deng, Lingli; Gu, Haiwei; Himmati, Farhan; Abu Zaid, Mohammad; Chiorean, Elena Gabriela; Raftery, Daniel

    2015-10-01

    Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and a major cause of human morbidity and mortality. In addition to early detection, close monitoring of disease progression in CRC can be critical for patient prognosis and treatment decisions. Efforts have been made to develop new methods for improved early detection and patient monitoring; however, research focused on CRC surveillance for treatment response and disease recurrence using metabolomics has yet to be reported. In this proof of concept study, we applied a targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) metabolic profiling approach focused on sequential metabolite ratio analysis of serial serum samples to monitor disease progression from 20 CRC patients. The use of serial samples reduces patient to patient metabolic variability. A partial least squares-discriminant analysis (PLS-DA) model using a panel of five metabolites (succinate, N2, N2-dimethylguanosine, adenine, citraconic acid, and 1-methylguanosine) was established, and excellent model performance (sensitivity = 0.83, specificity = 0.94, area under the receiver operator characteristic curve (AUROC) = 0.91 was obtained, which is superior to the traditional CRC monitoring marker carcinoembryonic antigen (sensitivity = 0.75, specificity = 0.76, AUROC = 0.80). Monte Carlo cross validation was applied, and the robustness of our model was clearly observed by the separation of true classification models from the random permutation models. Our results suggest the potential utility of metabolic profiling for CRC disease monitoring. PMID:26342311

  3. Retrotransposon-Encoded Reverse Transcriptase in the Genesis, Progression and Cellular Plasticity of Human Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sinibaldi-Vallebona, Paola; Matteucci, Claudia [Department of Experimental Medicine and Biochemical Sciences, University ‘Tor Vergata’, Rome (Italy); Spadafora, Corrado, E-mail: cspadaf@tin.it [Italian National Institute of Health (ISS), Rome (Italy)

    2011-03-07

    LINE-1 (Long Interspersed Nuclear Elements) and HERVs (Human Endogenous Retroviruses) are two families of autonomously replicating retrotransposons that together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly those encoding the reverse transcriptase (RT) enzyme, are generally expressed at low levels in differentiated cells, but their expression is upregulated in transformed cells and embryonic tissues. Here we discuss a recently discovered RT-dependent mechanism that operates in tumorigenesis and reversibly modulates phenotypic and functional variations associated with tumor progression. Downregulation of active LINE-1 elements drastically reduces the tumorigenic potential of cancer cells, paralleled by reduced proliferation and increased differentiation. Pharmacological RT inhibitors (e.g., nevirapine and efavirenz) exert similar effects on tumorigenic cell lines, both in culture and in animal models. The HERV-K family play a distinct complementary role in stress-dependent transition of melanoma cells from an adherent, non-aggressive, to a non-adherent, highly malignant, growth phenotype. In synthesis, the retrotransposon-encoded RT is increasingly emerging as a key regulator of tumor progression and a promising target in a novel anti-cancer therapy.

  4. Mesenchymal Stem/Stromal Cells in Stromal Evolution and Cancer Progression

    OpenAIRE

    Francesca Cammarota; Laukkanen, Mikko O

    2016-01-01

    The study of cancer biology has mainly focused on malignant epithelial cancer cells, although tumors also contain a stromal compartment, which is composed of stem cells, tumor-associated fibroblasts (TAFs), endothelial cells, immune cells, adipocytes, cytokines, and various types of macromolecules comprising the extracellular matrix (ECM). The tumor stroma develops gradually in response to the needs of epithelial cancer cells during malignant progression initiating from increased local vascul...

  5. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

    OpenAIRE

    Mahajan, Nupam P.; Liu, Yuanbo; Majumder, Samarpan; Warren, Maria R.; Parker, Carol E.; Mohler, James L.; Earp, H. Shelton; Whang, Young E.

    2007-01-01

    Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth o...

  6. Pro-oncogene Pokemon promotes breast cancer progression by upregulating survivin expression

    OpenAIRE

    ZU, XUYU; Ma, Jun; Liu, Hongxia; Liu, Feng; Tan, Chunyan; Yu, Lingling; Wang, Jue; Xie, Zhenhua; Cao, Deliang; Jiang, Yuyang

    2011-01-01

    Introduction Pokemon is an oncogenic transcription factor involved in cell growth, differentiation and oncogenesis, but little is known about its role in human breast cancer. In this study, we aimed to reveal the role of Pokemon in breast cancer progression and patient survival and to understand its underlying mechanisms. Methods Tissue microarray analysis of breast cancer tissues from patients with complete clinicopathological data and more than 20 years of follow-up were used to evaluate Po...

  7. Effects and potential mechanisms of exercise training on cancer progression: A translational perspective

    OpenAIRE

    Betof, Allison S.; Dewhirst, Mark W.; Jones, Lee W.

    2012-01-01

    Over the past decade there has been increasing research and clinical interest in the role of exercise therapy/rehabilitation as an adjunct therapy to improve symptom control and management following a cancer diagnosis. More recently, the field of ‘exercise – oncology’ has broadened in scope to investigate whether the benefits extend beyond symptom control to modulate cancer-specific outcomes (i.e., cancer progression and metastasis). Here we review the extant epidemiological evidence examinin...

  8. Diagnosis of lung cancer in a patient with pneumoconiosis and progressive massive fibrosis using MRI

    International Nuclear Information System (INIS)

    We report the MRI features and correlative pathologic findings of a lung cancer in a patient with progressive massive fibrosis (PMF). In this case, MRI was able to distinguish the lung cancer as a high signal intensity area, and the fibrotic mass as a low signal intensity area, on both T1-weighted and T2-weighted images when compared with muscle. MRI is potentially useful in distinguishing cancer tissue from PMF in patients with pneumoconiosis. (orig.)

  9. Interleukin-17 Could Promote Breast Cancer Progression at Several Stages of the Disease

    OpenAIRE

    Thomas Welte; Xiang H.-F. Zhang

    2015-01-01

    Metastatic disease accounts for more than 90% of deaths from breast cancer. Yet the factors that trigger metastasis, often years after primary tumor removal, are not understood well. Recently the proinflammatory cytokine interleukin- (IL-) 17 family has been associated with poor prognosis in breast cancer. Here we review current literature on the pathogenic mechanisms driven by IL-17 during breast cancer progression and connect these findings to metastasis. These include (1) direct effects of...

  10. CCN6: a modulator of breast cancer progression.

    Science.gov (United States)

    Leask, Andrew

    2016-06-01

    The expression of the CCN family of matricellular proteins is highly dysregulated in connective tissue pathologies such as fibrosis and highly metastatic cancers. Strategies targeting members of this family, especially CCN2, are under development as novel therapeutic approaches to highly metastatic cancers such as pancreatic cancer. In prior reports, the Kleer laboratory and colleagues have linked reduced expression of CCN6 (WISP3) with aggressive breast cancers. Loss of CCN6 was associated with elevated Akt phosphorylation and TAK1 activation. In a recent report, the same group reports that, by modulating Notch signaling, CCN6 can promote the maintenance of an epithelial phenotype and also reduce cancer cell migration and invasion, tumor initiation, and metastasis (Oncotarget in press DOI: 10.18632/oncotarget.7734 ). These results are consistent with the hypothesis that addition of CCN6 peptides may represent a novel, viable therapeutic approach to blocking aggressive breast cancers. PMID:27086280

  11. A Mouse Model for Human Anal Cancer

    OpenAIRE

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncoge...

  12. The multifaceted mechanism of Leptin signaling within tumor microenvironment in driving breast cancer growth and progression.

    Directory of Open Access Journals (Sweden)

    Sebastiano eAndò

    2014-11-01

    Full Text Available Adipokines represent likely candidates to mediate the increased breast cancer risk and the enhanced progression associated with obesity. Other contributors to obesity-related cancer progression are insulin/IGF-1 pathways and hormones. Among these, the adipokine leptin is the most intensively studied in both metabolism in general and in cancer due to the fact that leptin levels increase in proportion of fat mass. Leptin is primarily synthesized from adipocytes, but it is also produced by other cells including fibroblasts. In this latter case, it has been well demonstrated how cancer-associated fibroblasts express leptin receptor and secrete leptin which sustains a short autocrine loop and is able to target tumor epithelial cells enhancing breast cancer cell motility and invasiveness. In addition, it has been reported that leptin may induce breast cancer to undergo a transition from epithelial to spindle-like mesenchymal morphology, activating the signaling pathways devoted to the EMT. Thus, it emerges how leptin may play a crucial role in mediating malignant cell and tumor microenvironment interactions. Here, we present an overview of the role of leptin in breast cancer, covering the following topics: 1 leptin as an amplifier of estrogen signaling in tumor epithelial cells contributing to the promotion of carcinogenesis; 2 leptin as a crucial player in mediating tumor-stroma interaction and influencing EMT-linked mechanisms, that may sustain breast cancer growth and progression; 3 leptin and leptin receptor targeting as novel therapeutic strategies for breast cancer treatment.

  13. A mathematical prognosis model for pancreatic cancer patients receiving immunotherapy.

    Science.gov (United States)

    Li, Xuefang; Xu, Jian-Xin

    2016-10-01

    Pancreatic cancer is one of the most deadly types of cancer since it typically spreads rapidly and can seldom be detected in its early stage. Pancreatic cancer therapy is thus a challenging task, and appropriate prognosis or assessment for pancreatic cancer therapy is of critical importance. In this work, based on available clinical data in Niu et al. (2013) we develop a mathematical prognosis model that can predict the overall survival of pancreatic cancer patients who receive immunotherapy. The mathematical model incorporates pancreatic cancer cells, pancreatic stellate cells, three major classes of immune effector cells CD8+ T cells, natural killer cells, helper T cells, and two major classes of cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ). The proposed model describes the dynamic interaction between tumor and immune cells. In order for the model to be able to generate appropriate prognostic results for disease progression, the distribution and stability properties of equilibria in the mathematical model are computed and analysed in absence of treatments. In addition, numerical simulations for disease progression with or without treatments are performed. It turns out that the median overall survival associated with CIK immunotherapy is prolonged from 7 to 13months compared with the survival without treatment, this is consistent with the clinical data observed in Niu et al. (2013). The validity of the proposed mathematical prognosis model is thus verified. Our study confirms that immunotherapy offers a better prognosis for pancreatic cancer patients. As a direct extension of this work, various new therapy methods that are under exploration and clinical trials could be assessed or evaluated using the newly developed mathematical prognosis model. PMID:27338302

  14. Surfactant Protein A Suppresses Lung Cancer Progression by Regulating the Polarization of Tumor-Associated Macrophages

    OpenAIRE

    Mitsuhashi, Atsushi; Goto, Hisatsugu; Kuramoto, Takuya; Tabata, Sho; Yukishige, Sawaka; Abe, Shinji; Hanibuchi, Masaki; Kakiuchi, Soji; Saijo, Atsuro; Aono, Yoshinori; Uehara, Hisanori; Yano, Seiji; Ledford, Julie G.; Sone, Saburo; Nishioka, Yasuhiko

    2013-01-01

    Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcino...

  15. Bioluminescence imaging of estrogen receptor activity during breast cancer progression.

    Science.gov (United States)

    Vantaggiato, Cristina; Dell'Omo, Giulia; Ramachandran, Balaji; Manni, Isabella; Radaelli, Enrico; Scanziani, Eugenio; Piaggio, Giulia; Maggi, Adriana; Ciana, Paolo

    2016-01-01

    Estrogen receptors (ER) are known to play an important regulatory role in mammary gland development as well as in its neoplastic transformation. Although several studies highlighted the contribution of ER signaling in the breast transformation, little is known about the dynamics of ER state of activity during carcinogenesis due to the lack of appropriate models for measuring the extent of receptor signaling in time, in the same animal. To this aim, we have developed a reporter mouse model for the non-invasive in vivo imaging of ER activity: the ERE-Luc reporter mouse. ERE-Luc is a transgenic mouse generated with a firefly luciferase (Luc) reporter gene driven by a minimal promoter containing an estrogen responsive element (ERE). This model allows to measure receptor signaling in longitudinal studies by bioluminescence imaging (BLI). Here, we have induced sporadic mammary cancers by treating systemically ERE-Luc reporter mice with DMBA (9,10-dimethyl 1,2-benzanthracene) and measured receptor signaling by in vivo imaging in individual animals from early stage until a clinically palpable tumor appeared in the mouse breast. We showed that DMBA administration induces an increase of bioluminescence in the whole abdominal area 6 h after treatment, the signal rapidly disappears. Several weeks later, strong bioluminescence is observed in the area corresponding to the mammary glands. In vivo and ex vivo imaging analysis demonstrated that this bioluminescent signal is localized in the breast area undergoing neoplastic transformation. We conclude that this non-invasive assay is a novel relevant tool to identify the activation of the ER signaling prior the morphological detection of the neoplastic transformation. PMID:27069764

  16. The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bishop, Jennifer L.; Thaper, Daksh; Zoubeidi, Amina, E-mail: azoubeidi@prostatecentre.com [The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver British Columbia, V6H 3Z6 (Canada)

    2014-04-09

    The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed.

  17. Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer.

    Science.gov (United States)

    Friedrich, Teresa; Söhn, Michaela; Gutting, Tobias; Janssen, Klaus-Peter; Behrens, Hans-Michael; Röcken, Christoph; Ebert, Matthias P A; Burgermeister, Elke

    2016-06-01

    Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p=0.001; n=1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments. PMID:27428427

  18. On progress of nuclear activation model calculations

    International Nuclear Information System (INIS)

    Progress of work on improved methods of nuclear model calculations for nuclear activation data carried out at IFIN-HH in 2003-2004 is reported. In order to provide accurate predictions of further interest for the European Activation File (EAF-2005), no use of normalization or free parameters are involved. Model calculations carried out by using the computer codes EMPIRE-II and STAPRE-H have been validated by analysis of activation cross sections of all W and Ta stable isotopes and compared with the corresponding predictions obtained with the code TALYS. The accurate description of these reaction cross sections is obtained by using a consistent local parameter set, being fully due to the start of proton pre-equilibrium contribution due to the partial wave l = 7ℎ at incident energies of ∼ 14 MeV. This feature makes possible a faster increase of the STAPRE-H results for the (n,p) reaction cross sections just around this energy, while at 20 MeV they are in between the EMPIRE-II and TALYS predictions. It is thus pointed out the need for additional experimental data in the energy range above 15 MeV, similar to previous measurements at, e.g., JRC/IRMM. It is also shown that enlargement actions already in due course may have lower effectiveness concerning the preservation and development of knowledge and capabilities at Romanian R and D institutes as well as their integration into existing EC/JRC programmes and EU networks. While from the beginning EC asked CEEC to improve their R and D infrastructure to better benefit from the enlargement process, no real step forward has been done in this respect in Romania. The present conditions at IFIN-HH well below the limits making possible a real work have made thus not possible a further co-operation with JRC/IRMM, where we found previously the best opportunities for a sound common work, simply because no study completion may be done now in Bucharest. (author)

  19. A favorable view: progress in cancer prevention and screening.

    Science.gov (United States)

    Greenwald, Peter

    2007-01-01

    Clifton Leaf, in his article "Why We're Losing the War on Cancer," presents criticisms of past research approaches and the small impact of this research thus far on producing cures or substantially extending the life of many cancer patients. It is true that gains in long-term survival for people with advanced cancers have been modest, hindered in part by the heterogeneity of tumors, which allows the cancers to persist using alternate molecular pathways and so evade many cancer therapeutics. In contrast, clinical trials have demonstrated that it is possible to reduce the incidence or improve cancer survival through prevention and early detection. Strides have been made in preventing or detecting early the four deadliest cancers in the United States (i.e., lung, breast, prostate, and colorectal). For example, 7-year follow-up data from the Breast Cancer Prevention Trial (BCPT) provides evidence that tamoxifen reduces the occurrence of invasive breast tumors by more than 40%; recent studies using aromatase inhibitors and raloxifene are also promising. The Prostate Cancer Prevention Trial (PCPT) showed that finasteride reduced prostate cancer incidence by 25%, and the ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT) is investigating selenium and vitamin E for prostate cancer prevention based on encouraging results from earlier studies. Living a healthy lifestyle, including regular physical activity, avoiding obesity, and eating primarily a plant-based diet has been associated with a lower risk of colorectal cancer. In addition, noninvasive stool DNA tests for early detection are being studied, which may lessen the reluctance of people to be screened for colorectal polyps and cancer. Behavioral and medical approaches for smoking prevention are ways to reduce the incidence of lung cancer, with antinicotine vaccines on the horizon that may help former smokers to avoid relapse. The US National Lung Screening Trial is testing whether early detection via

  20. The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the Apc(Min/+ mouse.

    Directory of Open Access Journals (Sweden)

    James P White

    Full Text Available Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The Apc(Min/+ mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the Apc(Min/+ mouse is not known. Cachexia progression was studied in Apc(Min/+ mice that were either weight stable (WS or had initial (≤5%, intermediate (6-19%, or extreme (≥20% body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172, AMPK activity, and raptor phosphorylation (Ser 792 were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process.

  1. Chemoprevention in gastrointestinal physiology and disease. Targeting the progression of cancer with natural products: a focus on gastrointestinal cancer.

    Science.gov (United States)

    Khoogar, Roxane; Kim, Byung-Chang; Morris, Jay; Wargovich, Michael J

    2016-05-01

    The last decade has witnessed remarkable progress in the utilization of natural products for the prevention and treatment of human cancer. Many agents now in the pipeline for clinical trial testing have evolved from our understanding of how human nutritional patterns account for widespread differences in cancer risk. In this review, we have focused on many of these promising agents arguing that they may provide a new strategy for cancer control: natural products once thought to be only preventive in their mode of action now are being explored for efficacy in tandem with cancer therapeutics. Natural products may reduce off-target toxicity of therapeutics while making cancers more amenable to therapy. On the horizon is the use of certain natural products, in their own right, as mitigants of late-stage cancer, a new frontier for small-molecule natural product drug discovery. PMID:26893159

  2. Tight junctions: a barrier to the initiation and progression of breast cancer?

    LENUS (Irish Health Repository)

    Brennan, Kieran

    2010-01-01

    Breast cancer is a complex and heterogeneous disease that arises from epithelial cells lining the breast ducts and lobules. Correct adhesion between adjacent epithelial cells is important in determining the normal structure and function of epithelial tissues, and there is accumulating evidence that dysregulated cell-cell adhesion is associated with many cancers. This review will focus on one cell-cell adhesion complex, the tight junction (TJ), and summarize recent evidence that TJs may participate in breast cancer development or progression. We will first outline the protein composition of TJs and discuss the functions of the TJ complex. Secondly we will examine how alterations in these functions might facilitate breast cancer initiation or progression; by focussing on the regulatory influence of TJs on cell polarity, cell fate and cell migration. Finally we will outline how pharmacological targeting of TJ proteins may be useful in limiting breast cancer progression. Overall we hope to illustrate that the relationship between TJ alterations and breast cancer is a complex one; but that this area offers promise in uncovering fundamental mechanisms linked to breast cancer progression.

  3. [Mechanisms responsible for the progression of scirrhous gastric cancer].

    Science.gov (United States)

    Yashiro, Masakazu; Ohira, Masaichi; Muguruma, Kazuya; Shinto, Osamu; Hirakawa, Kosei

    2012-10-01

    Scirrhous gastric carcinoma is characterized by rapid cancer cell infiltration and proliferation accompanied by extensive stromal fibrosis. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors, FGF7 and TGFbeta produced by organ-specific fibroblasts. Peritoneal fibroblasts morphologically change mesothelial cells, and stimulate the migratory capability of cancer cells. A FGFR2 phosphorylation inhibitor prolongs the survival of mice with peritoneal metastasis of scirrhous gastric cancer. A TGFbetaR inhibitor decreases the growth of fibroblast, and invasion-stimulating activity of fibroblasts on cancer cells. A FGFR2 phosphorylation inhibitor or TGFbetaR inhibitor appears therapeutically promising in scirrhous gastric carcinoma. PMID:23198567

  4. Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression*

    Science.gov (United States)

    Mills, Lisa D.; Zhang, Lizhi; Marler, Ronald; Svingen, Phyllis; Fernandez-Barrena, Maite G.; Dave, Maneesh; Bamlet, William; McWilliams, Robert R.; Petersen, Gloria M.; Faubion, William; Fernandez-Zapico, Martin E.

    2014-01-01

    The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways. PMID:24737325

  5. Expression of the Y-Encoded TSPY is Associated with Progression of Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Tatsuo Kido

    2010-09-01

    Full Text Available TSPY is a Y-encoded gene that is expressed in normal testicular germ cells and various cancer types including germ cell tumor, melanoma, hepatocellular carcinoma, and prostate cancer. Currently, the correlation between TSPY expression and oncogenic development has not been established, particularly in somatic cancers. To establish such correlation, we analyzed the expression of TSPY, in reference to its interactive oncoprotein, EEF1A, tumor biomarker, AMACR, and normal basal cell biomarker, p63, in 41 cases of clinical prostate cancers (CPCa, 17 cases of latent prostate cancers (LPCa, and 19 cases of non-cancerous prostate (control by immunohistochemistry. Our results show that TSPY was detected more frequently (78% in the clinical prostate cancer specimens than those of latent prostate cancer (47% and control (50%. In the latent cancer group, the levels of TSPY expression could be correlated with increasing Gleason grades. TSPY expression was detected in seven out of nine high-grade latent cancer samples (Gleason 7 and more. The expression of the TSPY binding partner EEF1A was detectable in all prostate specimens, but the levels were higher in cancer cells in clinical and latent prostate cancer specimens than normal prostatic cells. These observations suggest that expressions of TSPY and its binding partner EEF1A are associated with the development and progression of prostate cancer.

  6. [Palliative care in non-cancer, chronic, progressive diseases].

    Science.gov (United States)

    Radványi, Ildikó; Nagy, Lajos; Balogh, Sándor; Csikós, Ágnes

    2015-10-18

    Malignant and other chronic diseases cause the death of 2.5 million people in Europe annually. It is anticipated that this number will grow due to the aging of the European population. The death of a significant proportion of patients having progressive chronic disease is preceded by an extended end of life stadium. In this stage the patients have severe symptoms and pain that necessitate their symptomatic treatment and palliative care. The assessment of the life expectancy of patients, estimation of the prognosis of their illness and, therefore, selection of patients with a need of intensified palliative care often pose difficulties. This paper provides a summary on the basic elements of "good palliative care". It introduces the most frequent models for the procession of chronic diseases and those indicators that help practicing doctors to recognise easier patients with a need of intensified palliative care, and as a result provides more adequate medical attendance that is better suited to the specific needs of the patients. PMID:26551310

  7. The ensemble of genetic factors and angiogenic signals via VEGF receptors in lung cancer progression.

    Science.gov (United States)

    Danish, Qazi; Mokhdomi, Taseem A; Bukhari, Shoiab; Ahmad, Raies

    2015-01-01

    Lung cancer is the major cause of cancer-related mortality worldwide owing to its late-stage detection and aggressive behavior. Epidemiologically, several genetic and epigenetic factors contribute to the development of lung cancer. Angiogenesis, a critical process in tumor progression has become an important target for anti-cancer therapy particularly in lung cancer. Besides commercially available angiogenic inhibitors, numerous anti-angiogenic therapies have been developed to limit tumor growth, although, most of them have not proved beneficial in terms of long-term survival. Despite, logical advances in treatment strategies, NSCLC still remains a major health concern due to poor prognosis of the diseases state. This calls for a comprehensive analysis of signaling processes governing tumor angiogenesis and treatment options available thereof for development of a sustainable strategy to control cancer. In this review, several aspects of lung cancer have been discussed starting from its pathological characterization to the development of modern therapeutics. PMID:26406951

  8. Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor–microenvironment interactions

    International Nuclear Information System (INIS)

    A comprehensive overview of breast cancer development and progression suggests that the process is influenced by intrinsic properties of the tumor cells, as well as by microenvironmental factors. Indeed, in breast carcinoma, an intensive interplay exists between the tumor cells on one hand, and inflammatory cells/cytokines/chemokines on the other. The purpose of the present review is to outline the reciprocal interactions that exist between these different elements, and to shed light on their potential involvement in breast cancer development and progression

  9. Optimizing mouse models for precision cancer prevention.

    Science.gov (United States)

    Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory

    2016-03-01

    As cancer has become increasingly prevalent, cancer prevention research has evolved towards placing a greater emphasis on reducing cancer deaths and minimizing the adverse consequences of having cancer. 'Precision cancer prevention' takes into account the collaboration of intrinsic and extrinsic factors in influencing cancer incidence and aggressiveness in the context of the individual, as well as recognizing that such knowledge can improve early detection and enable more accurate discrimination of cancerous lesions. However, mouse models, and particularly genetically engineered mouse (GEM) models, have yet to be fully integrated into prevention research. In this Opinion article, we discuss opportunities and challenges for precision mouse modelling, including the essential criteria of mouse models for prevention research, representative success stories and opportunities for more refined analyses in future studies. PMID:26893066

  10. The role of mitochondria in the development and progression of lung cancer

    Directory of Open Access Journals (Sweden)

    Emily R Roberts

    2013-03-01

    Full Text Available The influence of mitochondria in human health and disease is a rapidly expanding topic in the scientific literature due to their integral roles in cellular death and survival. Mitochondrial biology and alterations in function were first linked to cancer in the 1920s with the discovery of the Warburg effect. The utilization of aerobic glycolysis in ATP synthesis was the first of many observations of metabolic reprogramming in cancer. Mitochondrial dysfunction in cancer has expanded to include defects in mitochondrial genomics and biogenesis, apoptotic signaling and mitochondrial dynamics. This review will focus on the role of mitochondria and their influence on cancer initiation, progression and treatment in the lung.

  11. Cancer Stem Cells – Basics, Progress and Future Potential

    OpenAIRE

    Bapat S.A

    2010-01-01

    The primary characteristics of adult stem cells are maintaining prolonged quiescence, ability to self-renew and plasticity to differentiate into multiple cell types. These properties are evolutionarily conserved from fruit fly to humans. Similar to normal tissue repair in organs, the stem cell concept is inherently impregnated in the etiology of cancer. Tumors contain a minor population of tumor-initiating cells, called "cancer stem cells" that maintain some similarities in self-renewal and d...

  12. Steps in Prostate Cancer Progression that lead to Bone Metastasis

    OpenAIRE

    Jin, Jung-Kang; Dayyani, Farshid; Gallick, Gary E.

    2011-01-01

    Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone remain incompletely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bi-directional interactions between the tumor and the bone microenvironment. In this review, we discuss the current...

  13. Exosomes in Tumor Microenvironment Influence Cancer Progression and Metastasis

    OpenAIRE

    Kahlert, Christoph; Kalluri, Raghu

    2013-01-01

    Exosomes are small membrane vesicles of endocytic origin with a size of 50 – 100 nm. They can contain microRNAs, mRNAs, DNA fragments and proteins, which are shuttled from a donar cell to recipient cells. Many different cell types including immune cells, mesenchymal cells and cancer cells release exosomes. There is emerging evidence that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with tumor environment. Here, we discuss different mechani...

  14. Chemokines and their receptors in lung cancer progression and metastasis*

    OpenAIRE

    Cheng, Zeng-hui; Shi, Yu-xin; Yuan, Min; Xiong, Dan; Zheng, Jiang-hua; Zhang, Zhi-Yong

    2016-01-01

    Lung cancer is the leading cause of cancer-related mortality around the world. Despite advancements in diagnosis, surgical techniques, and neoadjuvant chemoradiotherapy over the last decade, the mortality rate is still high and the 5-year survival is a dismal 15%. Fortunately, early detection by low-dose computed tomography (LDCT) scans has reduced mortality by 20%; yet, overall, 5-year-survival remains low at less than 20%. Therefore, in order to ameliorate this situation, a thorough underst...

  15. DKC1 overexpression associated with prostate cancer progression

    OpenAIRE

    Sieron, P; Hader, C; Hatina, J; Engers, R; Wlazlinski, A; Müller, M.; Schulz, W A

    2009-01-01

    Background: Dyskerin encoded by the DKC1 gene is a predominantly nucleolar protein essential for the formation of pseudouridine in RNA and the telomerase RNA subunit hTR. Inherited mutations inactivating dyskerin cause dyskeratosis congenita, a syndrome with progeroid features characterised by skin defects and haematopoiesis failure, as well as cancer susceptibility. In this study, we report DKC1 overexpression in prostate cancers. Methods: Expression of DKC1 was measured by quantitative RT–P...

  16. Clinical Trial Design for Testing the Stem Cell Model for the Prevention and Treatment of Cancer

    OpenAIRE

    Wicha, Max S.; Madhuri Kakarala; Reddy, Rishindra M.

    2011-01-01

    The cancer stem cell model introduces new strategies for the prevention and treatment of cancers. In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size. These new approac...

  17. James P. Allison received the 2014 Szent-Györgi Prize for Progress in Cancer Research

    OpenAIRE

    Jie Zhao; Peter Scully; Sujuan Ba

    2014-01-01

    The Szent-Gyorgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)-a leading cancer research charitable organization in the United States that is committed to supporting innovative cancer research on the global scale that aims to cure cancer. Each year, the Szent-Gyorgyi Prize honors an outstanding researcher whose original discoveries have expanded our understanding of cancer and resulted in notable adv...

  18. CRISPR-Cas9: A Revolutionary Tool for Cancer Modelling

    Directory of Open Access Journals (Sweden)

    Raul Torres-Ruiz

    2015-09-01

    Full Text Available The cancer-modelling field is now experiencing a conversion with the recent emergence of the RNA-programmable CRISPR-Cas9 system, a flexible methodology to produce essentially any desired modification in the genome. Cancer is a multistep process that involves many genetic mutations and other genome rearrangements. Despite their importance, it is difficult to recapitulate the degree of genetic complexity found in patient tumors. The CRISPR-Cas9 system for genome editing has been proven as a robust technology that makes it possible to generate cellular and animal models that recapitulate those cooperative alterations rapidly and at low cost. In this review, we will discuss the innovative applications of the CRISPR-Cas9 system to generate new models, providing a new way to interrogate the development and progression of cancers.

  19. Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression.

    Science.gov (United States)

    Lee, Hsin-Chen; Huang, Kuo-Hung; Yeh, Tien-Shun; Chi, Chin-Wen

    2014-04-14

    Energy metabolism reprogramming was recently identified as one of the cancer hallmarks. One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the past decades, several types of somatic mtDNA alterations have been identified in gastric cancer. However, the role of these mtDNA alterations in gastric cancer progression remains unclear. In this review, we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer. The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed. We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers. The two primary mutation types (transition mutations and mononucleotide or dinucleotide repeat instability) imply potential causative factors. Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer. The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies. PMID:24744584

  20. Building a better model of cancer

    Directory of Open Access Journals (Sweden)

    DeGregori James

    2006-10-01

    Full Text Available Abstract The 2006 Cold Spring Harbor Laboratory meeting on the Mechanisms and Models of Cancer was held August 16–20. The meeting featured several hundred presentations of many short talks (mostly selected from the abstracts and posters, with the airing of a number of exciting new discoveries. We will focus this meeting review on models of cancer (primarily mouse models, highlighting recent advances in new mouse models that better recapitulate sporadic tumorigenesis, demonstrations of tumor addiction to tumor suppressor inactivation, new insight into senescence as a tumor barrier, improved understanding of the evolutionary paths of cancer development, and environmental/immunological influences on cancer.

  1. Study on “Progressive Modular” Practice Teaching Model

    OpenAIRE

    Ying Han; Wei Zhao; Qing Liu; Xiang Qian

    2014-01-01

    Progressive modular” practice teaching model is the effective path of full and organic integration of theory and practice to explore increasing the cadre’s capacity to deal with complicated reality problems. To perfect further “progressive modular” practice teaching model, this teaching model must be thought as the important breakthrough of professional education reform to establish and perfect coordination system, to improve the comprehensive quality of teachers, to increase cooperation, un...

  2. Role of Procalcitonin and Interleukin-6 in Predicting Cancer, and Its Progression Independent of Infection.

    Directory of Open Access Journals (Sweden)

    Anne-Marie Chaftari

    Full Text Available Procalcitonin (PCT and Interleukin-6 (IL-6 have emerged as biomarkers for different inflammatory conditions. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients. This cross-sectional study included residual plasma samples collected from cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer. We identified 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml compared to cancer patients with stage I-III disease (0.127 ng/ml (p<0.0001 and stage IV disease (0.190 ng/ml (p<0.0001. It was also higher in febrile cancer patients (0.310 ng/ml compared to non-febrile cancer patients (0.1 ng/ml (p<0.0001. Median IL-6 level was significantly lower in the control group (0 pg/ml than in non-febrile cancer patients with stages I-III (7.376 pg/ml or stage IV (9.635 pg/ml (p<0.0001. Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. In addition, PCT is useful in detecting progression of cancer and predicting bacteremia or sepsis in febrile cancer patients.

  3. Biomarkers to Distinguish Aggressive Cancers from Non-aggressive or Non-progressing Cancer — EDRN Public Portal

    Science.gov (United States)

    Distinguishing aggressive cancers from non-aggressive or non-progressing cancers is an issue of both clinical and public health importance particularly for those cancers with an available screening test. With respect to breast cancer, mammographic screening has been shown in randomized trials to reduce breast cancer mortality, but given the limitations of its sensitivity and specificity some breast cancers are missed by screening. These so called interval detected breast cancers diagnosed between regular screenings are known to have a more aggressive clinical profile. In addition, of those cancers detected by mammography some are indolent while others are more likely to recur despite treatment. The pilot study proposed herein is highly responsive to the EDRN supplement titled “Biomarkers to Distinguish Aggressive Cancers from Nonaggressive or Non-progressing Cancers” in that it addresses both of the research objectives related to these issues outlined in the notice for this supplement: Aim 1: To identify biomarkers in tumor tissue related to risk of interval detected vs. mammography screen detected breast cancer focusing on early stage invasive disease. We will compare gene expression profiles using the whole genome-cDNA-mediated Annealing, Selection, extension and Ligation (DASL) assay of 50 screen detected cancers to those of 50 interval detected cancers. Through this approach we will advance our understanding of the molecular characteristics of interval vs. screen detected breast cancers and discover novel biomarkers that distinguish between them. Aim 2: To identify biomarkers in tumor tissue related to risk of cancer recurrence among patients with screen detected early stage invasive breast cancer. Using the DASL assay we will compare gene expression profiles from screen detected early stage breast cancer that either recurred within five years or never recurred within five years. These two groups of patients will be matched on multiple factors including

  4. Modeling of pool swell dynamics. Progress report

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, W.G.; Huber, P.W.; Sonin, A.A.

    1977-03-01

    The purpose of this research program is to develop and verify the scaling laws which apply to LOCA-induced pool swell in BWR pressure-suppression containment systems. The work has now progressed to a stage where several critical series of experiments have been completed. The experimental test program for checking the scaling laws is outlined. Some of the experimental results obtained to date and the conclusions one can draw from them are summarized.

  5. Likelihood-free methods for tumor progression modeling

    OpenAIRE

    Herold, Daniela

    2014-01-01

    Since it became clear that the number of newly diagnosed cancer cases and the number of deaths from cancer worldwide increases from year to year, a great effort has been put into the field of cancer research. One major point of interest is how and by means of which intermediate steps the development of cancer from an initially benign mass of cells into a large malignant and deadly tumor takes place. In order to shed light onto the details of this process, many models have been developed in th...

  6. Molecular genetics of cancer and tumorigenesis: Drosophila models

    Institute of Scientific and Technical Information of China (English)

    Wu-Min Deng

    2011-01-01

    Why do some cells not respond to normal control of cell division and become tumorous? Which signals trigger some tumor cells to migrate and colonize other tissues? What genetic factors are responsible for tumorigenesis and cancer development? What environmental factors play a role in cancer formation and progression? In how many ways can our bodies prevent and restrict the growth of cancerous cells?How can we identify and deliver effective drugs to fight cancer? In the fight against cancer,which kills more people than any other disease,these and other questions have long interested researchers from a diverse range of fields.To answer these questions and to fight cancer more effectively,we must increase our understanding of basic cancer biology.Model organisms,including the fruit fly Drosophila melanogaster,have played instrumental roles in our understanding of this devastating disease and the search for effective cures.Drosophila and its highly effective,easy-touse,and ever-expanding genetic tools have contributed toand enriched our knowledge of cancer and tumor formation tremendously.

  7. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    Directory of Open Access Journals (Sweden)

    Koushik Chattopadhyay

    2011-01-01

    Full Text Available Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ′HPV′, ′cervical′, ′CIN′, ′polymorphism(s′, ′cervical′ + FNx01the name of the geneFNx01 and ′HPV′ + FNx01the name of the geneFNx01. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.

  8. Cancer Development, Progression, and Therapy: An Epigenetic Overview

    Directory of Open Access Journals (Sweden)

    McKenna Longacre

    2013-10-01

    Full Text Available Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell–cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.

  9. The fundamental role of mechanical properties in the progression of cancer disease and inflammation

    International Nuclear Information System (INIS)

    The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in

  10. HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression.

    Science.gov (United States)

    Chang, Shuai; Liu, Junsong; Guo, Shaochun; He, Shicai; Qiu, Guanglin; Lu, Jing; Wang, Jin; Fan, Lin; Zhao, Wei; Che, Xiangming

    2016-06-01

    A long non-coding RNA named HOTTIP (HOXA transcript at the distal tip) coordinates the activation of various 5' HOXA genes which encode master regulators of development through targeting the WDR5/MLL complex. HOTTIP acts as an oncogene in several types of cancers, whereas its biological function in gastric cancer has never been studied. In the present study, we investigated the role of HOTTIP in gastric cancer. We found that HOTTIP was upregulated in gastric cancer cell lines. Knockdown of HOTTIP in gastric cancer cells inhibited cell proliferation, migration and invasion. Moreover, downregulation of HOTTIP led to decreased expression of homeobox protein Hox-A13 (HOXA13) in gastric cancer cell lines. HOXA13 was involved in HOTTIP‑induced malignant phenotypes of gastric cancer cells. Our data showed that the levels of HOTTIP and HOXA13 were both markedly upregulated in gastric cancer tissues compared with their counterparts in non-tumorous tissues. Furthermore, the expression levels of HOTTIP and HOXA13 were both higher in gastric cancer which was poorly differentiated, at advanced TNM stages and exhibited lymph node-metastasis. Spearman analyses indicated that HOTTIP and HOXA13 had a highly positive correlation both in non-tumor mucosae and cancer lesions. Collectively, these findings suggest that HOTTIP and HOXA13 play important roles in gastric cancer progression and provide a new insight into therapeutic treatment for the disease. PMID:27108607

  11. FYN promotes breast cancer progression through epithelial-mesenchymal transition.

    Science.gov (United States)

    Xie, Ye-Gong; Yu, Yue; Hou, Li-Kun; Wang, Xin; Zhang, Bin; Cao, Xu-Chen

    2016-08-01

    FYN, one of the members of the Src family of kinases (SFKs), has been reported to be overexpressed in various types of cancers and correlated with cell motility and proliferation. However, the mechanism is still unclear. In the present study, we found that FYN was overexpressed in breast cancer and overexpression of FYN promoted cell proliferation, migration and invasion in the MCF10A cells, whereas depletion of FYN suppressed cell proliferation, migration and invasion in the MDA-MB-231 cells. Moreover, FYN upregulated the expression of mesenchymal markers and epithelial-mesenchymal transition (EMT)-related transcription factors, and downregulated the expression of epithelial markers, suggesting that FYN induces EMT in breast cancer cells. Furthermore, FYN was transcriptionally regulated by FOXO1 and mediated FGF2-induced EMT through both the PI3K/AKT and ERK/MAPK pathways. PMID:27349276

  12. [Research progress of relationship between exosomes and breast cancer].

    Science.gov (United States)

    Bi, Tao-Ling; Sun, Jin-Jian; Tian, Yu-Zi; Zhou, Ye-Fang

    2016-06-25

    Exosomes are nanosized small membrane microvesicles of endocytic origin secreted by most cell types. Exosomes, through its carrying protein or RNA from derived cells, affect gene regulation networks or epigenetic reorganization of receptor cell, and then modulate the physiological processes of cells. Studies have shown that external exosomes secreted by breast cancer cells or other cells play an important role in the development of tumor, including cell migration, cell differentiation and the immune response, etc. In this article, the latest studies were summarized to provide an overview of current understanding of exosomes in breast cancer. PMID:27350208

  13. Accident progression modelling: containment event trees

    International Nuclear Information System (INIS)

    Containment Event Trees (CETs) are used to represent the various potential accident progressions following core melt. The EVNTRE code has a sophisticated Monte-Carlo capability. In this paper the small CET approach uses Decompositions Event Trees (DETs) to analyse the issues behind the CET headers and large CET approach (EVNTRE/NUREG-1150) are presented. The equipment survivability impact in CET, source term assignment via grouping of sequences into categories or by use of parametric code, sensitivity studies versus full Monte-Carlo simulation for study of the impact of uncertainties are also discussed

  14. SOXs in human prostate cancer: implication as progression and prognosis factors

    International Nuclear Information System (INIS)

    SOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa). The gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa. The microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P < 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the up-regulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance. Our data offer the convince

  15. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy

    DEFF Research Database (Denmark)

    Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske;

    2014-01-01

    investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8). INTERPRETATION: No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with......BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final...... analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early...

  16. Effects of Honey and Its Mechanisms of Action on the Development and Progression of Cancer

    Directory of Open Access Journals (Sweden)

    Omotayo O. Erejuwa

    2014-02-01

    Full Text Available Honey is a natural product known for its varied biological or pharmacological activities—ranging from anti-inflammatory, antioxidant, antibacterial, antihypertensive to hypoglycemic effects. This review article focuses on the role of honey in modulating the development and progression of tumors or cancers. It reviews available evidence (some of which is very recent with regards to the antimetastatic, antiproliferative and anticancer effects of honey in various forms of cancer. These effects of honey have been thoroughly investigated in certain cancers such as breast, liver and colorectal cancer cell lines. In contrast, limited but promising data are available for other forms of cancers including prostate, bladder, endometrial, kidney, skin, cervical, oral and bone cancer cells. The article also underscores the various possible mechanisms by which honey may inhibit growth and proliferation of tumors or cancers. These include regulation of cell cycle, activation of mitochondrial pathway, induction of mitochondrial outer membrane permeabilization, induction of apoptosis, modulation of oxidative stress, amelioration of inflammation, modulation of insulin signaling and inhibition of angiogenesis. Honey is highly cytotoxic against tumor or cancer cells while it is non-cytotoxic to normal cells. The data indicate that honey can inhibit carcinogenesis by modulating the molecular processes of initiation, promotion, and progression stages. Thus, it may serve as a potential and promising anticancer agent which warrants further experimental and clinical studies.

  17. THE LATEST PROGRESS OF GASTRIC CANCER SURGERY IN JAPAN

    Institute of Scientific and Technical Information of China (English)

    Keiichi; Maruyama; Professor

    2007-01-01

    @@ Mortality rate of gastric cancer in Japan had been the highest in the world.Development of early detection and effective treatment was the most important social demand.For the early detection,Japan developed"double contrast X-ray","endoscopy and endoscopic biopsy", and"mass screening system".

  18. Human Subperitoneal Fibroblast and Cancer Cell Interaction Creates Microenvironment That Enhances Tumor Progression and Metastasis

    OpenAIRE

    Kojima, Motohiro; Higuchi, Youichi; Yokota, Mitsuru; Ishii, Genichiro; Saito, Norio; Aoyagi, Kazuhiko; Sasaki, Hiroki; Ochiai, Atsushi

    2014-01-01

    Backgrounds Peritoneal invasion in colon cancer is an important prognostic factor. Peritoneal invasion can be objectively identified as periotoneal elastic laminal invasion (ELI) by using elastica stain, and the cancer microenvironment formed by the peritoneal invasion (CMPI) can also be observed. Cases with ELI more frequently show distant metastasis and recurrence. Therefore, CMPI may represent a particular milieu that facilitates tumor progression. Pathological and biological investigation...

  19. Oncogenic Alternative Splicing Switches: Role in Cancer Progression and Prospects for Therapy

    OpenAIRE

    Serena Bonomi; Stefania Gallo; Morena Catillo; Daniela Pignataro; Giuseppe Biamonti; Claudia Ghigna

    2013-01-01

    Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer ...

  20. MicroRNA-490 inhibits tumorigenesis and progression in breast cancer

    OpenAIRE

    Zhao L; Zheng XY

    2016-01-01

    Lin Zhao,1 Xin-Yu Zheng1,21Department of Breast Surgery, the First Hospital of China Medical University, 2The First Laboratory, Cancer Institute of China Medical University, Shenyang, People’s Republic of ChinaAbstract: MicroRNAs are consistently reported to regulate gene expression in all cancer cell types by modulating a wide range of biological processes, including cell proliferation, differentiation, and apoptosis, which are associated with tumor development and progression. Previou...

  1. Matrix Metalloproteinases: The Gene Expression Signatures of Head and Neck Cancer Progression

    OpenAIRE

    Shinji Iizuka; Naozumi Ishimaru; Yasusei Kudo

    2014-01-01

    Extracellular matrix degradation by matrix metalloproteinases (MMPs) plays a pivotal role in cancer progression by promoting motility, invasion and angiogenesis. Studies have shown that MMP expression is increased in head and neck squamous cell carcinomas (HNSCCs), one of the most common cancers in the world, and contributes to poor outcome. In this review, we examine the expression pattern of MMPs in HNSCC by microarray datasets and summarize the current knowledge of MMPs, specifically MMP-1...

  2. Development of A Mouse Model of Menopausal Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Smith

    2014-02-01

    Full Text Available Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; questions of the cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology.A potentially useful model is the germ cell-deficient Wv (white spotting variant mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation. Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer.Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.

  3. Cancer and birth defects surveillance system for communities around the Savannah River Site. Annual progress report

    International Nuclear Information System (INIS)

    The US DOE funded this grant to the Medical University of South Carolina for a cancer and birth defects registry for an initial three year period which was completed as of April 29, 1994. While this Technical Progress Report is prepared principally to document the activities of year 03, it also summarizes the accomplishments of the first two years in order to put into perspective the energy and progress of the program over the entire three year funding cycle

  4. FGFR1 amplification and the progression of non-invasive to invasive breast cancer

    OpenAIRE

    Gru, Alejandro A.; Allred, D. Craig

    2012-01-01

    The incidence of invasive breast cancer (IBC) can be dramatically reduced by improving our abilities to detect and treat ductal carcinoma in situ (DCIS). Progress will be based on a detailed understanding of molecular mechanisms responsible for tumor progression. An interesting study by Jang and colleagues evaluated and compared the frequency of amplification of four oncogenes (HER2, c-MYC, CCND1 and FGFR1) in large cohorts of pure DCIS, in the DCIS component of IBC, and in corresponding IBC....

  5. Cancer and birth defects surveillance system for communities around the Savannah River Site. Annual progress report

    Energy Technology Data Exchange (ETDEWEB)

    Dunbar, J.B.

    1994-05-01

    The US DOE funded this grant to the Medical University of South Carolina for a cancer and birth defects registry for an initial three year period which was completed as of April 29, 1994. While this Technical Progress Report is prepared principally to document the activities of year 03, it also summarizes the accomplishments of the first two years in order to put into perspective the energy and progress of the program over the entire three year funding cycle.

  6. The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Shusuke Akamatsu

    2015-08-01

    Full Text Available More potent targeting of the androgen receptor (AR in advanced prostate cancer is driving an increased incidence of neuroendocrine prostate cancer (NEPC, an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-β signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target.

  7. Catastrophic shifts and lethal thresholds in a propagating front model of unstable tumour progression

    CERN Document Server

    Amor, Daniel R

    2014-01-01

    Unstable dynamics characterizes the evolution of most solid tumors. Because of an increased failure of maintaining genome integrity, a cumulative increase in the levels of gene mutation and loss is observed. Previous work suggests that instability thresholds to cancer progression exist, defining phase transition phenomena separating tumor-winning scenarios from tumor extinction or coexistence phases. Here we present an integral equation approach to the quasispecies dynamics of unstable cancer. The model exhibits two main phases, characterized by either the success or failure of cancer tissue. Moreover, the model predicts that tumor failure can be due to either a reduced selective advantage over healthy cells or excessive instability. We also derive an approximate, analytical solution that predicts the front speed of aggressive tumor populations on the instability space.

  8. An integrated model for radiation induced cancer (IMRIC)

    International Nuclear Information System (INIS)

    The ultimate aim for radiation induced cancer modeling must be to arrive at cancer risk estimates in the human, based (partly or entirely) on data obtained in the laboratory. Current risk estimates for the stochastic radiation effect of cancer induction derive entirely from epidemiological data, largely of the Japanese survivors of the A-bombs, with little input of laboratory information. These data relate to high doses and high dose-rates and it is difficult to see how much more information can be extracted from them. Because of rapid progress in many fields, including molecular biology, cellular studies and experiments with laboratory animals, it is argued here that the time is now ripe for an attempt to be made to model the entire sequence of events from the absorption of radiation energy to the manifestation of a malignancy in the human. (author)

  9. Animal models of ovarian cancer

    OpenAIRE

    Shaw Tanya J; Vanderhyden Barbara C; Ethier Jean-François

    2003-01-01

    Abstract Ovarian cancer is the most lethal of all of the gynecological cancers and can arise from any cell type of the ovary, including germ cells, granulosa or stromal cells. However, the majority of ovarian cancers arise from the surface epithelium, a single layer of cells that covers the surface of the ovary. The lack of a reliable and specific method for the early detection of epithelial ovarian cancer results in diagnosis occurring most commonly at late clinical stages, when treatment is...

  10. Research Progress of MicroRNA in Early Detection of Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Ze-Hua Wang

    2015-01-01

    Full Text Available Objective: This review aimed to update the progress of microRNA (miRNA in early detection of ovarian cancer. We discussed the current clinical diagnosis methods and biomarkers of ovarian cancer, especially the methods of miRNA in early detection of ovarian cancer. Data Sources: We collected all relevant studies about miRNA and ovarian cancer in PubMed and CNKI from 1995 to 2015. Study Selection: We included all relevant studies concerning miRNA in early detection of ovarian cancer, and excluded the duplicated articles. Results: miRNAs play a key role in various biological processes of ovarian cancer, such as development, proliferation, differentiation, apoptosis and metastasis, and these phenomena appear in the early-stage. Therefore, miRNA can be used as a new biomarker for early diagnosis of ovarian cancer, intervention on miRNA expression of known target genes, and potential target genes can achieve the effect of early prevention. With the development of nanoscience and technology, analysis methods of miRNA are also quickly developed, which may provide better characterization of early detection of ovarian cancer. Conclusions: In the near future, miRNA therapy could be a powerful tool for ovarian cancer prevention and treatment, and combining with the new analysis technology and new nanomaterials, point-of-care tests for miRNA with high throughput, high sensitivity, and strong specificity are developed to achieve the application of diagnostic kits in screening of early ovarian cancer.

  11. Saffron Aqueous Extract Inhibits the Chemically-induced Gastric Cancer Progression in the Wistar Albino Rat

    Directory of Open Access Journals (Sweden)

    S. Zahra Bathaie

    2013-01-01

    Full Text Available Objective(s: Gastric cancer is the first and second leading cause of cancer related death in Iranian men and women, respectively. Gastric cancer management is based on the surgery, radiotherapy and chemotherapy. In the present study, for the first time, the beneficial effect of saffron (Crocus sativus L. aqueous extract (SAE on the 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG-induced gastric cancer in rat was investigated. Materials and Methods: MNNG was used to induce gastric cancer and then, different concentrations of SAE were administered to rats. After sacrificing, the stomach tissue was investigated by both pathologist and flow cytometry, and several biochemical parameters was determined in the plasma (or serum and stomach of rats. Results: Pathologic data indicated the induction of cancer at different stages from hyperplasia to adenoma in rats; and the inhibition of cancer progression in the gastric tissue by SAE administration; so that, 20% of cancerous rats treated with higher doses of SAE was completely normal at the end of experiment and there was no rat with adenoma in the SAE treated groups. In addition, the results of the flow cytometry/ propidium iodide staining showed that the apoptosis/proliferation ratio was increased due to the SAE treatment of cancerous rats. Moreover, the significantly increased serum LDH and decreased plasma antioxidant activity due to cancer induction fell backwards after treatment of rats with SAE. But changes in the other parameters (Ca2+, tyrosine kinase activity and carcino-embryonic antigen were not significant. Conclusion: SAE inhibits the progression of gastric cancer in rats, in a dose dependent manner.

  12. Metastatic colorectal cancer-past, progress and future

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The clinical management of metastatic (stage Ⅳ)colorectal cancer (CRC) is a common challenge faced by surgeons and physicians. The last decade has seen exciting developments in the management of CRC, with significant improvements in prognosis for patients diagnosed with stage Ⅳ disease. Treatment options have expanded from 5-fluorouracil alone to a range of pharmaceutical and interventional therapies,improving survival, and providing a cure in selected cases. Enhanced understanding of the biologic pathways most important in colorectal carcinogenesis has led to a new generation of drugs showing promise in advanced disease. It is hoped that in the near future the treatment paradigm of metastatic CRC will be analogous to that of a chronic illness, rather than a rapidly terminal condition.This overview discusses the epidemiology of advanced CRC and currently available therapeutic options including medical, surgical, ablative and novel modalities in the management of metastatic colorectal cancer.

  13. Recent progress in 8igenomic research of liver cancer

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Along the course of occurrence and development of liver cancer,the corresponding somatic cells accumulate some important genetic variations.These variations may be divided into two categories.For the genetic changes closely related to etiology of liver cancer,the well-known cases include insertion and integration of the hepatitis B virus(HBV) DNA after infection,and mutations at site 249 of the tumor suppressor gene p53 induced by exposure to aflatoxin B1.The secondary genetic changes include amplification and deletion of certain chromosome regions,mutations in p53 at the sites other than 249,as well as the mutational activation of the Wnt/β-catenin signal pathway.The tumor cells with these genetic variations may gradually become the dominant clones under evolutionary selection.Besides,identification of genetic susceptible against risk of liver malignancy is also an important aspect of research in this field.

  14. Supramolecular nanofibrils inhibit cancer progression in vitro and in vivo

    OpenAIRE

    Kuang, Yi; Du, Xuewen; Zhou, Jie; Xu, Bing

    2014-01-01

    The recent discovery of the inverse comorbidity between cancer and Alzheimer’s disease implies that one may use amyloids to inhibit tumors. During the conversion of a dipeptide segment (Phe-Phe) in β-amyloid into a supramolecular hydrogelator, we obtained a small molecule (1) that can self-assembly into nanofibrils via multiple intermolecular hydrogen bonding and aromatic-aromatic interactions. Interestingly, while the monomers of 1 are innocuous, the nanofibrils formed by 1 can selectively i...

  15. Research Progress of Lung Cancer with Leptomeningeal Metastasis

    OpenAIRE

    MA, CHUNHUA; Jiang, Rong; LI, JINDUO; Wang, Bin(Department of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai, 200240, China); Sun, Liwei; Lv, Yuan

    2014-01-01

    Leptomeningeal metastases is one of the most serious complications of lung cancer, the patients with poor prognosis. Leptomeningeal metastasis in patients with lack specificity of clinical manifestations. The main clinical performance are the damage of cerebral symptoms, cranial nerve and spinal nerve. The diagnosis primarily based on the history of tumor, clinical symptoms, enhance magnetic resnance image (MRI) scan and cerebrospinal fluid cytology. In recent years, new ways of detecting cli...

  16. MUC1 Regulates PDGFA Expression During Pancreatic Cancer Progression

    OpenAIRE

    Sahraei, Mahnaz; Roy, Lopamudra Das; CURRY, JENNIFER M.; Teresa, Tinder L; Nath, Sritama; Besmer, Dahlia; Kidiyoor, Amritha; Dalia, Ritu; Gendler, Sandra J.; Mukherjee, Pinku

    2012-01-01

    Pancreatic Ductal Adenocarcinoma (PDA) has one of the worst prognoses of all cancers. Mucin 1 (MUC1), a transmembrane mucin glycoprotein, is a key modulator of several signaling pathways that affect oncogenesis, motility, and metastasis. Its expression is known to be associated with poor prognosis in patients. However, the precise mechanism remains elusive. We report a novel association of MUC1 with Platelet-Derived Growth Factor-A (PDGFA). PDGFA is one of the many drivers of tumor growth, an...

  17. Recent Progress in Cancer-Related Lymphedema Treatment and Prevention

    OpenAIRE

    Shaitelman, Simona F; Cromwell, Kate D.; Rasmussen, John C.; Stout, Nicole L; Armer, Jane M.; Lasinski, Bonnie B.; Cormier, Janice N

    2014-01-01

    This article provides an overview of the recent developments in the diagnosis, treatment, and prevention of cancer-related lymphedema. Lymphedema incidence by tumor site is evaluated. Measurement techniques and trends in patient education and treatment are also summarized to include current trends in therapeutic and surgical treatment options as well as longer-term management. Finally, an overview of the policies related to insurance coverage and reimbursement will give the clinician an overv...

  18. Oxide behaviour modelling progress in COMETHE

    International Nuclear Information System (INIS)

    An attempt has been made to develop a global model which simultaneously describes many important aspects of uranium oxide under irradiation. The individual models describing fuel structural changes, swelling and gas release, which were earlier separate from one another, are now part of a more realistic integral fuel model. Fission gas release depends now on an explicitely calculated open porosity, which is generated by fuel swelling; the latter is in turn connected to fission gas release. The paper describes the individual oxide models and how they are linked together. (author)

  19. Obesity and Cancer Progression: Is There a Role of Fatty Acid Metabolism?

    Directory of Open Access Journals (Sweden)

    Seher Balaban

    2015-01-01

    Full Text Available Currently, there is renewed interest in elucidating the metabolic characteristics of cancer and how these characteristics may be exploited as therapeutic targets. Much attention has centered on glucose, glutamine and de novo lipogenesis, yet the metabolism of fatty acids that arise from extracellular, as well as intracellular, stores as triacylglycerol has received much less attention. This review focuses on the key pathways of fatty acid metabolism, including uptake, esterification, lipolysis, and mitochondrial oxidation, and how the regulators of these pathways are altered in cancer. Additionally, we discuss the potential link that fatty acid metabolism may serve between obesity and changes in cancer progression.

  20. Matrix Metalloproteinases: The Gene Expression Signatures of Head and Neck Cancer Progression

    Energy Technology Data Exchange (ETDEWEB)

    Iizuka, Shinji [Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 (United States); Ishimaru, Naozumi; Kudo, Yasusei, E-mail: yasusei@tokushima-u.ac.jp [Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-8-15 Kuramoto, Tokushima 770-8504 (Japan)

    2014-02-13

    Extracellular matrix degradation by matrix metalloproteinases (MMPs) plays a pivotal role in cancer progression by promoting motility, invasion and angiogenesis. Studies have shown that MMP expression is increased in head and neck squamous cell carcinomas (HNSCCs), one of the most common cancers in the world, and contributes to poor outcome. In this review, we examine the expression pattern of MMPs in HNSCC by microarray datasets and summarize the current knowledge of MMPs, specifically MMP-1, -3, -7 -10, -12, -13, 14 and -19, that are highly expressed in HNSCCs and involved cancer invasion and angiogenesis.

  1. Matrix Metalloproteinases: The Gene Expression Signatures of Head and Neck Cancer Progression

    International Nuclear Information System (INIS)

    Extracellular matrix degradation by matrix metalloproteinases (MMPs) plays a pivotal role in cancer progression by promoting motility, invasion and angiogenesis. Studies have shown that MMP expression is increased in head and neck squamous cell carcinomas (HNSCCs), one of the most common cancers in the world, and contributes to poor outcome. In this review, we examine the expression pattern of MMPs in HNSCC by microarray datasets and summarize the current knowledge of MMPs, specifically MMP-1, -3, -7 -10, -12, -13, 14 and -19, that are highly expressed in HNSCCs and involved cancer invasion and angiogenesis

  2. Altering the intratumoral localization of macrophages to inhibit cancer progression

    Science.gov (United States)

    Casazza, Andrea; Mazzone, Massimiliano

    2014-01-01

    Hypoxia confers to macrophages angiogenic and immunosuppressive properties which promote tumor growth and progression. Preventing the migration of macrophages into hypoxic tumor regions hinders angiogenesis and restores the tumor-suppressive properties of these immune cells. We have recently uncovered a neuropilin 1- and semaphorin 3A-dependent signaling pathway that defines the repositioning of macrophages to hypoxic tumor niches, a discovery that generates new options for the development of complementary anticancer treatments. PMID:24800172

  3. Altering the intratumoral localization of macrophages to inhibit cancer progression

    OpenAIRE

    Casazza, Andrea; Mazzone, Massimiliano

    2014-01-01

    Hypoxia confers to macrophages angiogenic and immunosuppressive properties which promote tumor growth and progression. Preventing the migration of macrophages into hypoxic tumor regions hinders angiogenesis and restores the tumor-suppressive properties of these immune cells. We have recently uncovered a neuropilin 1- and semaphorin 3A-dependent signaling pathway that defines the repositioning of macrophages to hypoxic tumor niches, a discovery that generates new options for the development of...

  4. Liver cancer mortality rate model in Thailand

    Science.gov (United States)

    Sriwattanapongse, Wattanavadee; Prasitwattanaseree, Sukon

    2013-09-01

    Liver Cancer has been a leading cause of death in Thailand. The purpose of this study was to model and forecast liver cancer mortality rate in Thailand using death certificate reports. A retrospective analysis of the liver cancer mortality rate was conducted. Numbering of 123,280 liver cancer causes of death cases were obtained from the national vital registration database for the 10-year period from 2000 to 2009, provided by the Ministry of Interior and coded as cause-of-death using ICD-10 by the Ministry of Public Health. Multivariate regression model was used for modeling and forecasting age-specific liver cancer mortality rates in Thailand. Liver cancer mortality increased with increasing age for each sex and was also higher in the North East provinces. The trends of liver cancer mortality remained stable in most age groups with increases during ten-year period (2000 to 2009) in the Northern and Southern. Liver cancer mortality was higher in males and increase with increasing age. There is need of liver cancer control measures to remain on a sustained and long-term basis for the high liver cancer burden rate of Thailand.

  5. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice.

    Science.gov (United States)

    Gu, Jian-Wei; Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-05-15

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer

  6. Identifying association model for single-nucleotide polymorphisms of ORAI1 gene for breast cancer

    OpenAIRE

    Chang, Wei-Chiao; Fang, Yong-Yuan; Chang, Hsueh-Wei; Chuang, Li-Yeh; Lin, Yu-Da; Hou, Ming-Feng; Yang, Cheng-Hong

    2014-01-01

    Background ORAI1 channels play an important role for breast cancer progression and metastasis. Previous studies indicated the strong correlation between breast cancer and individual single nucleotide polymorphisms (SNPs) of ORAI1 gene. However, the possible SNP-SNP interaction of ORAI1 gene was not investigated. Results To develop the complex analyses of SNP-SNP interaction, we propose a genetic algorithm (GA) to detect the model of breast cancer association between five SNPs (rs12320939, rs1...

  7. Expression of OATP family members in hormone-related cancers: potential markers of progression.

    Directory of Open Access Journals (Sweden)

    Heather Pressler

    Full Text Available The organic anion transporting polypeptide (OATP family of transporters has been implicated in prostate cancer disease progression probably by transporting hormones or drugs. In this study, we aimed to elucidate the expression, frequency, and relevance of OATPs as a biomarker in hormone-dependent cancers. We completed a study examining SLCO1B3, SLCO1B1 and SLCO2B1 mRNA expression in 381 primary, independent patient samples representing 21 cancers and normal tissues. From a separate cohort, protein expression of OATP1B3 was examined in prostate, colon, and bladder tissue. Based on expression frequency, SLCO2B1 was lower in liver cancer (P = 0.04 which also trended lower with decreasing differentiation (P = 0.004 and lower magnitude in pancreatic cancer (P = 0.05. SLCO2B1 also had a higher frequency in thyroid cancer (67% than normal (0% and expression increased with stage (P = 0.04. SLCO1B3 was expressed in 52% of cancerous prostate samples and increased SLCO1B3 expression trended with higher Gleason score (P = 0.03. SLCO1B3 expression was also higher in testicular cancer (P = 0.02. SLCO1B1 expression was lower in liver cancer (P = 0.04 which trended lower with liver cancer grade (P = 0.0004 and higher with colon cancer grade (P = 0.05. Protein expression of OATP1B3 was examined in normal and cancerous prostate, colon, and bladder tissue samples from an independent cohort. The results were similar to the transcription data, but showed distinct localization. OATPs correlate to differentiation in certain hormone-dependent cancers, thus may be useful as biomarkers for assessing clinical treatment and stage of disease.

  8. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne Vibeke; Knoop, Ann; Jensen, Jeanette Dupont; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    2015-01-01

    progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each...

  9. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne Vibeke; Knoop, Ann; Jensen, Jeanette Dupont; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each...

  10. Immediate treatment with bicalutamide 150mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer

    DEFF Research Database (Denmark)

    See, W; Iversen, P; Wirth, M;

    2003-01-01

    To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer.......To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer....

  11. Mouse models of anemia of cancer.

    Directory of Open Access Journals (Sweden)

    Airie Kim

    Full Text Available Anemia of cancer (AC may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI, with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC.

  12. Flood Progression Modelling and Impact Analysis

    DEFF Research Database (Denmark)

    Mioc, Darka; Anton, François; Nickerson, B.;

    People living in the lower valley of the St. John River, New Brunswick, Canada, frequently experience flooding when the river overflows its banks during spring ice melt and rain. To better prepare the population of New Brunswick for extreme flooding, we developed a new flood prediction model that...... computes floodplain polygons before the flood occurs. This allows emergency managers to access the impact of the flood before it occurs and make the early decisions for evacuation of the population and flood rescue. This research shows that the use of GIS and LiDAR technologies combined with hydrological...... modelling can significantly improve the decision making and visualization of flood impact needed for emergency planning and flood rescue. Furthermore, the 3D GIS application we developed for modelling flooded buildings and infrastructure provides a better platform for modelling and visualizing flood...

  13. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK

    DEFF Research Database (Denmark)

    Baker, A-M; Bird, D; Lang, G;

    2013-01-01

    The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic...

  14. Defining progression in nonmuscle invasive bladder cancer: it is time for a new, standard definition

    NARCIS (Netherlands)

    Lamm, D.; Persad, R.; Brausi, M.; Buckley, R.; Witjes, J.A.; Palou, J.; Bohle, A.; Kamat, A.M.; Colombel, M.; Soloway, M.

    2014-01-01

    PURPOSE: Despite being one of the most important clinical outcomes in nonmuscle invasive bladder cancer, there is currently no standard definition of disease progression. Major clinical trials and meta-analyses have used varying definitions or have failed to define this end point altogether. A stand

  15. Proteomic biomarkers for overall and progression-free survival in ovarian cancer patients

    DEFF Research Database (Denmark)

    Høgdall, Estrid; Fung, Eric T; Christensen, Ib Jarle;

    2010-01-01

    To determine if the level of apolipoprotein A1, hepcidin, transferrin, inter-a trypsin IV internal fragment, transthyretin (TT), connective-tissue activating protein 3 (CTAP3), serum amyloid A1, ß-2 microglobulin (B2M) might have impact on overall and progression-free survival for ovarian cancer...

  16. Proteomic biomarkers for overall and progression-free survival in ovarian cancer patients

    DEFF Research Database (Denmark)

    Høgdall, Estrid; Fung, Eric T; Christensen, Ib Jarle;

    2010-01-01

    To determine if the level of apolipoprotein A1, hepcidin, transferrin, inter-α trypsin IV internal fragment, transthyretin (TT), connective-tissue activating protein 3 (CTAP3), serum amyloid A1, β-2 microglobulin (B2M) might have impact on overall and progression-free survival for ovarian cancer...

  17. Magnetic-mediated hyperthermia for cancer treatment: Research progress and clinical trials

    International Nuclear Information System (INIS)

    Research progress and frontiers of magnetic-mediated hyperthermia (MMH) are presented, along with clinical trials in Germany, the US, Japan, and China. Special attention is focused on MMH mediated by magnetic nanoparticles, and multifunctional magnetic devices for cancer multimodality treatment are also introduced. (topical review - magnetism, magnetic materials, and interdisciplinary research)

  18. Adjuvant Strategies for Resectable Pancreatic Cancer: Have We Made Progress?

    Directory of Open Access Journals (Sweden)

    Suzanne Russo

    2012-03-01

    Full Text Available Substantial controversy remains regarding the optimal adjuvant treatment for patients with resectable pancreatic adenocarcinoma. Despite improvements in radiation techniques, systemic therapies, and incorporation of targeted agents, the 5-year survival rates for early stage patients remains less than 25% and the optimal adjuvant treatment approach remains unclear. Here we summarize the data presented at the 2012 American Society of Clinical Oncology (ASCO Gastrointestinal Cancers Symposium regarding controversial issues surrounding the role, timing, and selection of patients for adjuvant chemoradiation strategies following curative resection for pancreatic adenocarcinoma. (Abstracts #301, #333, and #206.

  19. Animal models and therapeutic molecular targets of cancer: utility and limitations

    Directory of Open Access Journals (Sweden)

    Cekanova M

    2014-10-01

    Full Text Available Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. Keywords: mouse cancer model, companion animal cancer model, dogs, cats, molecular targets

  20. Animal Models of Cancer Pain

    OpenAIRE

    Pacharinsak, Cholawat; Beitz, Alvin

    2008-01-01

    Modern cancer therapies have significantly increased patient survival rates in both human and veterinary medicine. Since cancer patients live longer they now face new challenges resulting from severe, chronic tumor-induced pain. Unrelieved cancer pain significantly decreases the quality of life of such patients; thus the goal of pain management is to not only to alleviate pain, but also to maintain the patient's physiological and psychological well-being. The major impediment for developing n...

  1. Lost in translation: animal models and clinical trials in cancer treatment

    OpenAIRE

    Mak, Isabella WY; Evaniew, Nathan; Ghert, Michelle

    2014-01-01

    Due to practical and ethical concerns associated with human experimentation, animal models have been essential in cancer research. However, the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression. Therefore the safety and efficacy identified in animal studies is generally not translated to human trials. Animal mo...

  2. Retrospective study of the effect of disease progression on patient reported outcomes in HER-2 negative metastatic breast cancer patients

    Directory of Open Access Journals (Sweden)

    Yu Elaine

    2011-06-01

    Full Text Available Abstract Background This retrospective study evaluated the impact of disease progression and of specific sites of metastasis on patient reported outcomes (PROs that assess symptom burden and health related quality of life (HRQoL in women with metastatic breast cancer (mBC. Methods HER-2 negative mBC patients (n = 102 were enrolled from 7 U.S. community oncology practices. Demographic, disease and treatment characteristics were abstracted from electronic medical records and linked to archived Patient Care Monitor (PCM assessments. The PCM is a self-report measure of symptom burden and HRQoL administered as part of routine care in participating practices. Linear mixed models were used to examine change in PCM scores over time. Results Mean age was 57 years, with 72% of patients Caucasian, and 25% African American. Median time from mBC diagnosis to first disease progression was 8.8 months. Metastasis to bone (60%, lung (28% and liver (26% predominated at initial metastatic diagnosis. Results showed that PCM items assessing fatigue, physical pain and trouble sleeping were sensitive to either general effects of disease progression or to effects associated with specific sites of metastasis. Progression of disease was also associated with modest but significant worsening of General Physical Symptoms, Treatment Side Effects, Acute Distress and Impaired Performance index scores. In addition, there were marked detrimental effects of liver metastasis on Treatment Side Effects, and of brain metastasis on Acute Distress. Conclusions Disease progression has a detrimental impact on cancer-related symptoms. Delaying disease progression may have a positive impact on patients' HRQoL.

  3. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne-Vibeke; Knoop, Ann S; Jensen, Jeanette D; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    2015-01-01

    necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer......Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer...... progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each...

  4. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne Vibeke; Knoop, Ann; Jensen, Jeanette Dupont; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer......Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer...... progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each...

  5. Role of Interleukin 17 in Lung Carcinogenesis and Lung Cancer Progression

    Directory of Open Access Journals (Sweden)

    Jiandong MEI

    2016-01-01

    Full Text Available Interleukin 17 (IL-17 is an important pro-inflammatory cytokine. It plays a critical role in mediating pathogen defense reactions, and the pathological inflammation of autoimmune diseases. IL-17 is also involved in various inflammation-related carcinogenesis. Cigarette smoking is one of the most important risk factors of lung cancer. Chronic inflammation caused by smoking and other factors is accompanied with overexpression of IL-17 within the airway, which reveals a potential relationship between IL-17 and lung carcinogenesis. Furthermore, IL-17 also plays a role in lung cancer progression via different mechanisms. In this paper, we summarized the results of current studies on IL-17 and lung carcinogenesis, as well as lung cancer progression.

  6. ANIMAL MODELS OF CANCER: A REVIEW

    Directory of Open Access Journals (Sweden)

    Archana M. Navale

    2013-01-01

    Full Text Available Cancer is the second leading cause of death worldwide. In USA three persons out of five will develop some type of cancer. Beyond these statistics of mortality, the morbidity due to cancer presents a real scary picture. Last 50 years of research has rendered some types of cancer curable, but still the major fear factor associated with this disease is unchanged. Animal models are classified according to the method of induction of cancer in the animal. Spontaneous tumor models are the most primitive models. Although these models show good resemblance to the natural disease in humans, they were not capable of keeping pace with developing experimental therapeutics programs. It has therefore been necessary to take a further step towards artificiality, away from the clinical problem in the search for satisfactory testing method. From this step, the journey of artificially induced tumor models started. It is possible to induce cancer reproducibly in animals by exposing them to various agents and now, by transplanting tumor cells or tissue. The development of Genetically Engineered Animal models has provided a great help in knowing the disease. This article takes a review of present animal models used in anti-cancer drug discovery.

  7. Flood Progression Modelling and Impact Analysis

    OpenAIRE

    D. Mioc; F. Anton; Nickerson, B.; M. Santos; Adda, P.; T. Tienaah; Ahmad, A; Mezouaghi, M.; MacGillivray, E.; Morton, A.; P. Tang

    2011-01-01

    People living in the lower valley of the St. John River, New Brunswick, Canada, frequently experience flooding when the river overflows its banks during spring ice melt and rain. To better prepare the population of New Brunswick for extreme flooding, we developed a new flood prediction model that computesfloodplain polygons before the flood occurs. This allows emergency managers to access the impact of the flood before it occurs and make the early decisions for evacuation of the population an...

  8. A Model for Counselling Cancer Patients.

    Science.gov (United States)

    Jevne, Ronna F.; Nekolaichuk, Cheryl L.; Williamson, F. Helen A.

    1998-01-01

    Describes a model for counseling cancer patients that integrates the unique features of the cancer experience within a basic counseling framework. It combines a nine-step problem-solving approach with a biopsychosocial perspective, placing greater emphasis on the person than the problem. Utilizes innovative questioning techniques and strategies.…

  9. Progress and remaining challenges for cancer control in Latin America and the Caribbean.

    Science.gov (United States)

    Strasser-Weippl, Kathrin; Chavarri-Guerra, Yanin; Villarreal-Garza, Cynthia; Bychkovsky, Brittany L; Debiasi, Marcio; Liedke, Pedro E R; Soto-Perez-de-Celis, Enrique; Dizon, Don; Cazap, Eduardo; de Lima Lopes, Gilberto; Touya, Diego; Nunes, Joāo Soares; St Louis, Jessica; Vail, Caroline; Bukowski, Alexandra; Ramos-Elias, Pier; Unger-Saldaña, Karla; Brandao, Denise Froes; Ferreyra, Mayra E; Luciani, Silvana; Nogueira-Rodrigues, Angelica; de Carvalho Calabrich, Aknar Freire; Del Carmen, Marcela G; Rauh-Hain, Jose Alejandro; Schmeler, Kathleen; Sala, Raúl; Goss, Paul E

    2015-10-01

    Cancer is one of the leading causes of mortality worldwide, and an increasing threat in low-income and middle-income countries. Our findings in the 2013 Commission in The Lancet Oncology showed several discrepancies between the cancer landscape in Latin America and more developed countries. We reported that funding for health care was a small percentage of national gross domestic product and the percentage of health-care funds diverted to cancer care was even lower. Funds, insurance coverage, doctors, health-care workers, resources, and equipment were also very inequitably distributed between and within countries. We reported that a scarcity of cancer registries hampered the design of credible cancer plans, including initiatives for primary prevention. When we were commissioned by The Lancet Oncology to write an update to our report, we were sceptical that we would uncover much change. To our surprise and gratification much progress has been made in this short time. We are pleased to highlight structural reforms in health-care systems, new programmes for disenfranchised populations, expansion of cancer registries and cancer plans, and implementation of policies to improve primary cancer prevention. PMID:26522157

  10. MR Differentiation of Lung Cancer from Progressive Massive Fibrosis in Patients with Coal Worker's Pneumoconiosis

    International Nuclear Information System (INIS)

    To analyze the potential of MR to distinguish lung cancer from progressive massive fibrosis (PMF) in patients with coal worker's pneumoconiosis. The study consisted of 9 patients with pathologically proven lung cancer and 26 PMFs in 17 patients. All the patients had radiologic evidence of pneumoconiosis. T1-weighted FLASH images were obtained before and 0.5, 1, 2, 3, 4, 5, 7.5, 10, 12.5, and 15 minutes after injection of Gd-DTPA. T2-weighted fast spin-echo images were obtained. The imaging findings were evaluated for enhancement time curve, contrast uptake equivalent (CE), and enhancement factor (EF). On T1WI, there was no significant signal intensity difference between lung cancer and PMF. On T2WI, all lung cancer showed high signal intensity, as opposed to all PMFs which showed low signal intensity except for one PMF. Only one PMF showed high signal intensity on T2WI. For the dynamic contrast study, lung cancer showed faster and slightly stronger enhancement than PMFs. For a delayed image, most of the lung cancers (78%) showed washout, as opposed to a plateau in most of PMFs (73%) (p=0.0153). However, no difference was detected between the EFmax of lung cancer and PMFs (p=0.349). MR is potentially a useful tool in distinguishing lung cancer from PMFs in patients with coal worker's pneumoconiosis

  11. Current evidence linking polyunsaturated fatty acids (PUFAs with cancer risk and progression

    Directory of Open Access Journals (Sweden)

    MariaAzrad

    2013-09-01

    Full Text Available There is increasing evidence that polyunsaturated fatty acids (PUFAs play a role in cancer risk and progression. The n-3 family of PUFAs includes alpha-linolenic acid (ALA, eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA while the n-6 family includes linolenic acid (LA and arachidonic acid (AA. EPA and DHA are precursors for anti-inflammatory lipid mediators while AA is a precursor for pro-inflammatory lipid mediators. Collectively, PUFAs play crucial roles in maintaining cellular homeostasis, and perturbations in dietary intake or PUFA metabolism could result in cellular dysfunction and contribute to cancer risk and progression. Epidemiologic studies provide an inconsistent picture of the associations between dietary PUFAs and cancer. This discrepancy may reflect the difficulties in collecting accurate dietary data; however, it also may reflect genetic variation in PUFA metabolism which has been shown to modify physiological levels of PUFAs and cancer risk. Also, host-specific mutations as a result of cellular transformation could modify metabolism of PUFAs in the target-tissue. Clinical trials have shown that supplementation with PUFAs or foods high in PUFAs can affect markers of inflammation, immune function, tumor biology and prognosis. Preclinical investigations have begun to elucidate how PUFAs may mediate cell proliferation, apoptosis and angiogenesis and the signaling pathways involved in these processes. The purpose of this review is to summarize the current evidence linking PUFAs and their metabolites with cancer and the molecular mechanisms that underlie this association. Identifying the molecular mechanism(s through which PUFAs affect cancer risk and progression will provide an opportunity to pursue focused dietary interventions that could translate into the development of personalized diets for cancer control.

  12. Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

    Directory of Open Access Journals (Sweden)

    Kucuk Omer

    2007-01-01

    Full Text Available Abstract Background We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC model established in our laboratory. Methods The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. Results In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. Conclusion Our studies in both RCC and prostate tumor models demonstrate that the

  13. Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

    International Nuclear Information System (INIS)

    We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more

  14. Chemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine

    Science.gov (United States)

    Stites, Edward C.

    2013-04-01

    Traditional experimental biology has provided a mechanistic understanding of cancer in which the malignancy develops through the acquisition of mutations that disrupt cellular processes. Several drugs developed to target such mutations have now demonstrated clinical value. These advances are unequivocal testaments to the value of traditional cellular and molecular biology. However, several features of cancer may limit the pace of progress that can be made with established experimental approaches alone. The mutated genes (and resultant mutant proteins) function within large biochemical networks. Biochemical networks typically have a large number of component molecules and are characterized by a large number of quantitative properties. Responses to a stimulus or perturbation are typically nonlinear and can display qualitative changes that depend upon the specific values of variable system properties. Features such as these can complicate the interpretation of experimental data and the formulation of logical hypotheses that drive further research. Mathematical models based upon the molecular reactions that define these networks combined with computational studies have the potential to deal with these obstacles and to enable currently available information to be more completely utilized. Many of the pressing problems in cancer biology and cancer medicine may benefit from a mathematical treatment. As work in this area advances, one can envision a future where such models may meaningfully contribute to the clinical management of cancer patients.

  15. Research Progress of Nutrition Support for Patients with Lung Cancer 
During Chemotherapy

    Directory of Open Access Journals (Sweden)

    Yiqiao LUO

    2014-12-01

    Full Text Available Primary lung cancer is one of the most common malignancies. Nowadays, both its morbidity and mortality rank first, patients with lung cancer are often goes with some affiliating symptoms such as malnutrition and weight loss. The side effects of cytotoxicity during chemotherapy may lead to further deteriorate of the nutritional status and worsen the anti-tumor therapy’s efficacy and the patients’ quality of life. With the development of palliative treatment and the higher request of patients for quality of life, nutritional support will be an important adjunctive treatment to maintain a good nutritional status and enhance the patients’ immunity during chemotherapy. It will play an active role in improving tolerability of chemotherapy and prognosis for patients with lung cancer. Here is a review about research progress of nutrition support treatment during chemotherapy for the patients with lung cancer.

  16. Correlation of CD44v6 expression with ovarian cancer progression and recurrence

    International Nuclear Information System (INIS)

    Previously some groups demonstrated that CD44 variant 6 (CD44v6) is correlated with progression and metastasis of ovarian cancer. However, a number of other groups failed to find such an association. Moreover, epithelial ovarian cancer is known to easily metastasize to distinct sites such as the pelvic and abdominal cavities, but the potential association of CD44v6 expression with site-specific metastasis of ovarian cancer has not been explored. This study sought to evaluate the expression of CD44 standard (CD44s) and CD44v6 in primary, metastatic and recurrent epithelial ovarian cancer to explore the potential association of CD44s and CD44v6 with tumor progression and recurrence. Tumor specimens were procured from patients with advanced (FIGO III, G3) and recurrent ovarian serous adenocarcinoma. CD44s and CD44v6 expression in the tumor tissues was evaluated by real-time RT-PCR and Western blot. Moreover, serum soluble CD44s or CD44v6 concentrations of early stage (FIGO I, G1), advanced (FIGO III, G3) and recurrent ovarian serous adenocarcinoma patients were determined by enzyme-linked immunosorbent assays (ELISA). CD44v6 expression in a different set of tumor samples on an ovarian cancer tissue chip was evaluated by immunohistochemistry (IHC) and the correlation of CD44v6 expression with clinicopathologic features was analyzed. Finally, the effects of knockdown of CD44v6 in SKOV3 cells on cell adhesion, invasion and migration were assessed. The expression of CD44v6, but not CD44s, is up-regulated in recurrent ovarian serous cancer compared to advanced primary tumor. CD44v6 expression is also preferentially increased in the tumor at the abdominal cavity metastasis site of advanced diseases. Consistently, serum soluble CD44v6 levels of recurrent ovarian cancer were higher than those of early stage and advanced primary diseases. The IHC data demonstrate that CD44v6 expression is correlated with clinicopathologic features and tumor progression. Lastly, knockdown of CD

  17. Prognostic nomogram to predict progression-free survival in patients with platinum-sensitive recurrent ovarian cancer

    OpenAIRE

    Lee, C.K.; Simes, R. J.; Brown, C.; Lord, S.; Wagner, U; Plante, M; Vergote, I; Pisano, C.; Parma, G.; Burges, A.; Bourgeois, H; Hogberg, T; Bentley, J; Angleitner-Boubenizek, L; Ferrero, A.

    2011-01-01

    BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n = 955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n = 340). The proportional-hazards model (n...

  18. Validation of Novel Biomarkers for Prostate Cancer Progression by the Combination of Bioinformatics, Clinical and Functional Studies

    Science.gov (United States)

    Väänänen, Riina-Minna; Mattsson, Jesse; Li, Yifeng; Tallgrén, Terhi; Tong Ochoa, Natalia; Bjartell, Anders; Åkerfelt, Malin; Taimen, Pekka; Boström, Peter J.

    2016-01-01

    The identification and validation of biomarkers for clinical applications remains an important issue for improving diagnostics and therapy in many diseases, including prostate cancer. Gene expression profiles are routinely applied to identify diagnostic and predictive biomarkers or novel targets for cancer. However, only few predictive markers identified in silico have also been validated for clinical, functional or mechanistic relevance in disease progression. In this study, we have used a broad, bioinformatics-based approach to identify such biomarkers across a spectrum of progression stages, including normal and tumor-adjacent, premalignant, primary and late stage lesions. Bioinformatics data mining combined with clinical validation of biomarkers by sensitive, quantitative reverse-transcription PCR (qRT-PCR), followed by functional evaluation of candidate genes in disease-relevant processes, such as cancer cell proliferation, motility and invasion. From 300 initial candidates, eight genes were selected for validation by several layers of data mining and filtering. For clinical validation, differential mRNA expression of selected genes was measured by qRT-PCR in 197 clinical prostate tissue samples including normal prostate, compared against histologically benign and cancerous tissues. Based on the qRT-PCR results, significantly different mRNA expression was confirmed in normal prostate versus malignant PCa samples (for all eight genes), but also in cancer-adjacent tissues, even in the absence of detectable cancer cells, thus pointing to the possibility of pronounced field effects in prostate lesions. For the validation of the functional properties of these genes, and to demonstrate their putative relevance for disease-relevant processes, siRNA knock-down studies were performed in both 2D and 3D organotypic cell culture models. Silencing of three genes (DLX1, PLA2G7 and RHOU) in the prostate cancer cell lines PC3 and VCaP by siRNA resulted in marked growth arrest

  19. Specific changes in the expression of imprinted genes in prostate cancer-implications for cancer progression and epigenetic regulation

    Institute of Scientific and Technical Information of China (English)

    Teodora Ribarska; Klaus-Marius Bastian; Annemarie Koch; Wolfgang A Schulz

    2012-01-01

    Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation,enhancer of zeste homologue 2 (EZH2)overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer.DNA methylation,EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes.Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes,expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2).A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms.Instead,selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes,which might function in the prostate to limit cell growth induced viathe PI3K/Akt pathway,modulate androgen responses and regulate differentiation.Whereas dysregulation of IG F2 may constitute an early change in prostate carcinogenesis,inactivation of this imprinted gene network is rather associated with cancer progression.

  20. "It's Back! My Remission Is Over": Online Communication of Disease Progression Among Adolescents With Cancer.

    Science.gov (United States)

    Keim-Malpass, Jessica; Stegenga, Kristin; Loudin, Beth; Kennedy, Christine; Kools, Susan

    2016-05-01

    Cancer in adolescence presents unique challenges to patients and families due to the dramatic physical and psychological vulnerabilities that occur during a time of identity development. Additionally, adolescents who experience progression of their cancer, or failure of first-line therapies, represent an understudied group within pediatric oncology. Illness blogs offer a unique opportunity to understand the experience of a chronic or serious illness through a naturalistic and longitudinal perspective that is inherently patient centered. The purpose of this exploratory qualitative study was to describe the experiences of adolescents with cancer who experienced disease progression through analysis of their online illness blogs. Seven illness blogs written by adolescents with cancer diagnosed between the ages of 13 and 18 years were analyzed using thematic analysis. Several key themes were described among the adolescents, including normalizing the news, facing treatment failure, and reconciling chronos-the finite concept of time. These findings provide vital descriptive evidence for the experience of disease progression as described by adolescents, as well as identifying key points of further study and intervention development for nurse researchers and nurses who care for this vulnerable patient population. PMID:26483425

  1. Beyond a tumor suppressor: Soluble E-cadherin promotes the progression of cancer.

    Science.gov (United States)

    Hu, Qi-Ping; Kuang, Jing-Ya; Yang, Qing-Kai; Bian, Xiu-Wu; Yu, Shi-Cang

    2016-06-15

    E-cadherin (E-cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane-tethered form and a soluble form. Full-length E-cad is membrane tethered. As a type I transmembrane glycoprotein, E-cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E-cad (sE-cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full-length E-cad. The production of sE-cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE-cad can diffuse into the extracellular environment and the blood. As a paracrine/autocrine signaling molecule, sE-cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE-cad in tumorigenesis and tumor progression and its significance in clinical therapeutics. PMID:26704932

  2. Cancer modelling in the NGS era - Part I: Emerging technology and initial modelling.

    Science.gov (United States)

    Rovigatti, Ugo

    2015-11-01

    It is today indisputable that great progresses have been made in our molecular understanding of cancer cells, but an effective implementation of such knowledge into dramatic cancer-cures is still belated and yet desperately needed. This review gives a snapshot at where we stand today in this search for cancer understanding and definitive treatments, how far we have progressed and what are the major obstacles we will have to overcome both technologically and for disease modelling. In the first part, promising 3rd/4th Generation Sequencing Technologies will be summarized (particularly IonTorrent and OxfordNanopore technologies). Cancer modelling will be then reviewed from its origin in XIX Century Germany to today's NGS applications for cancer understanding and therapeutic interventions. Developments after Molecular Biology revolution (1953) are discussed as successions of three phases. The first, PH1, labelled "Clonal Outgrowth" (from 1960s to mid 1980s) was characterized by discoveries in cytogenetics (Nowell, Rowley) and viral oncology (Dulbecco, Bishop, Varmus), which demonstrated clonality. Treatments were consequently dominated by a "cytotoxic eradication" strategy with chemotherapeutic agents. In PH2, (from the mid 1980s to our days) the description of cancer as "Gene Networks" led to targeted-gene-therapies (TGTs). TGTs are the focus of Section 3: in view of their apparent failing (Ephemeral Therapies), alternative strategies will be discussed in review part II (particularly cancer immunotherapy, CIT). Additional Pitfalls impinge on the concepts of tumour heterogeneity (inter/intra; ITH). The described pitfalls set the basis for a new phase, PH3, which is called "NGS Era" and will be also discussed with ten emerging cancer models in the Review 2nd part. PMID:26427785

  3. Progress in studying scintillator proportionality: Phenomenological model

    Energy Technology Data Exchange (ETDEWEB)

    Bizarri, Gregory; Cherepy, Nerine; Choong, Woon-Seng; Hull, Giulia; Moses, William; Payne, Sephen; Singh, Jai; Valentine, John; Vasilev, Andrey; Williams, Richard

    2009-04-30

    We present a model to describe the origin of non-proportional dependence of scintillator light yield on the energy of an ionizing particle. The non-proportionality is discussed in terms of energy relaxation channels and their linear and non-linear dependences on the deposited energy. In this approach, the scintillation response is described as a function of the deposited energy deposition and the kinetic rates of each relaxation channel. This mathematical framework allows both a qualitative interpretation and a quantitative fitting representation of scintillation non-proportionality response as function of kinetic rates. This method was successfully applied to thallium doped sodium iodide measured with SLYNCI, a new facility using the Compton coincidence technique. Finally, attention is given to the physical meaning of the dominant relaxation channels, and to the potential causes responsible for the scintillation non-proportionality. We find that thallium doped sodium iodide behaves as if non-proportionality is due to competition between radiative recombinations and non-radiative Auger processes.

  4. Does phosphorylation of cofilin affect the progression of human bladder cancer?

    Directory of Open Access Journals (Sweden)

    Chung Hong

    2013-02-01

    Full Text Available Abstract Background We determined the differently expressed protein profiles and their functions in bladder cancer tissues with the aim of identifying possible target proteins and underlying molecular mechanisms for taking part in their progression. Methods We examined the expression of proteins by proteomic analysis and western blot in normal urothelium, non-muscle-invasive bladder cancers (NMIBCs, and muscle-invasive bladder cancers (MIBCs. The function of cofilin was analyzed using T24 human bladder cancer cells. Results The expression levels of 12 proteins were altered between bladder cancers and normal bladder tissues. Of these proteins, 14-3-3σ was upregulated in both NMIBCs and MIBCs compared with controls. On the other hand, myosin regulatory light chain 2, galectin-1, lipid-binding AI, annexin V, transthyretin, CARD-inhibitor of NF-κB-activating ligand, and actin prepeptide were downregulated in cancer samples. Cofilin, an actin-depolymerizing factor, was prominent in both NMIBCs and MIBCs compared with normal bladder tissues. Furthermore, we confirmed that cofilin phosphorylation was more prominent in MIBCs than in NMIBCs using immunoblotting and immunohistochemcal analyses. Epidermal growth factor (EGF increased the phosphorylation of cofilin and elevated the migration in T24 cells. Knockdown of cofilin expression with small interfering RNA attenuated the T24 cell migration in response to EGF. Conclusions These results demonstrate that the increased expression and phosphorylation of cofilin might play a role in the occurrence and invasiveness of bladder cancer. We suspected that changes in cofilin expression may participate in the progression of the bladder cancer.

  5. Local prostate cancer radiotherapy after prostate-specific antigen progression during primary hormonal therapy

    International Nuclear Information System (INIS)

    The outcome of patients after radiotherapy (RT) for localized prostate cancer in case of prostate-specific antigen (PSA) progression during primary hormonal therapy (HT) is not well known. A group of 27 patients presenting with PSA progression during primary HT for local prostate cancer RT was identified among patients who were treated in the years 2000–2004 either using external-beam RT (EBRT; 70.2Gy; n=261) or Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18Gy + 50.4Gy; n=71). The median follow-up period after RT was 68 months. Median biochemical recurrence free (BRFS), disease specific (DSS) and overall survival (OS) for patients with PSA progression during primary HT was found to be only 21, 54 and 53 months, respectively, with a 6-year BRFS, DSS and OS of 19%, 41% and 26%. There were no significant differences between different RT concepts (6-year OS of 27% after EBRT and 20% after EBRT with HDR-BT). Considering all 332 patients in multivariate Cox regression analysis, PSA progression during initial HT, Gleason score>6 and patient age were found to be predictive for lower OS (p<0.001). The highest hazard ratio resulted for PSA progression during initial HT (7.2 in comparison to patients without PSA progression during primary HT). PSA progression and a nadir >0.5 ng/ml during initial HT were both significant risk factors for biochemical recurrence. An unfavourable prognosis after PSA progression during initial HT needs to be considered in the decision process before local prostate radiotherapy. Results from other centres are needed to validate our findings

  6. RECENT PROGRESS IN NONLINEAR EDDY-VISCOSITY TURBULENCE MODELING

    Institute of Scientific and Technical Information of China (English)

    符松; 郭阳; 钱炜祺; 王辰

    2003-01-01

    This article presents recent progresses in turbulence modeling in the Unit for Turbulence Simulation in the Department of Engineering Mechanics at Tsinghua University. The main contents include: compact Non-Linear Eddy-Viscosity Model (NLEVM) based on the second-moment closure, near-wall low-Re non-linear eddy-viscosity model and curvature sensitive turbulence model.The models have been validated in a wide range of complex flow test cases and the calculated results show that the present models exhibited overall good performance.

  7. Accessing key steps of human tumor progression in vivo by using an avian embryo model

    Science.gov (United States)

    Hagedorn, Martin; Javerzat, Sophie; Gilges, Delphine; Meyre, Aurélie; de Lafarge, Benjamin; Eichmann, Anne; Bikfalvi, Andreas

    2005-02-01

    Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening. angiogenesis | animal model alternatives | glioblastoma

  8. Cavin-2 in oral cancer: A potential predictor for tumor progression.

    Science.gov (United States)

    Unozawa, Motoharu; Kasamatsu, Atsushi; Higo, Morihiro; Fukumoto, Chonji; Koyama, Tomoyoshi; Sakazume, Tomomi; Nakashima, Dai; Ogawara, Katsunori; Yokoe, Hidetaka; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-06-01

    Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc. PMID:26086332

  9. Neural protein gamma-synuclein interacting with androgen receptor promotes human prostate cancer progression

    International Nuclear Information System (INIS)

    Gamma-synuclein (SNCG) has previously been demonstrated to be significantly correlated with metastatic malignancies; however, in-depth investigation of SNCG in prostate cancer is still lacking. In the present study, we evaluated the role of SNCG in prostate cancer progression and explored the underlying mechanisms. First, alteration of SNCG expression in LNCaP cell line to test the ability of SNCG on cellular properties in vitro and vivo whenever exposing with androgen or not. Subsequently, the Dual-luciferase reporter assays were performed to evaluate whether the role of SNCG in LNCaP is through AR signaling. Last, the association between SNCG and prostate cancer progression was assessed immunohistochemically using a series of human prostate tissues. Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. Subsequently, mechanistic studies indicated that SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. Finally, immunohistochemical analysis revealed that SNCG was almost undetectable in benign or androgen-independent tissues prostate lesions. The high expression of SNCG is correlated with peripheral and lymph node invasion. Our data suggest that SNCG may serve as a biomarker for predicting human prostate cancer progression and metastasis. It also may become as a novel target for biomedical therapy in advanced prostate cancer

  10. WNT5A modulates cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Wei Wei; Hui-Hui Sun; Na Li; Hong-Yue Li; Xin Li; Qiang Li; Xiao-Hong Shen

    2014-01-01

    BACKGROUND: Although there are many studies on the mechanism of chemoresistance in cancers, studies on the relations between WNT5A and chemoresistance in pancreatic cancer are rare. The present study was to examine the role of WNT5A in the regulation of cell cycle progression and in chemoresistance in pancreatic cancer tissues and cell lines. METHODS: Fresh pancreatic cancer and paracarcinoma tissues were obtained from 32 patients. The expressions of WNT5A, AKT/p-AKT and Cyclin D1 were detected by immunohistochemistry, and the correlation between WNT5A expression and clinicopathological characteristics was analyzed. The relationship between WNT5A expression and gemcitabine resistance was studied in PANC-1 and MIAPaCa2 cell lines. The effect of WNT5A on the regulation of cell cycle and gemcitabine cytotoxicity were investigated. The associations among the expressions of p-AKT, Cyclin D1 and WNT5A were also analyzed in cell lines and the effect of WNT5A on restriction-point (R-point) progression was evaluated. RESULTS: WNT5A, p-AKT and Cyclin D1 were highly expressed in pancreatic cancer tissues, and the WNT5A expression was correlated with the TNM stages. In vitro, WNT5A expression was associated with gemcitabine chemoresistance. The percentage of cells was increased in G0/G1 phase and decreased in S phase after knockdown of WNT5A in PANC-1. WNT5A promoted Cyclin D1 expression through phosphorylation of AKT which consequently enhanced G1-S transition and gemcitabine resistance. Furthermore, WNT5A enhanced the cell cycle progression toward R-point through regulation of retinoblastoma protein (pRb) and pRb-E2F complex formation. CONCLUSIONS: WNT5A induced chemoresistance by regulation of G1-S transition in pancreatic cancer cells. WNT5A might serve as a predictor of gemcitabine response and as a potential target for tumor chemotherapy.

  11. The associations between the environmental exposure to polychlorinated biphenyls (PCBs) and breast cancer risk and progression

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Polychlorinated biphenyls(PCBs) are chlorinated biphenyl compounds with wide applications in the industry.In spite of a ban on their production in the late 1970s,PCBs,as a group of POPs,are still persistent and widely spread in the environment,posing potential threats to human health.The role of PCBs as etiologic agents for breast cancer has been intensively explored in a variety of in vivo,animal and epidemiologic studies.Initial investigations indicated higher levels of PCBs in mammary tissues or sera corresponded to the occurrence of breast cancer,but later studies showed no positive association between PCB exposure and breast cancer development.More recent data suggested that the CYP1A1 m2 polymorphisms might add increased risk to the etiology of breast cancer in women with environmental exposure to PCBs.PCBs are implicated in advancing breast cancer progression,and our unpublished data reveals that PCBs activate the ROCK signaling to enhance breast cancer metastasis.Therefore,the correlation between PCB exposure and breast cancer risk warrants further careful investigations.

  12. Bioinformatic Screening of Key Genes Controlling the Development 
and Progression of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Junlong WANG

    2012-11-01

    Full Text Available Background and objective Lung cancer is the most common cancer in the world. The gene expression profiling of lung cancer has been extensively investigated. However, only a few studies have identified the possible pathways and significant genes related to lung cancer. The aim of this study is to explore the large number of lung cancer-related microarray datasets and identify the crucial genes that can benefit the understanding of the progression and development of this disease. Methods To identify the genes that effected lung cancer at the mRNA level, gene set enrichment analysis was used to analyze six selected gene expression datasets. Results Among the six gene expression datasets, 3 up-regulated and 26 down-regulated pathways were found by gene set enrichment analysis. We found 11 significant genes with P<0.05 from the results of tight junction meta-analysis of the six data sets. Conclusion The tight junction pathway plays an important role in the study of the occurrence and development of lung cancer. Significant genes within the pathways will be further discussed in future studies.

  13. Overexpression of centromere protein H is significantly associated with breast cancer progression and overall patient survival

    Institute of Scientific and Technical Information of China (English)

    Wen-Ting Liao; Yan Feng; Men-Lin Li; Guang-Lin Liu; Man-Zhi Li; Mu-Sheng Zeng; Li-Bing Song

    2011-01-01

    Breast cancer is one of the leading causes of cancer death worldwide.This study aimed to analyze the expression of centromere protein H (CENP-H) in breast cancer and to correlate it with clinicopathologic data,including patient survival.Using reverse transcription-polymerase chain reaction and Westem blotting to detect the expression of CENP-H in normal mammary epithelial cells,immortalized mammary epithelial cell lines,and breast cancer cell lines,we observed that the mRNA and protein levels of CENP-H were higher in breast cancer cell lines and in immortalized mammary epithelial cells than in normal mammary epithelial cells.We next examined CENP-H expression in 307 paraffin-embedded archived samples of clinicopathologically characterized breast cancer using immunohistochemistry,and detected high CENP-H expression in 134 (43.6%) samples.Statistical analysis showed that CENP-H expression was related with clinical stage (P = 0.001),T classification (P = 0.032),N classification (P =0.018),and Ki-67 (P<0.001).Patients with high CENP-H expression had short overall survival.Multivariate analysis showed that CENP-H expression was an independent prognostic indicator for patient survival.Our results suggest that CENP-H protein is a valuable marker of breast cancer progression and prognosis.

  14. FoxD3 deficiency promotes breast cancer progression by induction of epithelial–mesenchymal transition

    International Nuclear Information System (INIS)

    Highlights: • FOXD3 is down-regulated in breast cancer tissues. • FOXD3 inhibits breast cancer cell proliferation and invasion. • FoxD3 deficiency induces epithelial–mesenchymal transition. - Abstract: The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial–mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy

  15. Mapping cancer cell metabolism with 13 C flux analysis: Recent progress and future challenges

    Directory of Open Access Journals (Sweden)

    Casey Scott Duckwall

    2013-01-01

    Full Text Available The reprogramming of energy metabolism is emerging as an important molecular hallmark of cancer cells. Recent discoveries linking specific metabolic alterations to cancer development have strengthened the idea that altered metabolism is more than a side effect of malignant transformation, but may in fact be a functional driver of tumor growth and progression in some cancers. As a result, dysregulated metabolic pathways have become attractive targets for cancer therapeutics. This review highlights the application of 13 C metabolic flux analysis (MFA to map the flow of carbon through intracellular biochemical pathways of cancer cells. We summarize several recent applications of MFA that have identified novel biosynthetic pathways involved in cancer cell proliferation and shed light on the role of specific oncogenes in regulating these pathways. Through such studies, it has become apparent that the metabolic phenotypes of cancer cells are not as homogeneous as once thought, but instead depend strongly on the molecular alterations and environmental factors at play in each case.

  16. LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression.

    Science.gov (United States)

    Mura, M; Hopkins, T G; Michael, T; Abd-Latip, N; Weir, J; Aboagye, E; Mauri, F; Jameson, C; Sturge, J; Gabra, H; Bushell, M; Willis, A E; Curry, E; Blagden, S P

    2015-09-24

    RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5'-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage-independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post-transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression. PMID:25531318

  17. Progress of research in miR-218 and cervical cancer

    Institute of Scientific and Technical Information of China (English)

    Kangkang Zeng; Wei Zhang; Xiaoxia Hu

    2013-01-01

    MicroRNAs (miRNAs) are smal endogenous non-coding RNAs which can specifical y silence gene expression, and thereby alter cel and organism phenotype. Deregulation of miRNA expression has been discovered in a variety of tumors and it is now clear that they contribute to cancer development and progression. Previous studies have indicated that miRNAs are involved in developmental timing, cel proliferation, apoptosis, morphogenesis [1], antiviral defense [2], and tumorigenesis [3]. In cancer pathways, altered expression of tumor suppressive or oncogenic miRNAs can disrupt regulatory mechanisms normal. Altered miRNAs expression patterns have been observed in a variety of diseased tissues. Cervical cancer is the most common malignant tumor in female reproductive tract. Recently more and more study showed a large number of miRNAs were down-regulated or up-regulated in cervical cancer. Recent data revealed that miRNA-218 (miR-218) played important roles in tumor initiation and development. This review focuses on analysis of miR-218 and wil provide some insight into the progress of cervical cancer.

  18. Upregulation of CENP-H in tongue cancer correlates with poor prognosis and progression

    Directory of Open Access Journals (Sweden)

    Weng Gui-Xiang

    2009-06-01

    Full Text Available Abstract Background Centromere protein H (CENP-H is one of the fundamental components of the human active kinetochore. Recently, CENP-H was identified to be associated with tumorigenesis. This study was aimed to investigate the clinicopathologic significance of CENP-H in tongue cancer. Methods RT-PCR, real time RT-PCR and Western blot were used to examine the expression of CENP-H in tongue cancer cell lines and biopsies. CENP-H protein level in paraffin-embedded tongue cancer tissues were tested by immunohistochemical staining and undergone statistical analysis. CENP-H-knockdown stable cell line was established by infecting cells with a retroviral vector pSuper-retro-CENP-H-siRNA. The biological function of CENP-H was tested by MTT assay, colony formation assay, and Bromodeoxyuridine (BrdU incorporation assay. Results CENP-H expression was higher in tongue cancer cell lines and cancer tissues (T than that in normal cell and adjacent noncancerous tongue tissues (N, respectively. It was overexpressed in 55.95% (94/168 of the paraffin-embedded tongue cancer tissues, and there was a strong correlation between CENP-H expression and clinical stage, as well as T classification. CENP-H can predict the prognosis of tongue cancer patients especially those in early stage. Depletion of CENP-H can inhibit the proliferation of tongue cancer cells (Tca8113 and downregulate the expression of Survivin. Conclusion These findings suggested that CENP-H involves in the development and progression of tongue cancer. CENP-H might be a valuable prognostic indicator for tongue cancer patients within early stage.

  19. Influence of sex differences on the progression of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; Uldall, Maria; Appel, Camilla;

    2013-01-01

    on the progression of cancer-induced bone pain. Materials and Methods: 4T1-luc2 mammary cancer cells were introduced into the femoral cavity of female and male BALB/cJ mice. Bioluminescence tumor signal, pain-related behavior and bone degradation were monitored for 14 days. Results: Female mice demonstrated...... a significantly greater bioluminescence signal on day 2 compared to male mice and, in addition, a significant earlier onset of pain-related behavior was observed in the females. No sex difference was observed for bone degradation. Finally, a strong correlation between pain-related behavior and bone degradation...

  20. Fibroblast-Mediated Collagen Remodeling Within the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by BrafV600E and Pten Loss.

    Science.gov (United States)

    Jolly, Lee Ann; Novitskiy, Sergey; Owens, Phillip; Massoll, Nicole; Cheng, Nikki; Fang, Wei; Moses, Harold L; Franco, Aime T

    2016-04-01

    Contributions of the tumor microenvironment (TME) to progression in thyroid cancer are largely unexplored and may illuminate a basis for understanding rarer aggressive cases of this disease. In this study, we investigated the relationship between the TME and thyroid cancer progression in a mouse model where thyroid-specific expression of oncogenic BRAF and loss of Pten (Braf(V600E)/Pten(-/-)/TPO-Cre) leads to papillary thyroid cancers (PTC) that rapidly progress to poorly differentiated thyroid cancer (PDTC). We found that fibroblasts were recruited to the TME of Braf(V600E)/Pten(-/-)/TPO-Cre thyroid tumors. Conditioned media from cell lines established from these tumors, but not tumors driven by mutant H-ras, induced fibroblast migration and proliferation in vitro Notably, the extracellular matrix of Braf(V600E)/Pten(-/-)/TPO-Cre tumors was enriched with stromal-derived fibrillar collagen, compared with wild-type or Hras-driven tumors. Further, type I collagen enhanced the motility of Braf(V600E)/Pten(-/-)/TPO-Cre tumor cells in vitro In clinical specimens, we found COL1A1 and LOX to be upregulated in PTC and expressed at highest levels in PDTC and anaplastic thyroid cancer. Additionally, increased expression levels of COL1A1 and LOX were associated with decreased survival in thyroid cancer patients. Overall, our results identified fibroblast recruitment and remodeling of the extracellular matrix as pivotal features of the TME in promoting thyroid cancer progression, illuminating candidate therapeutic targets and biomarkers in advanced forms of this malignancy. Cancer Res; 76(7); 1804-13. ©2016 AACR. PMID:26818109

  1. Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins.

    Science.gov (United States)

    Mullins, Stefanie R; Sameni, Mansoureth; Blum, Galia; Bogyo, Matthew; Sloane, Bonnie F; Moin, Kamiar

    2012-12-01

    The expression of the cysteine protease cathepsin B is increased in early stages of human breast cancer.To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, we employed a 3D reconstituted basement membrane overlay culture model of MCF10A human breast epithelial cells and isogenic variants that replicate the in vivo phenotypes of hyper plasia(MCF10AneoT) and atypical hyperplasia (MCF10AT1). MCF10A cells developed into polarized acinar structures with central lumens. In contrast, MCF10AneoT and MCF10AT1 cells form larger structures in which the lumens are filled with cells. CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L,reduced proliferation and increased apoptosis of MCF10A, MCF10AneoT and MCF10AT1 cells in 3D culture. We detected active cysteine cathepsins in the isogenic MCF10 variants in 3D culture with GB111, a cell-permeable activity based probe, and established differential inhibition of cathepsin B in our 3D cultures. We conclude that cathepsin B promotes proliferation and premalignant progression of breast epithelial cells. These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression. PMID:23667900

  2. Weight loss reversed obesity-induced HGF/c-Met pathway and basal-like breast cancer progression

    Directory of Open Access Journals (Sweden)

    Sneha eSundaram

    2014-07-01

    Full Text Available Epidemiologic studies demonstrate that obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC. Using the C3(1-TAg murine model of BBC, we previously demonstrated that mice displayed an early onset of tumors when fed obesogenic diets in the adult window of susceptibility. Obesity was also shown to elevate mammary gland expression and activation of hepatocyte growth factor (HGF/c-Met compared to lean controls, a pro-tumorigenic pathway associated with BBC in patients. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We sought to investigate whether weight loss in adulthood prior to tumor onset would protect mice from accelerated tumorigenesis observed in obese mice. Using a life-long model of obesity, C3(1-TAg mice were weaned onto and maintained on an obesogenic high fat diet. Obese mice displayed significant elevations in tumor progression, but not latency or burden. Tumor progression was significantly reversed when obese mice were induced to lose weight by switching to a control low fat diet prior to tumor onset compared to mice maintained on obesogenic diet. It is likely that other factors regulated tumor progression, hence we investigated the HGF/c-Met pathway known to regulate tumorigenesis. Importantly, HGF/c-Met expression in normal mammary glands and c-Met in tumors was elevated with obesity and was significantly reversed with weight loss. Changes in tumor growth could not be explained by measures of HGF action including phospho-AKT or phospho-S6. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin/adiponectin ratio were elevated by obesity and reduced with weight loss. In sum, weight loss significantly blunted the obesity-responsive pro-tumorigenic HGF/c-Met pathway and improved several metabolic risk factors associated with BBC, which together may have contributed to the dramatic reversal of obesity-driven tumor

  3. Computer model challenges breast cancer treatment strategy.

    Science.gov (United States)

    Retsky, M W; Swartzendruber, D E; Bame, P D; Wardwell, R H

    1994-01-01

    The breast cancer treatment failure rate remains unacceptably high. The current breast cancer treatment paradigm, based primarily on Gompertzian kinetics and animal models, advocates short-course, intensive chemotherapy subsequent to tumor debulking, citing drug resistance and host toxicity as the primary reasons for treatment failure. To better understand treatment failure, we have studied breast cancer from the perspective of computer modeling. Our results demonstrate breast cancers grow in an irregular fashion; this differs from the Gompertzian mode of animal models and thus challenges the validity of the current paradigm. Clinical and laboratory data support the concept of irregular growth rather than the common claim that human tumors grow in a Gompertzian fashion. Treatment failure mechanisms for breast cancer appear to differ from those for animal models, and thus treatments optimize on animal models may not be optimal for breast cancer. A failure mechanism consistent with our results involves temporarily dormant tumor cells in anatomical or pharmacological sanctuary, which eventually result in aggressive metastatic disease. PMID:7994590

  4. A male patient with acromegaly and breast cancer: treating acromegaly to control tumor progression

    International Nuclear Information System (INIS)

    Acromegaly is a rare disease associated with an increased risk of developing cancer. We report the case of a 72-year-old man who was diagnosed with acromegaly (IGF-1 770 ng/ml) and breast cancer. Four years before he suffered from a colon-rectal cancer. Pituitary surgery and octreotide-LAR treatment failed to control acromegaly. Normalization of IGF-1 (97 ng/ml) was obtained with pegvisomant therapy. Four years after breast cancer surgery, 2 pulmonary metastases were detected at chest CT. The patient was started on anastrozole, but, contrary to medical advice, he stopped pegvisomant treatment (IGF-I 453 ng/ml). Four months later, chest CT revealed an increase in size of the metastatic lesion of the left lung. The patient was shifted from anastrozole to tamoxifen and was restarted on pegvisomant, with normalization of serum IGF-1 levels (90 ng/ml). Four months later, a reduction in size of the metastatic lesion of the left lung was detected by CT. Subsequent CT scans throughout a 24-month follow-up showed a further reduction in size and then a stabilization of the metastasis. This is the first report of a male patient with acromegaly and breast cancer. The clinical course of breast cancer was closely related to the metabolic control of acromegaly. The rapid progression of metastatic lesion was temporally related to stopping pegvisomant treatment and paralleled a rise in serum IGF-1 levels. Normalization of IGF-1 after re-starting pegvisomant impressively reduced the progression of metastatic breast lesions. Control of acromegaly is mandatory in acromegalic patients with cancer. The online version of this article (doi:10.1186/s12885-015-1400-0) contains supplementary material, which is available to authorized users

  5. Causal Model Progressions as a Foundation for Intelligent Learning Environments.

    Science.gov (United States)

    White, Barbara Y.; Frederiksen, John R.

    This paper describes the theoretical underpinnings and architecture of a new type of learning environment that incorporates features of microworlds and of intelligent tutoring systems. The environment is based on a progression of increasingly sophisticated causal models that simulate domain phenomena, generate explanations, and serve as student…

  6. Modeling the Aneuploidy Control of Cancer

    Directory of Open Access Journals (Sweden)

    Wang Zhong

    2010-07-01

    Full Text Available Abstract Background Aneuploidy has long been recognized to be associated with cancer. A growing body of evidence suggests that tumorigenesis, the formation of new tumors, can be attributed to some extent to errors occurring at the mitotic checkpoint, a major cell cycle control mechanism that acts to prevent chromosome missegregation. However, so far no statistical model has been available quantify the role aneuploidy plays in determining cancer. Methods We develop a statistical model for testing the association between aneuploidy loci and cancer risk in a genome-wide association study. The model incorporates quantitative genetic principles into a mixture-model framework in which various genetic effects, including additive, dominant, imprinting, and their interactions, are estimated by implementing the EM algorithm. Results Under the new model, a series of hypotheses tests are formulated to explain the pattern of the genetic control of cancer through aneuploid loci. Simulation studies were performed to investigate the statistical behavior of the model. Conclusions The model will provide a tool for estimating the effects of genetic loci on aneuploidy abnormality in genome-wide studies of cancer cells.

  7. Carbohydrate Antigen Sialyl Lewis a – Its Pathophysiological ignificance and Induction Mechanism in Cancer Progression

    OpenAIRE

    Reiji Kannagi

    2007-01-01

    Carbohydrate antigen sialyl Lewis a (CA19-9) is the mostfrequently applied serum tumor marker for diagnosis of cancersin the digestive organs. Recent progress disclosed thepresence of a normal counterpart of the determinant, namelydisialyl Lewis a, which is predominantly expressed in nonmalignantepithelial cells of the digestive organs, while sialylLewis a is preferentially expressed in cancers. The disialylLewis a determinant carries one extra sialic residue attachedthrough a 2 6 linkage to ...

  8. Genomics and premalignant breast lesions: clues to the development and progression of lobular breast cancer

    OpenAIRE

    Mastracci, Teresa L; Boulos, Fouad I; Andrulis, Irene L.; Lam, Wan L.

    2007-01-01

    Advances in genomic technology have improved our understanding of the genetic events that parallel breast cancer development. Because almost all mammary carcinomas develop in the terminal duct lobular units of the breast, understanding the events involved in mammary gland development make it possible to recognize those events that, when altered, contribute to breast neoplasia. In this review we focus on lobular carcinomas, discussing the pathology, development, and progression of premalignant...

  9. Sympathetic Neurotransmitters and Tumor Angiogenesis—Link between Stress and Cancer Progression

    OpenAIRE

    Jason Tilan; Joanna Kitlinska

    2010-01-01

    Recent evidence supports a longstanding hypothesis that chronic stress can influence tumor growth and progression. It has been shown that sympathetic neurotransmitters, such as catecholamines and neuropeptides, can affect both cancer cell growth and tumor vascularization. Depending on neurotransmitter and type of tumor, these effects can be both stimulatory and inhibitory. Norepinephrine (NE) and epinephrine (E) are potent stimulators of vascularization, acting both by inducing the release of...

  10. The Significance of Histopathological Evaluation of Pancreatic Fibrosis to Estimate Pancreas Cancer Progression

    OpenAIRE

    Shinji Osada; Kaoru Tanaka; Satoshi Matsui; Yoshiyuki Sasaki; Hiroyuki Tomita; Yoshihiro Tanaka; Naoki Okumura; Nobuhisa Matsuhashi; Kazuhiro Yoshida

    2016-01-01

    Objective To estimate the importance of the role of pancreatic stellate cells in pancreas cancer progression, their properties were evaluated in relation to clinical details and patient prognosis. Patients and Methods Among patients who underwent surgical treatment from 2004 to 2013, the texture of the pancreatic specimens was evaluated by histopathological measurement length of fibrosis, fibrosis grade and the intensity of pancreatic stellate cell activity. Results 1. The histopathological m...

  11. Prostate cancer stem cells: The case for model systems

    Directory of Open Access Journals (Sweden)

    Paul G Hynes

    2012-01-01

    Full Text Available Advanced prostate cancers are treated with androgen deprivation therapy, which usually leads to a rapid and significant reduction in tumor burden but subsequent development of castration-resistant and metastatic disease almost always occurs. The source of tumor heterogeneity and the accompanying mechanisms leading to treatment resistance are major areas of prostate cancer research. Although our understanding of tumor heterogeneity is evolving, the functional isolation of tumor propagating populations, also known as cancer stem cells (CSCs, is fundamental to the identification and molecular characterization of castration-resistant prostate cancer cells. Of clinical importance, knowledge of prostate CSCs has implications for design of next generation-targeted therapies aimed at both eradicating primary tumor mass and preventing castration-resistant disease. The inability to routinely transplant fractionated primary human prostate tumors has prevented progress in analyzing the source of heterogeneous and treatment-resistant populations in prostate cancer. Here, we briefly overview the mechanisms of castration resistance, including the hypothesis for the existence of androgen-independent prostate CSCs. Finally, we discuss the interpretation of preclinical models and their utility for characterizing prostate CSCs in androgen-replete and androgen-deprived conditions.

  12. Public Health Action Model for Cancer Survivorship.

    Science.gov (United States)

    Moore, Angela R; Buchanan, Natasha D; Fairley, Temeika L; Lee Smith, Judith

    2015-12-01

    Long-term objectives associated with cancer survivors have been suggested by Healthy People 2020, including increasing the proportion of survivors living beyond 5 years after diagnosis and improving survivors' mental and physical health-related quality of life. Prior to reaching these objectives, several intermediate steps must be taken to improve the physical, social, emotional, and financial well-being of cancer survivors. Public health has a role in developing strategic, actionable, and measurable approaches to facilitate change at multiple levels to improve the lives of survivors and their families. The social ecological model has been used by the public health community as the foundation of multilevel intervention design and implementation, encouraging researchers and practitioners to explore methods that promote internal and external changes at the individual, interpersonal, organizational, community, and policy levels. The survivorship community, including public health professionals, providers, policymakers, survivors, advocates, and caregivers, must work collaboratively to identify, develop, and implement interventions that benefit cancer survivors. The National Action Plan for Cancer Survivorship highlights public health domains and associated strategies that can be the impetus for collaboration between and among the levels in the social ecological model and are integral to improving survivor outcomes. This paper describes the Public Health Action Model for Cancer Survivorship, an integrative framework that combines the National Action Plan for Cancer Survivorship with the social ecological model to demonstrate how interaction among the various levels may promote better outcomes for survivors. PMID:26590641

  13. Complex of MUC1, CIN85 and Cbl in Colon Cancer Progression and Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Cascio, Sandra, E-mail: sac131@pitt.edu [Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Fondazione Ri.Med, via Bandiera, Palermo 90133 (Italy); Finn, Olivera J., E-mail: sac131@pitt.edu [Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261 (United States)

    2015-02-10

    We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. Here, we examined specifically human colon carcinoma tissue microarrays (TMA) by immunohistochemistry for the expression of MUC1 and CIN85 and their potential role in cancer progression and metastasis. We detected a significant increase in expression of both MUC1 and CIN85 associated with advanced tumor stage and lymph node metastasis. We further investigated if Cbl could also be present in the MUC1/CIN85 complex. Co-immunoprecipitation assay showed that Cbl co-localized both with CIN85 and with MUC1 in a human colon cancer cell line. To begin to investigate the in vivo relevance of MUC1 overexpression and association with CIN85 and Cbl in cancer development and progression, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, the association of MUC1, CIN85 and Cbl was detected in colon tissues of AOM/DSS-treated MUC1 transgenic mice. MUC1/CIN85/Cbl complex appears to contribute to promotion and progression of colon cancer and thus increased expression of MUC1, CIN85 and Cbl in early stage colon cancer might be predictive of poor prognosis.

  14. Complex of MUC1, CIN85 and Cbl in Colon Cancer Progression and Metastasis

    International Nuclear Information System (INIS)

    We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. Here, we examined specifically human colon carcinoma tissue microarrays (TMA) by immunohistochemistry for the expression of MUC1 and CIN85 and their potential role in cancer progression and metastasis. We detected a significant increase in expression of both MUC1 and CIN85 associated with advanced tumor stage and lymph node metastasis. We further investigated if Cbl could also be present in the MUC1/CIN85 complex. Co-immunoprecipitation assay showed that Cbl co-localized both with CIN85 and with MUC1 in a human colon cancer cell line. To begin to investigate the in vivo relevance of MUC1 overexpression and association with CIN85 and Cbl in cancer development and progression, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, the association of MUC1, CIN85 and Cbl was detected in colon tissues of AOM/DSS-treated MUC1 transgenic mice. MUC1/CIN85/Cbl complex appears to contribute to promotion and progression of colon cancer and thus increased expression of MUC1, CIN85 and Cbl in early stage colon cancer might be predictive of poor prognosis

  15. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

    Science.gov (United States)

    Pannu, Vaishali; Rida, Padmashree C.G.; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J.; Rudd, Katie; Gupta, Meenakshi V.; Reid, Michelle D.; Cantuaria, Guilherme; Walczak, Claire E.; Aneja, Ritu

    2015-01-01

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  16. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

    Science.gov (United States)

    Hong, In-Sun

    2016-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a ‘danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

  17. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients.

    Science.gov (United States)

    Pannu, Vaishali; Rida, Padmashree C G; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J; Rudd, Katie; Gupta, Meenakshi V; Reid, Michelle D; Cantuaria, Guilherme; Walczak, Claire E; Aneja, Ritu

    2015-03-20

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  18. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

    Science.gov (United States)

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-10-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

  19. Ovarian Cancer Pathogenesis: A Model in Evolution

    Directory of Open Access Journals (Sweden)

    Alison M. Karst

    2010-01-01

    Full Text Available Ovarian cancer is a deadly disease for which there is no effective means of early detection. Ovarian carcinomas comprise a diverse group of neoplasms, exhibiting a wide range of morphological characteristics, clinical manifestations, genetic alterations, and tumor behaviors. This high degree of heterogeneity presents a major clinical challenge in both diagnosing and treating ovarian cancer. Furthermore, the early events leading to ovarian carcinoma development are poorly understood, thus complicating efforts to develop screening modalities for this disease. Here, we provide an overview of the current models of ovarian cancer pathogenesis, highlighting recent findings implicating the fallopian tube fimbria as a possible site of origin of ovarian carcinomas. The ovarian cancer model will continue to evolve as we learn more about the genetics and etiology of this disease.

  20. Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer

    International Nuclear Information System (INIS)

    Non-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at 'high risk' of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression. To investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with 'high-risk' non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases. We used Affymetrix GeneChip® Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays). Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a 'high-risk' tumor). However, about 25% of the 'high-risk' tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes. Chromosomal instability (CI) was associated with 'high risk' tumors

  1. Progestins reinitiate cell cycle progression in antiestrogen-arrested breast cancer cells through the B-isoform of progesterone receptor.

    Science.gov (United States)

    McGowan, Eileen M; Russell, Amanda J; Boonyaratanakornkit, Viroj; Saunders, Darren N; Lehrbach, Gillian M; Sergio, C Marcelo; Musgrove, Elizabeth A; Edwards, Dean P; Sutherland, Robert L

    2007-09-15

    Estrogen treatment of MCF-7 human breast cancer cells allows the reinitiation of synchronous cell cycle progression in antiestrogen-arrested cells. Here, we report that progestins also reinitiate cell cycle progression in this model. Using clonal cell lines derived from progesterone receptor (PR)-negative MCF-7M13 cells expressing wild-type or mutant forms of PRA and PRB, we show that this effect is mediated via PRB, not PRA. Cell cycle progression did not occur with a DNA-binding domain mutant of PRB but was unaffected by mutation in the NH(2)-terminal, SH3 domain interaction motif, which mediates rapid progestin activation of c-Src. Thus, the progestin-induced proliferative response in antiestrogen-inhibited cells is mediated primarily by the transcriptional activity of PRB. Analysis of selected cell cycle targets showed that progestin treatment induced levels of cyclin D1 expression and retinoblastoma protein (Rb) phosphorylation similar to those induced by estradiol. In contrast, progestin treatment resulted in only a 1.2-fold induction of c-Myc compared with a 10-fold induction by estradiol. These results support the conclusion that progestin, in a PRB-dependent manner, can overcome the growth-inhibitory effects of antiestrogens in estrogen receptor/PR-positive breast cancer cells by the induction of cyclin D1 expression. The mediation of this effect by PRB, but not PRA, further suggests a mechanism whereby abnormal regulation of the normal expression ratios of PR isoforms in breast cancer could lead to the attenuation of antiestrogen-mediated growth arrest. PMID:17875737

  2. LNCaP Atlas: Gene expression associated with in vivo progression to castration-recurrent prostate cancer

    Directory of Open Access Journals (Sweden)

    Marra Marco A

    2010-09-01

    Full Text Available Abstract Background There is no cure for castration-recurrent prostate cancer (CRPC and the mechanisms underlying this stage of the disease are unknown. Methods We analyzed the transcriptome of human LNCaP prostate cancer cells as they progress to CRPC in vivo using replicate LongSAGE libraries. We refer to these libraries as the LNCaP atlas and compared these gene expression profiles with current suggested models of CRPC. Results Three million tags were sequenced using in vivo samples at various stages of hormonal progression to reveal 96 novel genes differentially expressed in CRPC. Thirty-one genes encode proteins that are either secreted or are located at the plasma membrane, 21 genes changed levels of expression in response to androgen, and 8 genes have enriched expression in the prostate. Expression of 26, 6, 12, and 15 genes have previously been linked to prostate cancer, Gleason grade, progression, and metastasis, respectively. Expression profiles of genes in CRPC support a role for the transcriptional activity of the androgen receptor (CCNH, CUEDC2, FLNA, PSMA7, steroid synthesis and metabolism (DHCR24, DHRS7, ELOVL5, HSD17B4, OPRK1, neuroendocrine (ENO2, MAOA, OPRK1, S100A10, TRPM8, and proliferation (GAS5, GNB2L1, MT-ND3, NKX3-1, PCGEM1, PTGFR, STEAP1, TMEM30A, but neither supported nor discounted a role for cell survival genes. Conclusions The in vivo gene expression atlas for LNCaP was sequenced and support a role for the androgen receptor in CRPC.

  3. Stellar Evolution Models of Young Stars: Progress and Limitations

    CERN Document Server

    Feiden, Gregory A

    2015-01-01

    Stellar evolution models are a cornerstone of young star astrophysics, which necessitates that they yield accurate and reliable predictions of stellar properties. Here, I review the current performance of stellar evolution models against young astrophysical benchmarks and highlight recent progress incorporating non-standard physics, such as magnetic field and starspots, to explain observed deficiencies. While addition of these physical processes leads to improved agreement between models and observations, there are several fundamental limitations in our understanding about how these physical processes operate. These limitations inhibit our ability to form a coherent picture of the essential physics needed to accurately compute young stellar models, but provide rich avenues for further exploration.

  4. Progress in wall turbulence 2 understanding and modelling

    CERN Document Server

    Jimenez, Javier; Marusic, Ivan

    2016-01-01

    This is the proceedings of the ERCOFTAC Workshop on Progress in Wall Turbulence: Understanding and Modelling, that was held in Lille, France from June 18 to 20, 2014. The workshop brought together world specialists of near wall turbulence and stimulated exchanges between them around up-to-date theories, experiments, simulations and numerical models. This book contains a coherent collection of recent results on near wall turbulence including theory, new experiments, DNS, and modeling with RANS, LES.The fact that both physical understanding and modeling by different approaches are addressed by the best specialists in a single workshop is original.

  5. Sapodilla plum (Achras sapota) induces apoptosis in cancer cell lines and inhibits tumor progression in mice.

    Science.gov (United States)

    Srivastava, Mrinal; Hegde, Mahesh; Chiruvella, Kishore K; Koroth, Jinsha; Bhattacharya, Souvari; Choudhary, Bibha; Raghavan, Sathees C

    2014-01-01

    Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID:25142835

  6. Analysis of breast cancer progression using principal component analysis and clustering

    Indian Academy of Sciences (India)

    G Alexe; G S Dalgin; S Ganesan; C DeLisi; G Bhanot

    2007-08-01

    We develop a new technique to analyse microarray data which uses a combination of principal components analysis and consensus ensemble -clustering to find robust clusters and gene markers in the data. We apply our method to a public microarray breast cancer dataset which has expression levels of genes in normal samples as well as in three pathological stages of disease; namely, atypical ductal hyperplasia or ADH, ductal carcinoma in situ or DCIS and invasive ductal carcinoma or IDC. Our method averages over clustering techniques and data perturbation to find stable, robust clusters and gene markers. We identify the clusters and their pathways with distinct subtypes of breast cancer (Luminal, Basal and Her2+). We confirm that the cancer phenotype develops early (in early hyperplasia or ADH stage) and find from our analysis that each subtype progresses from ADH to DCIS to IDC along its own specific pathway, as if each was a distinct disease.

  7. Another road leads to HIF-1 activation: implications for prostate cancer progression

    Institute of Scientific and Technical Information of China (English)

    Yao Dai1; Kyungmi Bae2; Dietmar W Siemann1

    2012-01-01

    Hypoxia has been identified as a common environmental stress factor associated with therapeutic resistance and metastasis in human cancers.A major player in regulating the response to hypoxia is the transcriptional factor hypoxia-inducible factor 1 alpha (HIF-1α).Although HIF-1α is well known to be stabilized under hypoxia,the regulatory mechanism of HIF-1α signaling in malignant cells is not fully understood.In a recent paper,Yuan et al.1 identified a novel pathway that acts as a ‘vicious cycle'to amplify HIF- 1 activation in prostate cancer cells,hence suggesting potential biomarkers that may predict progression and poor prognosis in human prostate cancer (Figure 1).

  8. Role of the tumor microenvironment in regulating apoptosis and cancer progression.

    Science.gov (United States)

    Yaacoub, Katherine; Pedeux, Remy; Tarte, Karin; Guillaudeux, Thierry

    2016-08-10

    Apoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non-malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumor-microenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented. PMID:27224890

  9. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  10. MLF1IP is correlated with progression and prognosis in luminal breast cancer.

    Science.gov (United States)

    Huang, Du-Ping; Luo, Rong-Cheng

    2016-09-01

    Myeloid leukemia factor 1-interacting protein (MLF1IP) has been found to be involved in the progression of several malignancies. The potential correlation between MLF1IP and clinical outcome in patients with luminal breast cancer, however, remains unknown. In the present study, we demonstrated that MLF1IP was significantly upregulated in luminal breast cancer tissue compared with adjacent normal tissue both in validated cohort and TCGA cohort. Upregulated expression of MLF1IP was correlated with more often lymph node metastasis and negative progesterone receptor expression in TCGA cohorts. Kaplan-Meier analysis indicated that patients with high MLF1IP expression had significantly lower overall survival. Moreover, multivariate analysis revealed that high MLF1IP expression was independent high risk factor as well as old age (>60) and distant metastasis. This study provides new insights and evidences that MLF1IP over-expression plays important roles in progression of luminal breast cancer. However, the precise cellular mechanisms for MLF1IP in luminal breast cancer need to be further explored. PMID:27378428

  11. Emerging and Evolving Ovarian Cancer Animal Models

    OpenAIRE

    Bobbs, Alexander S; Jennifer M. Cole; Cowden Dahl, Karen D.

    2015-01-01

    Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect ...

  12. High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

    International Nuclear Information System (INIS)

    Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression. Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer. The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies. The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer

  13. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

    Energy Technology Data Exchange (ETDEWEB)

    Bajenova, Olga, E-mail: o.bazhenova@spbu.ru [Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034 (Russian Federation); Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034 (Russian Federation); Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); Chaika, Nina [Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); Tolkunova, Elena; Davydov-Sinitsyn, Alexander [Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064 (Russian Federation); Gapon, Svetlana [Boston Children' s Hospital, Boston, MA 02115 (United States); Thomas, Peter [Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); O’Brien, Stephen [Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034 (Russian Federation)

    2014-06-10

    Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein.

  14. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

    International Nuclear Information System (INIS)

    Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein

  15. Toward an Ising model of cancer and beyond

    Science.gov (United States)

    Torquato, Salvatore

    2011-02-01

    The holy grail of tumor modeling is to formulate theoretical and computational tools that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies to control cancer growth. In order to develop such a predictive model, one must account for the numerous complex mechanisms involved in tumor growth. Here we review the research work that we have done toward the development of an 'Ising model' of cancer. The Ising model is an idealized statistical-mechanical model of ferromagnetism that is based on simple local-interaction rules, but nonetheless leads to basic insights and features of real magnets, such as phase transitions with a critical point. The review begins with a description of a minimalist four-dimensional (three dimensions in space and one in time) cellular automaton (CA) model of cancer in which cells transition between states (proliferative, hypoxic and necrotic) according to simple local rules and their present states, which can viewed as a stripped-down Ising model of cancer. This model is applied to study the growth of glioblastoma multiforme, the most malignant of brain cancers. This is followed by a discussion of the extension of the model to study the effect on the tumor dynamics and geometry of a mutated subpopulation. A discussion of how tumor growth is affected by chemotherapeutic treatment, including induced resistance, is then described. We then describe how to incorporate angiogenesis as well as the heterogeneous and confined environment in which a tumor grows in the CA model. The characterization of the level of organization of the invasive network around a solid tumor using spanning trees is subsequently discussed. Then, we describe open problems and future promising avenues for future research, including the need to develop better molecular-based models that incorporate the true heterogeneous environment over wide range of length and time scales (via imaging data), cell motility

  16. Toward an Ising model of cancer and beyond

    International Nuclear Information System (INIS)

    The holy grail of tumor modeling is to formulate theoretical and computational tools that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies to control cancer growth. In order to develop such a predictive model, one must account for the numerous complex mechanisms involved in tumor growth. Here we review the research work that we have done toward the development of an 'Ising model' of cancer. The Ising model is an idealized statistical-mechanical model of ferromagnetism that is based on simple local-interaction rules, but nonetheless leads to basic insights and features of real magnets, such as phase transitions with a critical point. The review begins with a description of a minimalist four-dimensional (three dimensions in space and one in time) cellular automaton (CA) model of cancer in which cells transition between states (proliferative, hypoxic and necrotic) according to simple local rules and their present states, which can viewed as a stripped-down Ising model of cancer. This model is applied to study the growth of glioblastoma multiforme, the most malignant of brain cancers. This is followed by a discussion of the extension of the model to study the effect on the tumor dynamics and geometry of a mutated subpopulation. A discussion of how tumor growth is affected by chemotherapeutic treatment, including induced resistance, is then described. We then describe how to incorporate angiogenesis as well as the heterogeneous and confined environment in which a tumor grows in the CA model. The characterization of the level of organization of the invasive network around a solid tumor using spanning trees is subsequently discussed. Then, we describe open problems and future promising avenues for future research, including the need to develop better molecular-based models that incorporate the true heterogeneous environment over wide range of length and time scales (via imaging data), cell

  17. Clinical Trial Design for Testing the Stem Cell Model for the Prevention and Treatment of Cancer

    International Nuclear Information System (INIS)

    The cancer stem cell model introduces new strategies for the prevention and treatment of cancers. In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size. These new approaches mandate a change in the design of clinical trials and biomarkers chosen for efficacy assessment for preventative, neoadjuvant, adjuvant, and palliative treatments. Cancer treatments could be evaluated by assessing stem cell markers before and after treatment. Targeted stem cell specific treatment of cancers may not result in “complete” or “partial” responses radiologically, as stem cell targeting may not reduce the tumor bulk, but eliminate further tumorigenic potential. These changes are discussed using breast, pancreatic, and lung cancer as examples

  18. Clinical Trial Design for Testing the Stem Cell Model for the Prevention and Treatment of Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, Rishindra M., E-mail: reddyrm@med.umich.edu [Medical Center, University of Michigan, 1500 E. Medical Center Drive, 2120 Taubman Center, Ann Arbor, MI 48109 (United States); Kakarala, Madhuri; Wicha, Max S. [Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109 (United States)

    2011-06-20

    The cancer stem cell model introduces new strategies for the prevention and treatment of cancers. In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size. These new approaches mandate a change in the design of clinical trials and biomarkers chosen for efficacy assessment for preventative, neoadjuvant, adjuvant, and palliative treatments. Cancer treatments could be evaluated by assessing stem cell markers before and after treatment. Targeted stem cell specific treatment of cancers may not result in “complete” or “partial” responses radiologically, as stem cell targeting may not reduce the tumor bulk, but eliminate further tumorigenic potential. These changes are discussed using breast, pancreatic, and lung cancer as examples.

  19. Branching process models of cancer

    CERN Document Server

    Durrett, Richard

    2015-01-01

    This volume develops results on continuous time branching processes and applies them to study rate of tumor growth, extending classic work on the Luria-Delbruck distribution. As a consequence, the authors calculate the probability that mutations that confer resistance to treatment are present at detection and quantify the extent of tumor heterogeneity. As applications, the authors evaluate ovarian cancer screening strategies and give rigorous proofs for results of Heano and Michor concerning tumor metastasis. These notes should be accessible to students who are familiar with Poisson processes and continuous time. Richard Durrett is mathematics professor at Duke University, USA. He is the author of 8 books, over 200 journal articles, and has supervised more than 40 Ph.D. students. Most of his current research concerns the applications of probability to biology: ecology, genetics, and most recently cancer.

  20. A Segmented Signal Progression Model for the Modern Streetcar System

    Directory of Open Access Journals (Sweden)

    Baojie Wang

    2015-01-01

    Full Text Available This paper is on the purpose of developing a segmented signal progression model for modern streetcar system. The new method is presented with the following features: (1 the control concept is based on the assumption of only one streetcar line operating along an arterial under a constant headway and no bandwidth demand for streetcar system signal progression; (2 the control unit is defined as a coordinated intersection group associated with several streetcar stations, and the control joints must be streetcar stations; (3 the objective function is built to ensure the two-way streetcar arrival times distributing within the available time of streetcar phase; (4 the available time of streetcar phase is determined by timing schemes, intersection structures, track locations, streetcar speeds, and vehicular accelerations; (5 the streetcar running speed is constant separately whether it is in upstream or downstream route; (6 the streetcar dwell time is preset according to historical data distribution or charging demand. The proposed method is experimentally examined in Hexi New City Streetcar Project in Nanjing, China. In the experimental results, the streetcar system operation and the progression impacts are shown to affect transit and vehicular traffic. The proposed model presents promising outcomes through the design of streetcar system segmented signal progression, in terms of ensuring high streetcar system efficiency and minimizing negative impacts on transit and vehicular traffic.

  1. Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression.

    Science.gov (United States)

    Suárez-Arroyo, Ivette J; Rios-Fuller, Tiffany J; Feliz-Mosquea, Yismeilin R; Lacourt-Ventura, Mercedes; Leal-Alviarez, Daniel J; Maldonado-Martinez, Gerónimo; Cubano, Luis A; Martínez-Montemayor, Michelle M

    2016-01-01

    The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors. PMID:26958085

  2. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer.

    Science.gov (United States)

    Antonio, Nicole; Bønnelykke-Behrndtz, Marie Louise; Ward, Laura Chloe; Collin, John; Christensen, Ib Jarle; Steiniche, Torben; Schmidt, Henrik; Feng, Yi; Martin, Paul

    2015-09-01

    There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of Ras(G12V)-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome. PMID:26136213

  3. Progress in Edge plasma transport modeling on JET

    International Nuclear Information System (INIS)

    Recent progress in edge plasma modeling on the JET tokamak is briefly, and somewhat selectively, reviewed. This ongoing modeling activity is aimed at developing a predictive capability for ITER based on numerical models verified and validated upon JET experimental data. Topics include both steady-state and transient particle and power exhaust, the effect of edge/SOL turbulence and edge localized modes, and first wall material migration. (copyright 2008 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  4. A simple model of scientific progress - with examples

    CERN Document Server

    Scorzato, Luigi

    2016-01-01

    One of the main goals of scientific research is to provide a description of the empirical data which is as accurate and comprehensive as possible, while relying on as few and simple assumptions as possible. In this paper, I propose a definition of the notion of "few and simple assumptions" that is not affected by known problems. This leads to the introduction of a simple model of scientific progress that is based only on empirical accuracy and conciseness. An essential point in this task is the understanding of the role played by "measurability" in the formulation of a scientific theory. This is the key to prevent artificially concise formulations. The model is confronted here with many possible objections and with challenging cases of real progress. Although I cannot exclude that the model might have some limitations, it includes all the cases of genuine progress examined here, and no spurious one. In this model, I stress the role of the "state of the art", which is the collection of all the theories that ar...

  5. Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer.

    Science.gov (United States)

    Rybicki, Benjamin A; Rundle, Andrew; Kryvenko, Oleksandr N; Mitrache, Nicoleta; Do, Kieu C; Jankowski, Michelle; Chitale, Dhananjay A; Trudeau, Sheri; Belinsky, Steven A; Tang, Deliang

    2016-06-15

    In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue-prior to malignant transformation-may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received "definitive" treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease. PMID:26860439

  6. Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer

    International Nuclear Information System (INIS)

    Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively

  7. Noncoding RNA Expression Aberration Is Associated with Cancer Progression and Is a Potential Biomarker in Esophageal Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Hidetaka Sugihara

    2015-11-01

    Full Text Available Esophageal cancer is one of the most common cancers worldwide. Esophageal squamous cell carcinoma (ESCC is the major histological type of esophageal cancer in Eastern Asian countries. Several types of noncoding RNAs (ncRNAs function as key epigenetic regulators of gene expression and are implicated in various physiological processes. Unambiguous evidence indicates that dysregulation of ncRNAs is deeply implicated in carcinogenesis, cancer progression and metastases of various cancers, including ESCC. The current review summarizes recent findings on the ncRNA-mediated mechanisms underlying the characteristic behaviors of ESCC that will help support the development of biomarkers and the design of novel therapeutic strategies.

  8. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy

    Directory of Open Access Journals (Sweden)

    Muz B

    2015-12-01

    Full Text Available Barbara Muz, Pilar de la Puente, Feda Azab, Abdel Kareem Azab Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine in St Louis, MO, USA Abstract: Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFκB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment. Keywords: hypoxia, cancer, metastasis, angiogenesis, treatment resistance 

  9. Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis.

    Directory of Open Access Journals (Sweden)

    Xun Yuan

    Full Text Available Various studies have evaluated the significance of Notch1 expression in breast cancer, but the results have ever been disputed. By using 21 studies involving 3867 patients, this meta-analysis revealed that the expression of Notch1 was significantly higher in breast cancer than in normal tissues (OR=7.21; 95%CI, 4.7-11.07 and that higher Notch1 expression was associated with transition from ductal carcinoma in situ (DCIS to invasive cancer (OR=3.75; 95% CI, 1.8-7.78. Higher Notch1 activity was observed in the basal subtype of breast cancer (OR=2.53; 95% CI, 1.18-5.43. Moreover, patients with Notch1 overexpression exhibited significantly worse overall and recurrence-free survival. Our meta-analysis suggests that Notch inhibitors may be useful in blocking the early progression of DCIS and that the outcomes of clinical trials for Notch1-targeting therapeutics could be improved by the molecular stratification of breast cancer patients.

  10. Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model

    OpenAIRE

    Lacerda, Lara; Debeb, Bisrat G; Smith, Daniel; Larson, Richard; Solley, Travis; Xu, Wei; Krishnamurthy, Savitri; Gong, Yun; Levy, Lawrence B; Buchholz, Thomas; Ueno, Naoto T.; Klopp, Ann; Woodward, Wendy A.

    2015-01-01

    Introduction Inflammatory breast cancer (IBC) is an aggressive type of breast cancer, characterized by very rapid progression, enlargement of the breast, skin edema causing an orange peel appearance (peau d’orange), erythema, thickening, and dermal lymphatic invasion. It is characterized by E-cadherin overexpression in the primary and metastatic disease, but to date no robust molecular features that specifically identify IBC have been reported. Further, models that recapitulate all of these c...

  11. Progress in Earth System Modeling since the ENIAC Calculation

    Science.gov (United States)

    Fung, I.

    2009-05-01

    The success of the first numerical weather prediction experiment on the ENIAC computer in 1950 was hinged on the expansion of the meteorological observing network, which led to theoretical advances in atmospheric dynamics and subsequently the implementation of the simplified equations on the computer. This paper briefly reviews the progress in Earth System Modeling and climate observations, and suggests a strategy to sustain and expand the observations needed to advance climate science and prediction.

  12. Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xiaolei Li

    2016-03-01

    Full Text Available (1 Background: Transient receptor potential vanilloid 3 (TRPV3 is a member of the TRP channels family of Ca2+-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC; (2 Methods: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca2+]i. Flow cytometry was used to analyze cell cycle; (3 Results: TRPV3 was overexpressed in 65 of 96 (67.7% human lung cancer cases and correlated with differentiation (p = 0.001 and TNM stage (p = 0.004. Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca2+]i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4 Conclusions: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC.

  13. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    International Nuclear Information System (INIS)

    Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer

  14. Foxp3 promoter polymorphism (rs3761548) in breast cancer progression: a study from India.

    Science.gov (United States)

    Jahan, Parveen; Ramachander, V R Vinish; Maruthi, G; Nalini, S; Latha, K Prasanna; Murthy, T S R

    2014-04-01

    Breast cancer is the most common female neoplasm that drives the transformation of normal mammary epithelial cells into highly malignant derivatives. Forkhead Box Protein3 (Foxp3), a tumor suppressor/immunomodulatory gene, which controls the function of Treg cells and oncogenes is down regulated in breast cancer. The main aim of the present study is to evaluate the potential influence of Foxp3-3279 C>A polymorphism (rs3761548) and -2383 C>T polymorphism (rs3761549) in 202 breast cancer patients and 130 normal healthy women of Indian origin. The genotypes were determined using ARMS-PCR for rs3761548 and PCR-RFLP method for rs3761549 using specific primers. The results revealed lack of association of these two polymorphisms with breast cancer susceptibility. However, with respect to AA genotype of rs3761548, we found highly significant association with the advanced stage (T3-4) of the tumor (OR = 3.90; 95% confidence interval (CI) = 1.56-9.70; p = 0.03). Stratified data also revealed an association of homozygous mutant genotype with advanced stage of tumor in premenopausal women (OR = 4.56; 95% CI = 1.07-19.38; p = 0.04) with disease duration of <6 months (OR =  .10; 95% CI = 1.80-20.50; p = 0.002) suggestive of modulating effect of rs3761548 in tumor progression. We conclude that Foxp3 rs37161548 has a potential to be a polymorphic marker for tumor progression in premenopausal breast cancer patients in Indian women. PMID:24338714

  15. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Kang Mei; Stephen, Josena K. [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202 (United States); Raju, Usha [Department of Pathology, Henry Ford Hospital, Detroit, 1 Ford Place, 1D, Detroit, MI 48202 (United States); Worsham, Maria J., E-mail: mworsha1@hfhs.org [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202 (United States)

    2011-03-29

    Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.

  16. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    Directory of Open Access Journals (Sweden)

    Maria J. Worsham

    2011-03-01

    Full Text Available Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia, and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA. Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.

  17. Carbohydrate Antigen Sialyl Lewis a – Its Pathophysiological ignificance and Induction Mechanism in Cancer Progression

    Directory of Open Access Journals (Sweden)

    Reiji Kannagi

    2007-06-01

    Full Text Available Carbohydrate antigen sialyl Lewis a (CA19-9 is the mostfrequently applied serum tumor marker for diagnosis of cancersin the digestive organs. Recent progress disclosed thepresence of a normal counterpart of the determinant, namelydisialyl Lewis a, which is predominantly expressed in nonmalignantepithelial cells of the digestive organs, while sialylLewis a is preferentially expressed in cancers. The disialylLewis a determinant carries one extra sialic residue attachedthrough a 2 6 linkage to the GlcNAc moiety compared tocancer-associated sialyl Lewis a, which carries only one 2 3linked sialic acid residue (monosialyl Lewis a. Disialyl Lewisa in normal epithelial cells serves as a ligand for immunosuppressivereceptors such as sialic acid binding immunoglobulin(Ig-like lectins (siglec-7 and -9 expressed on resident monocytes/macrophages and maintains immunological homeostasisof mucosal membranes in digestive organs. Epigenetic silencing of a gene for a 2 6 sialyltransferasein the early stages of carcinogenesis results in an impairment of 2 6 sialylation,leading to incomplete synthesis and accumulation of sialyl Lewis a, which lacks the 2 6linked sialic acid residue, in cancer cells. Simultaneous determination of serum levels of sialyl-and disialyl Lewis a, and calculation of the monosialyl/disialyl Lewis a ratio provideinformation useful for excluding a false-positive serum diagnosis, and also for averting theundesired influence of the Lewis blood group of patients on serum antigen levels. During thecourse of cancer progression in locally advanced cancers, tumor hypoxia induces transcriptionof several glycogenes involved in sialyl Lewis a synthesis. Expression of the determinant,consequently, is further accelerated in more malignant hypoxia-resistant cancer cellclones, which become predominant clones in advanced stage cancers and frequently develophematogenous metastasis. Sialyl Lewis a, as well as its positional isomer sialyl Lewis x,serves as a

  18. Progress in integrated energy-economy-environment model system development

    International Nuclear Information System (INIS)

    The Integrated Energy-Economy-Environment Model System has been developed for providing analytical tools for the system analysis and technology assessments in the field of nuclear research and development. This model system consists of the following four model groups. The first model block installs 5 models and can serve to analyze and generate long-term scenarios on economy-energy-environment evolution. The second model block installs 2 models and can serve to analyze the structural transition phenomena in energy-economy-environment interactions. The third model block installs 2 models and can handle power reactor installation strategy problem and long-term fuel cycle analysis. The fourth model block installs 5 models and codes and can treats cost-benefit-risk analysis and assessments. This report describes mainly the progress and the outlines of application of the model system in these years after the first report on the research and development of the model system (JAERI-M 84 - 139). (author)

  19. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy

    OpenAIRE

    Sullivan, James P.; Minna, John D.; Shay, Jerry W.

    2010-01-01

    The discovery of rare tumor cells with stem cell features first in leukemia and later in solid tumors has emerged as an important area in cancer research. It has been determined that these stem-like tumor cells, termed cancer stem cells, are the primary cellular component within a tumor that drives disease progression and metastasis. In addition to their stem-like ability to self-renew and differentiate, cancer stem cells are also enriched in cells resistant to conventional radiation therapy ...

  20. In Silico Experimental Modeling of Cancer Treatment

    OpenAIRE

    Trisilowati; D. G. Mallet

    2012-01-01

    In silico experimental modeling of cancer involves combining findings from biological literature with computer-based models of biological systems in order to conduct investigations of hypotheses entirely in the computer laboratory. In this paper, we discuss the use of in silico modeling as a precursor to traditional clinical and laboratory research, allowing researchers to refine their experimental programs with an aim to reducing costs and increasing research efficiency. We explain the metho...

  1. Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression.

    Science.gov (United States)

    Picon-Ruiz, Manuel; Pan, Chendong; Drews-Elger, Katherine; Jang, Kibeom; Besser, Alexandra H; Zhao, Dekuang; Morata-Tarifa, Cynthia; Kim, Minsoon; Ince, Tan A; Azzam, Diana J; Wander, Seth A; Wang, Bin; Ergonul, Burcu; Datar, Ram H; Cote, Richard J; Howard, Guy A; El-Ashry, Dorraya; Torné-Poyatos, Pablo; Marchal, Juan A; Slingerland, Joyce M

    2016-01-15

    Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. PMID:26744520

  2. A Novel Bioluminescence Orthotopic Mouse Model for Advanced Lung Cancer

    OpenAIRE

    Li, Bo; Torossian, Artour; Li, Wenyan; Schleicher, Stephen; Niu, Kathy; Giacalone, Nicholas J; Kim, Sung June; Chen, Heidi; Gonzalez, Adriana; Moretti, Luigi; Lu, Bo

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model ...

  3. Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression

    International Nuclear Information System (INIS)

    Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism. Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression. Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive

  4. Aberrant nocturnal cortisol and disease progression in women with breast cancer.

    Science.gov (United States)

    Zeitzer, Jamie M; Nouriani, Bita; Rissling, Michelle B; Sledge, George W; Kaplan, Katherine A; Aasly, Linn; Palesh, Oxana; Jo, Booil; Neri, Eric; Dhabhar, Firdaus S; Spiegel, David

    2016-07-01

    While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer. PMID:27314577

  5. Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression

    Directory of Open Access Journals (Sweden)

    Brian F. Zamarron, WanJun Chen

    2011-01-01

    Full Text Available Traditional wisdom holds that intact immune responses, such as immune surveillance or immunoediting, are required for preventing and inhibiting tumor development; but recent evidence has also indicated that unresolved immune responses, such as chronic inflammation, can promote the growth and progression of cancer. Within the immune system, cytotoxic CD8+ and CD4+ Th1 T cells, along with their characteristically produced cytokine IFN-γ, function as the major anti-tumor immune effector cells, whereas tumor associated macrophages (TAM or myeloid-derived suppressive cells (MDSC and their derived cytokines IL-6, TNF, IL-1β and IL-23 are generally recognized as dominant tumor-promoting forces. However, the roles played by Th17 cells, CD4+ CD25+ Foxp3+ regulatory T lymphocytes and immunoregulatory cytokines such as TGF-β in tumor development and survival remain elusive. These immune cells and the cellular factors produced from them, including both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development, and their ultimate role in cancer progression may rely heavily on the tumor microenvironment and the events leading to initial propagation of carcinogenesis.

  6. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.

    Directory of Open Access Journals (Sweden)

    Howard Y Chang

    2004-02-01

    Full Text Available Cancer invasion and metastasis have been likened to wound healing gone awry. Despite parallels in cellular behavior between cancer progression and wound healing, the molecular relationships between these two processes and their prognostic implications are unclear. In this study, based on gene expression profiles of fibroblasts from ten anatomic sites, we identify a stereotyped gene expression program in response to serum exposure that appears to reflect the multifaceted role of fibroblasts in wound healing. The genes comprising this fibroblast common serum response are coordinately regulated in many human tumors, allowing us to identify tumors with gene expression signatures suggestive of active wounds. Genes induced in the fibroblast serum-response program are expressed in tumors by the tumor cells themselves, by tumor-associated fibroblasts, or both. The molecular features that define this wound-like phenotype are evident at an early clinical stage, persist during treatment, and predict increased risk of metastasis and death in breast, lung, and gastric carcinomas. Thus, the transcriptional signature of the response of fibroblasts to serum provides a possible link between cancer progression and wound healing, as well as a powerful predictor of the clinical course in several common carcinomas.

  7. Recent Progress in Genetic and Epigenetic Profile of Diffuse Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Zhengxi He

    2015-01-01

    Full Text Available Gastric cancer (GC is the second leading cause of death from cancer worldwide, with 5-year survival rate for about 20% of the affected individuals. Although there is a decrease in the intestinal-type GC (IGC, the incidence of diffuse-type is still increasing, and its progression is notoriously aggressive. Clinically, diffuse GCs (DGCs propensity for invasion into adjacent tissue, with prominent stromal induction, which presents with linitis plastica, peritoneal implantation and remote metastasis, ends up in dismal prognosis, and translates into poor quality of life. So far, a few molecularly targeted drugs, including HER2 antagonists, have been developed against GC, but most in treating IGC. Thus, DGC constitutes a poor prognosis subgroup of GC with no known promising therapies. Recent genomic characterization of GC by whole-genome and whole-exome sequencing showed that a large number of known cancer-related genes are frequently mutated in gastric malignancies. In the light of this discovery, we did an extensive review of recent literature on progress in genetic and epigenetic profile of DGC. The summary of which makes us believe that it is possible to develop novel therapeutic strategies against this otherwise devastating disease that undergo massive invasion and metastasis.

  8. Model Checking of a Diabetes-Cancer Model

    Science.gov (United States)

    Gong, Haijun; Zuliani, Paolo; Clarke, Edmund M.

    2011-06-01

    Accumulating evidence suggests that cancer incidence might be associated with diabetes mellitus, especially Type II diabetes which is characterized by hyperinsulinaemia, hyperglycaemia, obesity, and overexpression of multiple WNT pathway components. These diabetes risk factors can activate a number of signaling pathways that are important in the development of different cancers. To systematically understand the signaling components that link diabetes and cancer risk, we have constructed a single-cell, Boolean network model by integrating the signaling pathways that are influenced by these risk factors to study insulin resistance, cancer cell proliferation and apoptosis. Then, we introduce and apply the Symbolic Model Verifier (SMV), a formal verification tool, to qualitatively study some temporal logic properties of our diabetes-cancer model. The verification results show that the diabetes risk factors might not increase cancer risk in normal cells, but they will promote cell proliferation if the cell is in a precancerous or cancerous stage characterized by losses of the tumor-suppressor proteins ARF and INK4a.

  9. PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jerfiz D. Constanzo

    2016-05-01

    Full Text Available The sequence of genomic alterations acquired by cancer cells during tumor progression and metastasis is poorly understood. Focal adhesion kinase (FAK is a non-receptor tyrosine kinase that integrates cytoskeleton remodeling, mitogenic signaling and cell survival. FAK has previously been reported to undergo nuclear localization during cell migration, cell differentiation and apoptosis. However, the mechanism behind FAK nuclear accumulation and its contribution to tumor progression has remained elusive. We report that amplification of FAK and the SUMO E3 ligase PIAS1 gene loci frequently co-occur in non-small cell lung cancer (NSCLC cells, and that both gene products are enriched in a subset of primary NSCLCs. We demonstrate that endogenous FAK and PIAS1 proteins interact in the cytoplasm and the cell nucleus of NSCLC cells. Ectopic expression of PIAS1 promotes proteolytic cleavage of the FAK C-terminus, focal adhesion maturation and FAK nuclear localization. Silencing of PIAS1 deregulates focal adhesion turnover, increases susceptibility to apoptosis in vitro and impairs tumor xenograft formation in vivo. Nuclear FAK in turn stimulates gene transcription favoring DNA repair, cell metabolism and cytoskeleton regulation. Consistently, ablation of FAK by CRISPR/Cas9 editing, results in basal DNA damage, susceptibility to ionizing radiation and impaired oxidative phosphorylation. Our findings provide insight into a mechanism regulating FAK cytoplasm-nuclear distribution and demonstrate that FAK activity in the nucleus promotes NSCLC survival and progression by increasing cell-ECM interaction and DNA repair regulation.

  10. Modelling Hydrological Consequences of Climate Change-Progress and Challenges

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The simulation of hydrological consequences of climate change has received increasing attention from the hydrology and land-surface modelling communities. There have been many studies of climate-change effects on hydrology and water resources which usually consist of three steps: (1) use of general circulation models (GCMs) to provide future global climate scenarios under the effect of increasing greenhouse gases,(2) use of downscaling techniques (both nested regional climate models, RCMs, and statistical methods)for "downscaling" the GCM output to the scales compatible with hydrological models, and (3) use of hydrologic models to simulate the effects of climate change on hydrological regimes at various scales.Great progress has been achieved in all three steps during the past few years, however, large uncertainties still exist in every stage of such study. This paper first reviews the present achievements in this field and then discusses the challenges for future studies of the hydrological impacts of climate change.

  11. BRAFV600E and microenvironment in thyroid cancer: a functional link to drive cancer progression

    OpenAIRE

    Nucera, Carmelo; Lawler, Jack; Parangi, Sareh

    2011-01-01

    Papillary thyroid cancer (PTC) rates continue to increase in the United States and Europe, and while most patients do well, some recur and die of their disease. Patients with PTC harboring the BRAFV600E mutation appear to display a more aggressive clinical behavior but little is known about the role of this mutation in crucial processes in the tumor microenvironment such as tumor adhesion, migration, invasion, and metastasis. The extracellular matrix (ECM) microenvironment is not merely a str...

  12. Human Cancer Classification: A Systems Biology- Based Model Integrating Morphology, Cancer Stem Cells, Proteomics, and Genomics

    OpenAIRE

    Halliday A Idikio

    2011-01-01

    Human cancer classification is currently based on the idea of cell of origin, light and electron microscopic attributes of the cancer. What is not yet integrated into cancer classification are the functional attributes of these cancer cells. Recent innovative techniques in biology have provided a wealth of information on the genomic, transcriptomic and proteomic changes in cancer cells. The emergence of the concept of cancer stem cells needs to be included in a classification model to capture...

  13. Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients

    International Nuclear Information System (INIS)

    Eph receptor A10 (EphA10) is a valuable breast cancer marker that is highly expressed in breast cancer tissues by comparison with normal breast tissues, as we previously reported. However, the role of EphA10 expression in breast cancer is not well understood. Here, we have analyzed the expression of EphA10 at the mRNA- and protein-level in clinical breast cancer tissues and then evaluated the relationship with clinicopathological parameters for each sample. EphA10 mRNA expression was quantified by real-time polymerase chain reaction using complimentary DNA (cDNA) samples derived from breast cancer patients. Lymph node (LN) metastasis and stage progression were significantly correlated with EphA10 expression at the mRNA level (P = 0.0091 and P = 0.034, respectively). Furthermore, immunohistochemistry (IHC) staining of breast cancer tissue microarrays (TMAs) revealed that EphA10 expression at the protein level was also associated with LN metastasis and stage progression (P = 0.016 and P = 0.011, respectively). These results indicate that EphA10 expression might play a role in tumor progression and metastasis. Our findings will help elucidate the role of EphA10 in clinical breast cancer progression

  14. Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients.

    Science.gov (United States)

    Nagano, Kazuya; Kanasaki, So-Ichiro; Yamashita, Takuya; Maeda, Yuka; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-Ichi

    2013-12-01

    Eph receptor A10 (EphA10) is a valuable breast cancer marker that is highly expressed in breast cancer tissues by comparison with normal breast tissues, as we previously reported. However, the role of EphA10 expression in breast cancer is not well understood. Here, we have analyzed the expression of EphA10 at the mRNA- and protein-level in clinical breast cancer tissues and then evaluated the relationship with clinicopathological parameters for each sample. EphA10 mRNA expression was quantified by real-time polymerase chain reaction using complimentary DNA (cDNA) samples derived from breast cancer patients. Lymph node (LN) metastasis and stage progression were significantly correlated with EphA10 expression at the mRNA level (P = 0.0091 and P = 0.034, respectively). Furthermore, immunohistochemistry (IHC) staining of breast cancer tissue microarrays (TMAs) revealed that EphA10 expression at the protein level was also associated with LN metastasis and stage progression (P = 0.016 and P = 0.011, respectively). These results indicate that EphA10 expression might play a role in tumor progression and metastasis. Our findings will help elucidate the role of EphA10 in clinical breast cancer progression. PMID:24403271

  15. Twisted epithelial-to-mesenchymal transition promotes progression of surviving bladder cancer T24 cells with hTERT-dysfunction.

    Directory of Open Access Journals (Sweden)

    Yan Xue

    Full Text Available BACKGROUND: Human cancer cells maintain telomeres to protect cells from senescence through telomerase activity (TA or alternative lengthening of telomeres (ALT in different cell types. Moreover, cellular senescence can be bypassed by Epithelial-to-mesenchymal transition (EMT during cancer progression in diverse solid tumors. However, it has not been elucidated the characteristics of telomere maintenance and progression ability after long-term culture in bladder cancer T24 cells with hTERT dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: In this study, by using a dominant negative mutant human telomerase reverse transcriptase (hTERT vector to inhibit TA in bladder cancer T24 cells, we observed the appearance of long phenotype of telomere length and the ALT-associated PML body (APB complex after the 27(th passage, indicating the occurrence of ALT-like pathway in surviving T24/DN868A cells with telomerase inhibition. Meanwhile, telomerase inhibition resulted in significant EMT as shown by change in cellular morphology concomitant with variation of EMT markers. Consistently, the surviving T24/DN868A cells showed increased progression ability in vitro and in vivo. In addition, we found Twist was activated to mediate EMT in surviving T24/DN868A samples. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings indicate that bladder cancer T24 cells may undergo the telomerase-to-ALT-like conversion and promote cancer progression at advanced stages through promoting EMT, thus providing novel possible insight into the mechanism of resistance to telomerase inhibitors in cancer treatment.

  16. Expression profiling of cervical cancers in Indian women at different stages to identify gene signatures during progression of the disease

    International Nuclear Information System (INIS)

    Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from Indian women, spanning International Federation of Gynaecology and Obstetrics (FIGO) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA–B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine–cytokine receptor interaction and WNT signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as SPP1, proliferating cell nuclear antigen (PCNA), STK17A, and DUSP1 among others that were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression

  17. Utility of SAM68 in the progression and prognosis for bladder cancer

    International Nuclear Information System (INIS)

    Muscle invasive bladder cancer (MIBC) is often lethal and non-MIBC (NMIBC) can recur and progress, yet prognostic markers are currently inadequate. SAM68, a member of RNA-binding proteins, has been reported to contribute to progression of other cancers. The aim of this study is to investigate the potential utility of SAM68 in the progression and prognosis of bladder cancer. Quantitative PCR and immunohistochemistry were utilized to examine the expression of SAM68 in ten pairs of MIBC and adjacent normal bladder urothelium, and eight pairs of MIBC and non-MIBC (NMIBC) tissues from the same patient. Moreover, SAM68 protein expression level and localization were examined by immunohistochemistry in 129 clinicopathologically characterized MIBC samples. Prognostic associations were determined by multivariable analysis incorporating standard prognostic factors. SAM68 expression was elevated in MIBC tissues compared with adjacent normal bladder urothelium, and was increased at both transcriptional and translational levels in MIBC tissues compared with NMIBC tissues of the same patient. For MIBC, high expression and nucleus-cytoplasm co-expression of SAM68 were associated with higher T-stage, higher N-stage and worse recurrence-free survival. Five-year recurrence-free survival was 80% and 52.9% for MIBC patients with low and high SAM68 expression, respectively (p = 0.001). SAM68 nucleus-cytoplasm co-expression associated with worse 5-year recurrence-free survival rate (49.2%) than SAM68 expression confined to the nucleus (82.5%) or cytoplasm (75.5%) alone. On multivariable analysis SAM68 expression level, SAM68 nucleus-cytoplasm co-expression, T-stage, and N-stage were all independent prognostic factors for recurrence-free survival of MIBC patients. SAM68 expression is increased in MIBC when compared to normal urothelium and NMIBC, and appears to be a potentially useful prognostic marker for MIBC

  18. Progress and challenges in psychosocial and behavioral research in cancer in the twentieth century.

    Science.gov (United States)

    Holland, J C

    1991-02-01

    Research in the psychosocial and behavioral aspects of cancer has shown steady growth since the 1950s, and its course of development has paralleled the history of medical techniques in treating cancer. Table 1 outlines this parallel evolution from the 1850s to the 1960s. The roles of the American Cancer Society and the National Cancer Institute (NCI) in spearheading and nurturing research in this area are documented. Interest in psychooncologic questions can be traced back for centuries to the search for etiologic factors and psychologic variables that would explain individual vulnerability to cancer. The first psychologic studies of cancer patients were reported in 1951 and 1952 from the Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center, respectively. The 1970s saw new interest in psychosocial and behavioral research with many issues being addressed for the first time: better care of the terminally ill through more humanistic approaches including better means of pain control; ethical concerns related to patient rights and their status as subjects in experimental protocols; trying to measure quality of life for cancer patients on protocols; seeing the need for multidisciplinary collaborative groups to make up for the absence of formal training in this area; and the need to design valid, accurate measuring scales specific to the symptomology of patients with cancer. Table 4 outlines how the 1980s gave increasing recognition and support to the psychosocial dimensions of cancer. This period produced a series of key conferences that examined a broad research and education perspective and produced recommendations that remain a benchmark in regard to instrumentation, conceptual models, pitfalls of psychosocial research, training, and education, and the organization of research efforts. New precision has been added to the field in the past 6 years: studies measuring concurrent psychologic, endocrine, and immune function; use of statistical modeling

  19. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: vadlamudi@uthscsa.edu [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)

    2011-03-29

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

  20. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    International Nuclear Information System (INIS)

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications

  1. SURGICAL TREATMENT OF PATIENTS WITH PROSTATE CANCER AT HIGH RISK OF PROGRESSION

    Directory of Open Access Journals (Sweden)

    K. M. Nyushko

    2014-07-01

    Full Text Available Prostate cancer (PC is one of the most burning problems of modern urologic oncology. Patients at its high risk are characterized by a more aggressive course of the disease and significantly lower tumor-specific and relapse-free survival rates. Hormone therapy and radiotherapy are one of the conventional treatments in patients with PC at high risk of progression. Nonetheless, more and more publications demonstrating the efficiency and safety of surgical therapy in this contingent of patients are recently appearing. This paper presents the results of surgical treat-ment in 499 patients with PC at high risk of progression, who have undergone radical prostatectomy with extended pelvic lymphadenectomy at the Department of Urologic Oncology, P.A. Herzen Moscow Oncology Research Institute. 

  2. Models of Understanding: Historical Constructions of Breast Cancer in Medicine and Public Health

    Science.gov (United States)

    Petersen, Jennifer

    2004-01-01

    The era of technical and scientific progress ushered in with the twentieth century brought new medical knowledge such as the Halstead 'radical' mastectomy, which promised a cure for breast cancer. These advances in medical knowledge were premised on an epidemiological model of disease, which shaped the treatment and public understanding of breast…

  3. Nanoparticle-Based Drug Delivery for Therapy of Lung Cancer: Progress and Challenges

    Directory of Open Access Journals (Sweden)

    Anish Babu

    2013-01-01

    Full Text Available The last decade has witnessed enormous advances in the development and application of nanotechnology in cancer detection, diagnosis, and therapy culminating in the development of the nascent field of “cancer nanomedicine.” A nanoparticle as per the National Institutes of Health (NIH guidelines is any material that is used in the formulation of a drug resulting in a final product smaller than 1 micron in size. Nanoparticle-based therapeutic systems have gained immense popularity due to their ability to overcome biological barriers, effectively deliver hydrophobic therapies, and preferentially target disease sites. Currently, many formulations of nanocarriers are utilized including lipid-based, polymeric and branched polymeric, metal-based, magnetic, and mesoporous silica. Innovative strategies have been employed to exploit the multicomponent, three-dimensional constructs imparting multifunctional capabilities. Engineering such designs allows simultaneous drug delivery of chemotherapeutics and anticancer gene therapies to site-specific targets. In lung cancer, nanoparticle-based therapeutics is paving the way in the diagnosis, imaging, screening, and treatment of primary and metastatic tumors. However, translating such advances from the bench to the bedside has been severely hampered by challenges encountered in the areas of pharmacology, toxicology, immunology, large-scale manufacturing, and regulatory issues. This review summarizes current progress and challenges in nanoparticle-based drug delivery systems, citing recent examples targeted at lung cancer treatment.

  4. The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance.

    Science.gov (United States)

    Zarif, Jelani C; Miranti, Cindy K

    2016-05-01

    The androgen receptor (AR) remains the major oncogenic driver of prostate cancer, as evidenced by the efficacy of androgen deprivation therapy (ADT) in naïve patients, and the continued effectiveness of second generation ADTs in castration resistant disease. However, current ADTs are limited to interfering with AR ligand binding, either through suppression of androgen production or the use of competitive antagonists. Recent studies demonstrate 1) the expression of constitutively active AR splice variants that no longer depend on androgen, and 2) the ability of AR to signal in the cytoplasm independently of its transcriptional activity (non-genomic); thus highlighting the need to consider other ways to target AR. Herein, we review canonical AR signaling, but focus on AR non-genomic signaling, some of its downstream targets and how these effectors contribute to prostate cancer cell behavior. The goals of this review are to 1) re-highlight the continued importance of AR in prostate cancer as the primary driver, 2) discuss the limitations in continuing to use ligand binding as the sole targeting mechanism, 3) discuss the implications of AR non-genomic signaling in cancer progression and therapeutic resistance, and 4) address the need to consider non-genomic AR signaling mechanisms and pathways as a viable targeting strategy in combination with current therapies. PMID:26829214

  5. Progress and problems with the use of suicide genes for targeted cancer therapy.

    Science.gov (United States)

    Karjoo, Zahra; Chen, Xuguang; Hatefi, Arash

    2016-04-01

    Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated. PMID:26004498

  6. Research progress on chemopreventive effects of phytochemicals on colorectal cancer and their mechanisms

    Science.gov (United States)

    Yin, Teng-Fei; Wang, Min; Qing, Ying; Lin, Ying-Min; Wu, Dong

    2016-01-01

    Colorectal cancer (CRC) is a type of cancer with high morbidity and mortality rates worldwide and has become a global health problem. The conventional radiotherapy and chemotherapy regimen for CRC not only has a low cure rate but also causes side effects. Many studies have shown that adequate intake of fruits and vegetables in the diet may have a protective effect on CRC occurrence, possibly due to the special biological protective effect of the phytochemicals in these foods. Numerous in vitro and in vivo studies have demonstrated that phytochemicals play strong antioxidant, anti-inflammatory and anti-cancer roles by regulating specific signaling pathways and molecular markers to inhibit the occurrence and development of CRC. This review summarizes the progress on CRC prevention using the phytochemicals sulforaphane, curcumin and resveratrol, and elaborates on the specific underlying mechanisms. Thus, we believe that phytochemicals might provide a novel therapeutic approach for CRC prevention, but future clinical studies are needed to confirm the specific preventive effect of phytochemicals on cancer.

  7. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

    Directory of Open Access Journals (Sweden)

    Johannsen Manfred

    2008-06-01

    Full Text Available Abstract Background A Disintegrin And Metalloprotease (ADAM 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. Methods 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ2-test, correlations and univariate as well as multivariate survival analyses. Results ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. Conclusion ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts.

  8. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

    International Nuclear Information System (INIS)

    A Disintegrin And Metalloprotease (ADAM) 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ2-test), correlations and univariate as well as multivariate survival analyses. ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts

  9. Nrf2 and NF-κB and Their Concerted Modulation in Cancer Pathogenesis and Progression

    International Nuclear Information System (INIS)

    Reactive oxygen species, produced by oxidative stress, are implicated in the initiation, promotion, and malignant conversion of carcinogenesis through activation/suppression of redox-sensitive transcription factors. NF-E2-related factor 2 (Nrf2) encodes for antioxidant and general cytoprotection genes, while NF-κB regulates the expression of pro-inflammatory genes. A variety of anti-inflammatory or anti-carcinogenic phyto-chemicals suppress NF-κB signalling and activate the Nrf2-ARE pathway. In this review we consider the role of Nrf2 and NF-κB in cancer pathogenesis and progression, focusing on their concerted modulation and potential cross-talk

  10. Advanced and rapidly progressing head and neck cancer: good palliation following intralesional bleomycin.

    LENUS (Irish Health Repository)

    Quintyne, Keith Ian

    2011-09-01

    The authors herein report the case of a 61-year-old man undergoing adjuvant therapy for locally advanced laryngeal cancer, who developed parastomal recurrence in his radiation field around his tracheotomy site, while he was undergoing radiation therapy, and compromised the secure placement of his tracheotomy tube and maintenance of his upper airway. MRI restaging and biopsy confirmed recurrence and progressive disease in his mediastinum. He underwent local therapy with intralesional bleomycin with good palliation, and ability to maintain the patency of his upper airway.

  11. The Progress and Prospects of Putative Biomarkers for Liver Cancer Stem Cells in Hepatocellular Carcinoma.

    Science.gov (United States)

    Xiang, Yan; Yang, Ting; Pang, Bing-Yao; Zhu, Ying; Liu, Yong-Ning

    2016-01-01

    Accumulating evidence suggests that hepatocellular carcinoma (HCC) is organized by liver cancer stem cells (LCSCs), which are a subset of cells with "stem-like" characteristics. Identification of the LCSCs is a fundamental and important problem in HCC research. LCSCs have been investigated by various stem cell biomarkers. There is still lack of consensus regarding the existence of a "global" marker for LCSCs in HCC. In this review article, we summarize the progress and prospects of putative biomarkers for LCSCs in the past decades, which is essential to develop future therapies targeting CSCs and to predict prognosis and curative effect of these therapies. PMID:27610139

  12. A Bayesian nonlinear mixed-effects disease progression model

    Science.gov (United States)

    Kim, Seongho; Jang, Hyejeong; Wu, Dongfeng; Abrams, Judith

    2016-01-01

    A nonlinear mixed-effects approach is developed for disease progression models that incorporate variation in age in a Bayesian framework. We further generalize the probability model for sensitivity to depend on age at diagnosis, time spent in the preclinical state and sojourn time. The developed models are then applied to the Johns Hopkins Lung Project data and the Health Insurance Plan for Greater New York data using Bayesian Markov chain Monte Carlo and are compared with the estimation method that does not consider random-effects from age. Using the developed models, we obtain not only age-specific individual-level distributions, but also population-level distributions of sensitivity, sojourn time and transition probability. PMID:26798562

  13. HiJAK’d Signaling; the STAT3 Paradox in Senescence and Cancer Progression

    Energy Technology Data Exchange (ETDEWEB)

    Junk, Damian J.; Bryson, Benjamin L.; Jackson, Mark W., E-mail: mark.w.jackson@case.edu [Department of Pathology, Case Western Reserve University, Case Comprehensive Cancer Center, 2103 Cornell Road, WRB 3-134, Cleveland, OH 44106 (United States)

    2014-03-26

    Clinical and epidemiological data have associated chronic inflammation with cancer progression. Most tumors show evidence of infiltrating immune and inflammatory cells, and chronic inflammatory disorders are known to increase the overall risk of cancer development. While immune cells are often observed in early hyperplastic lesions in vivo, there remains debate over whether these immune cells and the cytokines they produce in the developing hyperplastic microenvironment act to inhibit or facilitate tumor development. The interleukin-6 (IL-6) family of cytokines, which includes IL-6 and oncostatin M (OSM), among others (LIF, CT-1, CNTF, and CLC), are secreted by immune cells, stromal cells, and epithelial cells, and regulate diverse biological processes. Each of the IL-6 family cytokines signals through a distinct receptor complex, yet each receptor complex uses a shared gp130 subunit, which is critical for signal transduction following cytokine binding. Activation of gp130 results in the activation of Signal Transducer and Activator of Transcription 3 (STAT3), and the Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K) signaling cascades. Tumor suppressive signaling can often be observed in normal cells following prolonged STAT3 activation. However, there is mounting evidence that the IL-6 family cytokines can contribute to later stages of tumor progression in many ways. Here we will review how the microenvironmental IL-6 family cytokine OSM influences each stage of the transformation process. We discuss the intrinsic adaptations a developing cancer cell must make in order to tolerate and circumvent OSM-mediated growth suppression, as well as the OSM effectors that are hijacked during tumor expansion and metastasis. We propose that combining current therapies with new ones that suppress the signals generated from the tumor microenvironment will significantly impact an oncologist’s ability to treat cancer.

  14. HiJAK’d Signaling; the STAT3 Paradox in Senescence and Cancer Progression

    Directory of Open Access Journals (Sweden)

    Damian J. Junk

    2014-03-01

    Full Text Available Clinical and epidemiological data have associated chronic inflammation with cancer progression. Most tumors show evidence of infiltrating immune and inflammatory cells, and chronic inflammatory disorders are known to increase the overall risk of cancer development. While immune cells are often observed in early hyperplastic lesions in vivo, there remains debate over whether these immune cells and the cytokines they produce in the developing hyperplastic microenvironment act to inhibit or facilitate tumor development. The interleukin-6 (IL-6 family of cytokines, which includes IL-6 and oncostatin M (OSM, among others (LIF, CT-1, CNTF, and CLC, are secreted by immune cells, stromal cells, and epithelial cells, and regulate diverse biological processes. Each of the IL-6 family cytokines signals through a distinct receptor complex, yet each receptor complex uses a shared gp130 subunit, which is critical for signal transduction following cytokine binding. Activation of gp130 results in the activation of Signal Transducer and Activator of Transcription 3 (STAT3, and the Mitogen-Activated Protein Kinase (MAPK and Phosphatidylinositol 3-Kinase (PI3K signaling cascades. Tumor suppressive signaling can often be observed in normal cells following prolonged STAT3 activation. However, there is mounting evidence that the IL-6 family cytokines can contribute to later stages of tumor progression in many ways. Here we will review how the microenvironmental IL-6 family cytokine OSM influences each stage of the transformation process. We discuss the intrinsic adaptations a developing cancer cell must make in order to tolerate and circumvent OSM-mediated growth suppression, as well as the OSM effectors that are hijacked during tumor expansion and metastasis. We propose that combining current therapies with new ones that suppress the signals generated from the tumor microenvironment will significantly impact an oncologist’s ability to treat cancer.

  15. HiJAK’d Signaling; the STAT3 Paradox in Senescence and Cancer Progression

    International Nuclear Information System (INIS)

    Clinical and epidemiological data have associated chronic inflammation with cancer progression. Most tumors show evidence of infiltrating immune and inflammatory cells, and chronic inflammatory disorders are known to increase the overall risk of cancer development. While immune cells are often observed in early hyperplastic lesions in vivo, there remains debate over whether these immune cells and the cytokines they produce in the developing hyperplastic microenvironment act to inhibit or facilitate tumor development. The interleukin-6 (IL-6) family of cytokines, which includes IL-6 and oncostatin M (OSM), among others (LIF, CT-1, CNTF, and CLC), are secreted by immune cells, stromal cells, and epithelial cells, and regulate diverse biological processes. Each of the IL-6 family cytokines signals through a distinct receptor complex, yet each receptor complex uses a shared gp130 subunit, which is critical for signal transduction following cytokine binding. Activation of gp130 results in the activation of Signal Transducer and Activator of Transcription 3 (STAT3), and the Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K) signaling cascades. Tumor suppressive signaling can often be observed in normal cells following prolonged STAT3 activation. However, there is mounting evidence that the IL-6 family cytokines can contribute to later stages of tumor progression in many ways. Here we will review how the microenvironmental IL-6 family cytokine OSM influences each stage of the transformation process. We discuss the intrinsic adaptations a developing cancer cell must make in order to tolerate and circumvent OSM-mediated growth suppression, as well as the OSM effectors that are hijacked during tumor expansion and metastasis. We propose that combining current therapies with new ones that suppress the signals generated from the tumor microenvironment will significantly impact an oncologist’s ability to treat cancer

  16. Progress in tritium retention and release modeling for ceramic breeders

    International Nuclear Information System (INIS)

    Tritium behavior in ceramic breeder blankets is a key design issue for this class of blanket because of its impact on safety and fuel self-sufficiency. Over the past 10-15 years, substantial theoretical and experimental efforts have been dedicated world-wide to develop a better understanding of tritium transport in ceramic breeders. Models that are available today seem to cover reasonably well all the key physical transport and trapping mechanisms. They have allowed for reasonable interpretation and reproduction of experimental data and have helped in pointing out deficiencies in material property data base, in providing guidance for future experiments, and in analyzing blanket tritium behavior. This paper highlights the progress in tritium modeling over the last decade. Key tritium transport mechanisms are briefly described along with the more recent and sophisticated models developed to help understand them. Recent experimental data are highlighted and model calibration and validation discussed. Finally, example applications to blanket cases are shown as illustration of progress in the prediction of ceramic breeder blanket tritium inventory

  17. Progress in tritium retention and release modeling for ceramic breeders

    International Nuclear Information System (INIS)

    Tritium behavior in ceramic breeder blankets is a key design issue for this class of blanket because of its impact on safety and fuel self-sufficiency. Over the past 10-15 years, substantial theoretical and experimental effort has been dedicated worldwide to the development of a better understanding of tritium transport in ceramic breeders. The models available today seem to cover reasonably well all of the key physical transport and trapping mechanisms. They allow for reasonable interpretation and reproduction of experimental data, help to point out deficiencies in the material property database, provide guidance for future experiments and aid in the analysis of blanket tritium behavior.This paper highlights the progress in tritium modeling over the last decade. Key tritium transport mechanisms are briefly described, together with the more recent, sophisticated models which have been developed to help understand them. Recent experimental data are highlighted and model calibration and validation are discussed. Finally, example applications to blanket cases are shown as an illustration of the progress in the prediction of ceramic breeder blanket tritium inventory. (orig.)

  18. Application of proteomics in the study of rodent models of cancer

    DEFF Research Database (Denmark)

    Terp, Mikkel Green; Ditzel, Henrik J

    tumor development from highly matched disease cases and controls with identical environmental and genetic backgrounds, thus providing an excellent method for biomarker discovery. Xenograft and genetically engineered mouse models have been widely used to identify proteomic patterns in tumor tissues and...... plasma samples associated with different stages of human cancer, including early cancer detection and development of metastasis. Here, we review proteomic strategies to identify proteins involved in key cancer processes within such animal models as well as biomarkers for diagnosis, prognosis, and...... monitoring of cancer progression and treatment response. Central to such studies is the ability to ensure at an early stage that the identified proteins are of clinical relevance by examining relevant specimens from larger cohorts of cancer patients....

  19. Cross-talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications.

    Science.gov (United States)

    Kundu, Somanath; Kumar, Sandeep; Bajaj, Avinash

    2015-07-01

    Increasing incidences of gastrointestinal (GI) cancer are linked to changes in lifestyle with excess of red meat/fat consumption, and elevated secretion of bile acids. Bile acids are strong signaling molecules that control various physiological processes. Failure in bile acid regulation has detrimental effects, often linked with development and promotion of cancer of digestive tract including esophagus, stomach, liver, and intestine. Excessive concentration of bile acids especially lipophillic secondary bile acids are cytotoxic causing apoptosis and reactive oxygen species-mediated damage to the cells. Resistance to this apoptosis and accumulation of mutations leads to progression of cancer. Cytotoxicity of bile acids is contingent on their chemical structure. In this review, we discuss the chemistry of bile acids, bile acid mediated cellular signaling processes, their role in GI cancer progression, and therapeutic potential of synthetic bile acid derivatives for cancer therapy. PMID:26177921

  20. Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study

    International Nuclear Information System (INIS)

    Cancer-related fatigue (CRF) is one of the most common and distressing side effects of cancer and its treatment. During and after radiotherapy breast cancer patients often suffer from CRF which frequently impairs quality of life (QoL). Despite the high prevalence of CRF in breast cancer patients and the severe impact on the physical and emotional well-being, effective treatment methods are scarce. Physical activity for breast cancer patients has been reported to decrease fatigue, to improve emotional well-being and to increase physical strength. The pathophysiological and molecular mechanisms of CRF and the molecular-biologic changes induced by exercise, however, are poorly understood. In the BEST trial we aim to assess the effects of resistance training on fatigue, QoL and physical fitness as well as on molecular, immunological and inflammatory changes in breast cancer patients during adjuvant radiotherapy. The BEST study is a prospective randomized, controlled intervention trial investigating the effects of a 12-week supervised progressive resistance training compared to a 12-week supervised muscle relaxation training in 160 patients with breast cancer undergoing adjuvant radiotherapy. To determine the effect of exercise itself beyond potential psychosocial group effects, patients in the control group perform a group-based progressive muscle relaxation training. Main inclusion criterion is histologically confirmed breast cancer stage I-III after lumpectomy or mastectomy with indication for adjuvant radiotherapy. Main exclusion criteria are acute infectious diseases, severe neurological, musculosceletal or cardiorespiratory disorders. The primary endpoint is cancer-related fatigue; secondary endpoints include immunological and inflammatory parameters analyzed in peripheral blood, saliva and urine. In addition, QoL, depression, physical performance and cognitive capacity will be assessed. The BEST study is the first randomized controlled trial comparing progressive

  1. The complex model of risk and progression of AMD estimation

    Directory of Open Access Journals (Sweden)

    V. S. Akopyan

    2012-01-01

    Full Text Available Purpose: to develop a method and a statistical model to estimate individual risk of AMD and the risk for progression to advanced AMD using clinical and genetic risk factors.Methods: A statistical risk assessment model was developed using stepwise binary logistic regression analysis. to estimate the population differences in the prevalence of allelic variants of genes and for the development of models adapted to the population of Moscow region genotyping and assessment of the influence of other risk factors was performed in two groups: patients with differ- ent stages of AMD (n = 74, and control group (n = 116. Genetic risk factors included in the study: polymorphisms in the complement system genes (C3 and CFH, genes at 10q26 locus (ARMS2 and HtRA1, polymorphism in the mitochondrial gene Mt-ND2. Clinical risk factors included in the study: age, gender, high body mass index, smoking history.Results: A comprehensive analysis of genetic and clinical risk factors for AMD in the study group was performed. Compiled statis- tical model assessment of individual risk of AMD, the sensitivity of the model — 66.7%, specificity — 78.5%, AUC = 0.76. Risk factors of late AMD, compiled a statistical model describing the probability of late AMD, the sensitivity of the model — 66.7%, specificity — 78.3%, AUC = 0.73. the developed system allows determining the most likely version of the current late AMD: dry or wet.Conclusion: the developed test system and the mathematical algorhythm for determining the risk of AMD, risk of progression to advanced AMD have fair diagnostic informative and promising for use in clinical practice.

  2. The complex model of risk and progression of AMD estimation

    Directory of Open Access Journals (Sweden)

    V. S. Akopyan

    2014-07-01

    Full Text Available Purpose: to develop a method and a statistical model to estimate individual risk of AMD and the risk for progression to advanced AMD using clinical and genetic risk factors.Methods: A statistical risk assessment model was developed using stepwise binary logistic regression analysis. to estimate the population differences in the prevalence of allelic variants of genes and for the development of models adapted to the population of Moscow region genotyping and assessment of the influence of other risk factors was performed in two groups: patients with differ- ent stages of AMD (n = 74, and control group (n = 116. Genetic risk factors included in the study: polymorphisms in the complement system genes (C3 and CFH, genes at 10q26 locus (ARMS2 and HtRA1, polymorphism in the mitochondrial gene Mt-ND2. Clinical risk factors included in the study: age, gender, high body mass index, smoking history.Results: A comprehensive analysis of genetic and clinical risk factors for AMD in the study group was performed. Compiled statis- tical model assessment of individual risk of AMD, the sensitivity of the model — 66.7%, specificity — 78.5%, AUC = 0.76. Risk factors of late AMD, compiled a statistical model describing the probability of late AMD, the sensitivity of the model — 66.7%, specificity — 78.3%, AUC = 0.73. the developed system allows determining the most likely version of the current late AMD: dry or wet.Conclusion: the developed test system and the mathematical algorhythm for determining the risk of AMD, risk of progression to advanced AMD have fair diagnostic informative and promising for use in clinical practice.

  3. A High-Fat Diet Containing Lard Accelerates Prostate Cancer Progression and Reduces Survival Rate in Mice: Possible Contribution of Adipose Tissue-Derived Cytokines

    Directory of Open Access Journals (Sweden)

    Han Jin Cho

    2015-04-01

    Full Text Available To examine the effects of high-fat diet (HFD containing lard on prostate cancer development and progression and its underlying mechanisms, transgenic adenocarcinoma mouse prostate (TRAMP and TRAMP-C2 allograft models, as well as in vitro culture models, were employed. In TRAMP mice, HFD feeding increased the incidence of poorly differentiated carcinoma and decreased that of prostatic intraepithelial neoplasia in the dorsolateral lobes of the prostate, which was accompanied by increased expression of proteins associated with proliferation and angiogenesis. HFD feeding also led to increased metastasis and decreased survival rate in TRAMP mice. In the allograft model, HFD increased solid tumor growth, the expression of proteins related to proliferation/angiogenesis, the number of lipid vacuoles in tumor tissues, and levels of several cytokines in serum and adipose tissue. In vitro results revealed that adipose tissue-conditioned media from HFD-fed mice stimulated the proliferation and migration of prostate cancer cells and angiogenesis compared to those from control-diet-fed mice. These results indicate that the increase of adipose tissue-derived soluble factors by HFD feeding plays a role in the growth and metastasis of prostate cancer via endocrine and paracrine mechanisms. These results provide evidence that a HFD containing lard increases prostate cancer development and progression, thereby reducing the survival rate.

  4. A new model of progressive pulmonary fibrosis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Last, J.A.; Gelzleichter, T.R.; Pinkerton, K.E.; Walker, R.M.; Witschi, H. (Univ. of California, Davis (United States))

    1993-08-01

    Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

  5. Opioid growth factor receptor (OGFR expression is downregulated with progression of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Beth Worley

    2015-12-01

    Full Text Available Purpose: Triple negative breast cancer (TNBC is an aggressive form of breast cancer that accounts for approximately 15% of the newly diagnosed cancers worldwide, and disproportionately affects younger women and women of color. Although many forms of breast cancer are successfully treated, new therapies are needed for TNBC. A novel regulatory system, the opioid growth factor (OGF – opioid growth factor receptor (OGFr axis, plays a determining role in neoplasia. OGF is an endogenous peptide that binds specifically to OGFr to inhibit cell replication. As some human cancers grow, OGFr expression is diminished, thus limiting the therapeutic efficacy of OGF. The OGF-OGFr axis is present in human TNBC cell line MDA-MB-231 and OGF  inhibits cell replication in a dosage-related, receptor-mediated manner. Methods: The present study investigated whether OGFr protein expression in human breast cancer cell lines grown in vitro or transplanted into nude mice, changed with the stage of proliferation or size of tumor using western blotting, semi-quantitative immunohistochemistry, and DNA synthesis techniques. Results: Comparison of log and confluent TNBC cultures revealed that OGF expression was significantly decreased in confluent cultures relative to levels in log-phase cells. Western blot analyses confirmed that OGFr was reduced in confluent TNBC and MCF-7 breast cancer cells in comparison to corresponding log-phase cells. Moreover, BrdU labeling was reduced in confluent cells. Small (<500 mm3 and large (>1000 mm3 TNBC tumors grown in nude mice were processed for semiquantitative   measurement of OGF and OGFr. The expression of both peptide and receptor in large tumors was downregulated relative to small tumors. Conclusion: The reduced expression of the inhibitory peptide and receptor diminishes the efficacy of the OGF-OGFr axis as a biotherapy. These data suggest that the OGF-OGFr pathway is altered with cancer progression and one or more elements of

  6. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    Science.gov (United States)

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  7. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    Science.gov (United States)

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  8. Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients.

    Science.gov (United States)

    Semenova, Ekaterina A; Kwon, Min-Chul; Monkhorst, Kim; Song, Ji-Ying; Bhaskaran, Rajith; Krijgsman, Oscar; Kuilman, Thomas; Peters, Dennis; Buikhuisen, Wieneke A; Smit, Egbert F; Pritchard, Colin; Cozijnsen, Miranda; van der Vliet, Jan; Zevenhoven, John; Lambooij, Jan-Paul; Proost, Natalie; van Montfort, Erwin; Velds, Arno; Huijbers, Ivo J; Berns, Anton

    2016-07-19

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting. PMID:27373156

  9. Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

    Directory of Open Access Journals (Sweden)

    Ekaterina A. Semenova

    2016-07-01

    Full Text Available Small cell lung cancer (SCLC is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

  10. Mitochondrial DNA content and mass increase in progression from normal to hyperplastic to cancer endometrium

    Directory of Open Access Journals (Sweden)

    Cormio Antonella

    2012-06-01

    Full Text Available Abstract Background An increase in mitochondrial DNA (mtDNA content and mitochondrial biogenesis associated with the activation of PGC-1α signalling pathway was previously reported in type I endometrial cancer. The aim of this study has been to evaluate if mtDNA content and the citrate synthase (CS activity, an enzyme marker of mitochondrial mass, increase in progression from control endometrium to hyperplasia to type I endometrial carcinoma. Results Given that no statistically significant change in mtDNA content and CS activity in endometrium taken from different phases of the menstrual cycle or in menopause was found, these samples were used as control. Our research shows, for the first time, that mtDNA content and citrate synthase activity increase in hyperplastic endometrium compared to control tissues, even if their levels remain lower compared to cancer tissue. In particular, mtDNA content increases seem to precede increases in CS activity. No statistically significant change in mtDNA content and in CS activity was found in relation to different histopathological conditions such as grade, myometrial invasion and stage. Conclusion MtDNA content and citrate synthase activity increases in pre-malignant lesions could be a potential molecular marker for progression from hyperplasia to carcinoma.

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

    Science.gov (United States)

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

    2016-06-01

    Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-β1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-β signaling pathway, such as mutations or loss of expression of TGF-β receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-β1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-β1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-β1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target. PMID:27010470

  12. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

    International Nuclear Information System (INIS)

    CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism

  13. Modeling pancreatic cancer with organoids

    NARCIS (Netherlands)

    Baker, Lindsey A; Tiriac, Hervé; Clevers, Hans; Tuveson, David A

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy for which new treatment and diagnostic approaches are urgently needed. In order for such breakthroughs to be discovered, researchers require systems that accurately model the development and biology of PDA. While cell lines, geneti

  14. Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR-200b.

    Science.gov (United States)

    Zhang, Shaorong; Zhang, Guanli; Liu, Jingying

    2016-08-01

    Long noncoding RNA PVT1 has been reported to be dysregulated and play vital roles in a variety of cancers. However, the functions and molecular mechanisms of PVT1 in cervical cancer remain unclear. The objective of this study was to investigate the expression, clinical significance, biological roles, and underlying functional mechanisms of PVT1 in cervical cancer. Our results revealed that PVT1 is upregulated in cervical cancer tissues. Enhanced expression of PVT1 is associated with larger tumor size, advanced International Federation of Gynecology and Obstetrics stage, and poor prognosis of cervical cancer patients. Using gain-of-function and loss-of-function approaches, we demonstrated that overexpression of PVT1 promotes cervical cancer cells proliferation, cell cycle progression and migration, and depletion of PVT1 inhibits cervical cancer cell proliferation, cell cycle progression, and migration. Mechanistically, we verified that PVT1 binds to EZH2, recruits EZH2 to the miR-200b promoter, increases histone H3K27 trimethylation level on the miR-200b promoter, and inhibits miR-200b expression. Furthermore, the effects of PVT1 on cervical cell proliferation and migration depend upon silencing of miR-200b. Taken together, our findings confirmed that PVT1 functions as an oncogene in cervical cancer and indicated that PVT1 is not only an important prognostic marker, but also a potential therapy target for cervical cancer. PMID:27272214

  15. FR901228 in Treating Patients With Refractory or Progressive Small Cell Lung Cancer or Non-small Cell Lung Cancer

    Science.gov (United States)

    2013-08-14

    Extensive Stage Small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer

  16. Establishment and identification of a rabbit model of peritoneal carcinomatosis from gastric cancer

    International Nuclear Information System (INIS)

    Gastric cancer peritoneal carcinomatosis is a common clinical problem, but there are no suitable large animal models to study this problem. This study was to establish a stable rabbit peritoneal carcinomatosis model of gastric cancer using VX2 tumor, and analyze the clinico-pathological features. VX2 tumor was implanted into 36 New Zealand rabbits by 3 methods: laparotomic orthotopic injection of cancer cells into the submucosal layer of the stomach (Group A), laparotomic implantation of tumor tissue into the greater omentum immediately beneath the gastric antrum (Group B), and percutaneous injection of tumor cells directly into the peritoneal cavity (Group C), 12 rabbits in each group. The animals were closely observed and detailed clinico-pathological studies were conducted. The success rates of peritoneal carcinomatosis formation were 100% (12/12), 91.7% (11/12) and 58.3% (7/12), respectively, for Groups A, B and C (P = 0.019, A versus C; P = 0.077, B versus C; P = 0.500, A versus B, Fisher's exact test). Two weeks after submucosal cancer cells injection in Group A, ulcerative gastric cancer with peritoneal carcinomatosis showed typical VX2 tumor pathology, with widespread intraperitoneal metastatic nodules, bloody ascites and perspicuous pulmonary metastases. The clinico-pathological progression pattern was very similar to patients of advanced gastric cancer with peritoneal carcinomatosis. Groups B and C showed similar pattern of cancer progression, but less aggressive. First large animal model of peritoneal carcinomatosis from gastric cancer has been established by laparotomic orthotopic injection of VX2 cancer cells into the submucosal layer of the stomach, providing a more suitable model for surgical interventional studies. The clinico-pathological features of this model resemble human peritoneal carcinomatosis

  17. EFFECTS OF MUTATION AND EXPRESSION OF PTEN GENE mRNA ON TUMORIGENESIS AND PROGRESSION OF EPITHELIAL OVARIAN CANCER

    Institute of Scientific and Technical Information of China (English)

    陈颖; 郑华川; 杨雪飞; 孙丽梅; 辛彦

    2004-01-01

    Objective To investigate the mutation and expression of tumor suppressor gene-PTEN mRNA and explore their roles in tumorigenesis and progression of ovarian cancer. Methods Mutated exon 5 of PTEN gene was examined in normal ovary (n = 5), ovarian cyst (n =5), ovarian borderline tumor (n=9), epithelial ovarian cancer (n=60), and ovarian cancer cell line (n= 1)by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). mRNA expression of PTEN gene was evaluated in corresponding tissues and cell line by reverse transcription polymerase chain reaction(RT-PCR). The mutation and mRNA expression of PTEN gene were compared with clinicopathological features of ovarian cancer. Results Mutated exon 5 of PTEN gene was detected only in 5 (7.1%) cases of epithelial ovarian cancer. mRNA expression level of PTEN gene in ovarian borderline tumor or ovarian cancer was lower than that in normal ovary or ovarian cyst (P < 0.05). The level of PTEN gene mRNA expression was negatively correlated with clinicopathological staging of ovarian cancer, whereas positively correlated with histological differentiation (P < 0.05). mRNA expression level of PTEN gene in ovarian endometrioid cancer was significantly lower than that in ovarian serous or mucinous cancer (P < 0.05). Conclusions Mutation of PTEN gene occurs in ovarian cancer. Down-regulated expression of PTEN is probably an important molecular event in tumorigenesis of ovarian cancer. Abnormal expression of PTEN gene is involved in progression of ovarian cancer. Reduced expression of PTEN gene is closely associated with tumorigenesis and pathobiological behaviors of ovarian endometrioid cancer.

  18. Progression-free survival as a potential surrogate for overall survival in metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Beauchemin C

    2014-06-01

    Full Text Available Catherine Beauchemin,1 Dan Cooper,2 Marie-Ève Lapierre,1 Louise Yelle,3 Jean Lachaine11Université de Montréal, Faculté de pharmacie, Montreal, 2Institut national d'excellence en santé et en services sociaux (INESSS, 3Centre Hospitalier de l'Université de Montréal – Hôpital Notre-Dame, Département de médecine, Université de Montréal, Montreal, QC, CanadaBackground: Progression-free survival (PFS and time to progression (TTP are frequently used to establish the clinical efficacy of anti-cancer drugs. However, the surrogacy of PFS/TTP for overall survival (OS remains a matter of uncertainty in metastatic breast cancer (mBC. This study assessed the relationship between PFS/TTP and OS in mBC using a trial-based approach.Methods: We conducted a systematic literature review according to the PICO method: 'Population' consisted of women with mBC; 'Interventions' and 'Comparators' were standard treatments for mBC or best supportive care; 'Outcomes' of interest were median PFS/TTP and OS. We first performed a correlation analysis between median PFS/TTP and OS, and then conducted subgroup analyses to explore possible reasons for heterogeneity. Then, we assessed the relationship between the treatment effect on PFS/TTP and OS. The treatment effect on PFS/TTP and OS was quantified by the absolute difference of median values. We also conducted linear regression analysis to predict the effects of a new anti-cancer drug on OS on the basis of its effects on PFS/TTP.Results: A total of 5,041 studies were identified, and 144 fulfilled the eligibility criteria. There was a statistically significant relationship between median PFS/TTP and OS across included trials (r=0.428; P<0.01. Correlation coefficient for the treatment effect on PFS/TTP and OS was estimated at 0.427 (P<0.01. The obtained linear regression equation was ΔOS =−0.088 (95% confidence interval [CI] −1.347–1.172 + 1.753 (95% CI 1.307–2.198 × ΔPFS (R2=0.86.Conclusion: Results of

  19. Models of breast cancer: quo vadis, animal modeling?

    International Nuclear Information System (INIS)

    Rodent models for breast cancer have for many decades provided unparalleled insights into cellular and molecular aspects of neoplastic transformation and tumorigenesis. Despite recent improvements in the fidelity of genetically engineered mice, rodent models are still being criticized by many colleagues for not being 'authentic' enough to the human disease. Motives for this criticism are manifold and range from a very general antipathy against the rodent model system to well-founded arguments that highlight physiological variations between species. Newly proposed differences in genetic pathways that cause cancer in humans and mice invigorated the ongoing discussion about the legitimacy of the murine system to model the human disease. The present commentary intends to stimulate a debate on this subject by providing the background about new developments in animal modeling, by disputing suggested limitations of genetically engineered mice, and by discussing improvements but also ambiguous expectations on the authenticity of xenograft models to faithfully mimic the human disease

  20. Progress of Platelet Derived Grow Factor Family in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yijun TIAN

    2014-01-01

    Full Text Available Non-small cell lung cancer (NSCLC is a malignant tumour with quite high cancer specific mortality, and it still lacks stable and reliable markers for NSCLC's prognosis. Platelet derived grow factor (PDGF and PDGFR has been considered to be involved in the process of cell proliferation, migration, metastasis and epithelial mesenchymal transition of cancer cell through various intracellular signal pathways. Pathology analysis showed that PDGF pathway mainly stimulates the proliferation of NSCLC tumour stroma through paracrine pattern, and some reaseach found that PDGF pathway directly promotes some NSCLC cell's proliferation. The expression of PDGF and PDGFR within NSCLC tissue correlates with status of lymphatic metastasis and patients’ prognosis. In clinical treatment of NSCLC, the great effect of PDGF pathway in angiogenesis and promoting distribution of chemotherapy by inhibition of PDGF should not be neglected. As an important pro-angiogenesis pathway, functions of PDGF in radiotherapy is dicovered by more and more fundamental research. This review focuses on the progress of PDGF pathway in NSCLC and aims to provide some new ideas for clinical and fundamental researchers.

  1. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

    International Nuclear Information System (INIS)

    Highlights: • SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). • Knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro. • Overexpression of SAMD9 suppressed proliferation and invasion in A549 cells in vitro. • Depletion of SAMD9 increases tumor formation in vivo. - Abstract: The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression

  2. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Qing; Yu, Tao; Ren, Yao-Yao; Gong, Ting; Zhong, Dian-Sheng, E-mail: zhongdsyx@126.com

    2014-11-07

    Highlights: • SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). • Knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro. • Overexpression of SAMD9 suppressed proliferation and invasion in A549 cells in vitro. • Depletion of SAMD9 increases tumor formation in vivo. - Abstract: The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression.

  3. Proinflammatory Cytokines in Prostate Cancer Development and Progression Promoted by High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Hua Xu

    2015-01-01

    Full Text Available Background. We aimed to examine whether proinflammatory cytokines participated in prostate cancer (PCa development and progression promoted by high-fat diet (HFD. Methods. TRAMP (transgenic adenocarcinoma mouse prostate mice were randomly divided into two groups: normal diet group and HFD group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24th, and 28th week, respectively. Levels of proinflammatory cytokines, including IL-1α, IL-1β, IL-6, and TNF-α, were tested by FlowCytomix. Prostate tissue of TRAMP mice was used for histology study. Results. A total of 13 deaths of TRAMP mice were observed, among which 3 (8.33% were from the normal diet group and 10 (27.78% from the HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P=0.032. Tumor formation rate at 20th week of age of HFD group was significantly higher than that of normal diet group (P=0.045. Proinflammatory cytokines levels, including IL-1α, IL-1β, IL-6, and TNF-α, were significantly higher in HFD TRAMP mice. Conclusions. HFD could promote TRAMP mouse PCa development and progression with elevated proinflammatory cytokines levels. Proinflammatory cytokines could contribute to PCa development and progression promoted by HFD.

  4. Vitamin D postpones the progression of epithelial ovarian cancer induced by 7, 12-dimethylbenz [a] anthracene both in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Liu LZ

    2016-04-01

    Full Text Available Lizhi Liu,1,* Zhiyong Hu,2,* Hemei Zhang,3 Yongfeng Hou,1 Zengli Zhang,4 Guangming Zhou,5 Bingyan Li1,5 1School of Public Health, Medical College of Soochow University, Suzhou, 2Department of Chronic Disease Management, Lishui Center for Disease Control and Prevention, Lishui, 3Department of Chronic Disease Management, Wenzhou Center for Disease Control and Prevention, Wenzhou, 4Department of Labor Hygiene and Environmental Health, School of Public Health, Soochow University, Suzhou, 5School of Radiation Medicine and Protection, Soochow University, Suzhou, People’s Republic of China *These authors contributed equally to this work Purpose: Ovarian cancer is the most lethal malignancy of the female reproductive system, and the prevention and treatment of ovarian carcinoma are still far from optimal. Epidemiological studies reported that ovarian cancer risk was inversely associated with low level of 25-hydroxy vitamin D [25(OH]. Therefore, this study focuses on exploring the chemoprevention of vitamin D on epithelial ovarian cancer induced by 7, 12-dimethylbenz [a] anthracene (DMBA.Methods: The mouse ovarian surface epithelial cells were isolated from estrus mice by mild trypsinization and maintained in completed culture medium by repeated passaging. The malignant transformation of mouse ovarian surface epithelial cells was induced by DMBA in vitro. DMBA was directly injected into the bursa of mouse ovary to produce optimized in vivo ovarian cancer model.Results: The results indicate that 1α,25 dihydroxyvitamin D3 may delay malignant transformation of mouse ovarian surface epithelial cells induced by DMBA and significantly decreased the colony formation rate from 18.4% to 3.2% (P<0.05. There was a negative correlation between incidence of DMBA-induced tumor and 25-hydroxy vitamin D level (R2=0.978, P<0.05. Vitamin D3 can delay the progression of ovarian cancer induced by DMBA, and the administration of vitamin D3 during the whole process worked

  5. James P. Allison received the 2014 Szent-Györgi Prize for Progress in Cancer Research

    Institute of Scientific and Technical Information of China (English)

    Jie Zhao,Peter Scully; Sujuan Ba

    2014-01-01

    The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)-a leading cancer research charitable organization in the United States that is committed to supporting innovative cancer research on the global scale that aims to cure cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher whose original discoveries have expanded our understanding of cancer and resulted in notable advances in cancer prevention, diagnosis, or treatment. The prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the history and mission of the Szent-Györgyi Prize, its role in promoting discovery-oriented cancer research, and the pioneering work led by the 2014 prize winner, Dr. James Alison. Dr. Alison’s work in the area of cancer immunotherapy led to the successful development of immune checkpoint therapy, and the first drug approved by the United States Food and Drug Administration for the treatment of metastatic melanoma.

  6. Frederick W. Alt received the 2015 Szent-Györgi Prize for Progress in Cancer Research.

    Science.gov (United States)

    Scully, Peter; Zhao, Jie; Ba, Sujuan

    2016-01-01

    The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)-a leading cancer research charitable organization in the United States that is committed to supporting scientific research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, significant research to the fight against cancer, and whose accomplishments have helped improve treatment options for cancer patients. The Prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the pioneering work led by the 2015 Prize winner, Dr. Frederick Alt. Dr. Alt's work in the area of cancer genetics over four decades has helped to shape the very roots of modern cancer research. His work continues to profoundly impact the approaches that doctors around the globe use to diagnose and treat cancer. In particular, his seminal discoveries of gene amplification and his pioneering work on molecular mechanisms of DNA damage repair have helped to usher in the era of genetically targeted therapy and personalized medicine. PMID:26843073

  7. Frederick W. Alt received the 2015 Szent-Györgi Prize forProgress inCancer Research

    Institute of Scientific and Technical Information of China (English)

    PeterScully; JieZhao; SujuanBa

    2016-01-01

    The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientiifc award established by the National Foundation for Cancer Research (NFCR)—a leading cancer research charitable organization in the United States that is committed to supporting scientiifc research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, signiifcant research to the ifght against cancer, and whose accomplishments have helped improve treatment options for cancer patients. The Prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the pio-neering work led by the 2015 Prize winner, Dr. Frederick Alt. Dr. Alt’s work in the area of cancer genetics over four decades has helped to shape the very roots of modern cancer research. His work continues to profoundly impact the approaches that doctors around the globe use to diagnose and treat cancer. In particular, his seminal discoveries of gene ampliifcation and his pioneering work on molecular mechanisms of DNA damage repair have helped to usher in the era of genetically targeted therapy and personalized medicine.

  8. The effect of progressive resistance training on lean body mass in post-treatment cancer patients - A systematic review

    DEFF Research Database (Denmark)

    Lønbro, Simon

    2014-01-01

    Loss of lean body mass is a common problem in many post-treatment cancer patients and may negatively affect physical capacity in terms of maximal muscle strength and functional performance. The purpose of this study was to systematically review the scientific evidence on the effect of progressive...... resistance training on lean body mass in post-treatment cancer patients. A comprehensive literature search was conducted and ultimately 12 studies were included. Methodological quality of the included studies was evaluated using the PEDro scale and the effect of progressive resistance training was reported...... 12 heterogenic studies there is moderate evidence supporting a positive effect of progressive resistance training on lean body mass in post-treatment cancer patients....

  9. Alzheimer's disease: a mathematical model for onset and progression

    CERN Document Server

    Bertsch, Michiel; Marcello, Norina; Tesi, Maria Carla; Tosin, Andrea

    2015-01-01

    In this paper we propose a mathematical model for the onset and progression of Alzheimer's disease based on transport and diffusion equations. We regard brain neurons as a continuous medium, and structure them by their degree of malfunctioning. Two different mechanisms are assumed to be relevant for the temporal evolution of the disease: i) diffusion and agglomeration of soluble polymers of amyloid, produced by damaged neurons; ii) neuron-to-neuron prion-like transmission. We model these two processes by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of the degree of malfunctioning of neurons. The second equation contains an integral term describing the random onset of the disease as a jump process localized in particularly sensitive areas of the brain. Even though we deliberately neglect many aspects of the complexity of the brain and the disease, numerical simulations are in good qualitative agreement with clinical...

  10. Loss of p53 attenuates the contribution of IL-6 deletion on suppressed tumor progression and extended survival in Kras-driven murine lung cancer.

    Directory of Open Access Journals (Sweden)

    Xiaohong Tan

    Full Text Available Interleukin-6 (IL-6 is involved in lung cancer tumorigenesis, tumor progression, metastasis, and drug resistance. Previous studies show that blockade of IL-6 signaling can inhibit tumor growth and increase drug sensitivity in mouse models. Clinical trials in non-small cell lung cancer (NSCLC reveal that IL-6 targeted therapy relieves NSCLC-related anemia and cachexia, although other clinical effects require further study. We crossed IL-6(-/- mice with Kras(G12D mutant mice, which develop lung tumors after activation of mutant Kras(G12D, to investigate whether IL-6 inhibition contributes to tumor progression and survival time in vivo. Kras(G12D; IL-6(-/- mice exhibited increased tumorigenesis, but slower tumor growth and longer survival, than Kras(G12D mice. Further, in order to investigate whether IL-6 deletion contributes to suppression of lung cancer metastasis, we generated Kras(G12D; p53(flox/flox; IL-6(-/- mice, which developed lung cancer with a trend for reduced metastases and longer survival than Kras(G12D; p53(flox/flox mice. Tumors from Kras(G12D; IL-6(-/- mice showed increased expression of TNFα and decreased expression of CCL-19, CCL-20 and phosphorylated STAT3(pSTAT3 than Kras(G12D mice; however, these changes were not present between tumors from Kras(G12D; p53(flox/flox; IL-6(-/- and Kras(G12D; p53(flox/flox mice. Upregulation of pSTAT3 and phosphorylated AKT(pAKT were observed in Kras(G12D tumors with p53 deletion. Taken together, these results indicate that IL-6 deletion accelerates tumorigenesis but delays tumor progression and prolongs survival time in a Kras-driven mouse model of lung cancer. However, these effects can be attenuated by p53 deletion.

  11. Modeling Diverse Pathways to Age Progressive Volcanism in Subduction Zones.

    Science.gov (United States)

    Kincaid, C. R.; Szwaja, S.; Sylvia, R. T.; Druken, K. A.

    2015-12-01

    One of the best, and most challenging clues to unraveling mantle circulation patterns in subduction zones comes in the form of age progressive volcanic and geochemical trends. Hard fought geological data from many subduction zones, like Tonga-Lau, the Cascades and Costa-Rica/Nicaragua, reveal striking temporal patterns used in defining mantle flow directions and rates. We summarize results from laboratory subduction models showing a range in circulation and thermal-chemical transport processes. These interaction styles are capable of producing such trends, often reflecting apparent instead of actual mantle velocities. Lab experiments use a glucose working fluid to represent Earth's upper mantle and kinematically driven plates to produce a range in slab sinking and related wedge transport patterns. Kinematic forcing assumes most of the super-adiabatic temperature gradient available to drive major downwellings is in the tabular slabs. Moreover, sinking styles for fully dynamic subduction depend on many complicating factors that are only poorly understood and which can vary widely even for repeated parameter combinations. Kinematic models have the benefit of precise, repeatable control of slab motions and wedge flow responses. Results generated with these techniques show the evolution of near-surface thermal-chemical-rheological heterogeneities leads to age progressive surface expressions in a variety of ways. One set of experiments shows that rollback and back-arc extension combine to produce distinct modes of linear, age progressive melt delivery to the surface through a) erosion of the rheological boundary layer beneath the overriding plate, and deformation and redistribution of both b) mantle residuum produced from decompression melting and c) formerly active, buoyant plumes. Additional experiments consider buoyant diapirs rising in a wedge under the influence of rollback, back-arc spreading and slab-gaps. Strongly deflected diapirs, experiencing variable rise

  12. Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

    Science.gov (United States)

    King, Claire M; Barbara, Cynthia; Prentice, Andrew; Brenton, James D; Charnock-Jones, D Stephen

    2016-01-01

    Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain--frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA. PMID:26456077

  13. MicroRNA-187-5p suppresses cancer cell progression in non-small cell lung cancer (NSCLC) through down-regulation of CYP1B1.

    Science.gov (United States)

    Mao, Ming; Wu, Zhouqing; Chen, Jiakuan

    2016-09-16

    Lung cancer remains a leading cause of cancer-associated mortality worldwide and non-small lung cancer (NSCLC) is responsible for over 80% of lung cancer-related deaths. Identifying novel molecular biomarker that can inhibit the progression of lung cancer will facilitate the development of new treatment strategies. Herein, we demonstrated that miR-187-5p is a tumor-suppressor miRNA in NSCLC progression. We found that expression of miR-187-5p was decreased obviously in NSCLC tissues. Down-regulation of miR-187-5p was associated with TNM stage and postoperative survival. Overexpression of miR-187-5p inhibited the growth and metastasis of NSCLC cells. The CYP1B1 was a direct target of miR-187-5p and promoted the growth and metastasis of NSCLC cells. Further study showed that CYP1B1 could reverse the inhibitory effect of miR-187-5p on growth and metastasis of NSCLC cells. Taken together, our data highlight the pivotal role of miR-187-5p in the progression of NSCLC. Thus, miR-187-5p may be a potential prognostic marker and of treatment relevance for NSCLC progression intervention. PMID:27495872

  14. Changes in autofluorescence based organoid model of muscle invasive urinary bladder cancer.

    Science.gov (United States)

    Palmer, Scott; Litvinova, Karina; Dunaev, Andrey; Fleming, Stewart; McGloin, David; Nabi, Ghulam

    2016-04-01

    Muscle invasive urinary bladder cancer is one of the most lethal cancers and its detection at the time of transurethral resection remains limited and diagnostic methods are urgently needed. We have developed a muscle invasive transitional cell carcinoma (TCC) model of the bladder using porcine bladder scaffold and the human bladder cancer cell line 5637. The progression of implanted cancer cells to muscle invasion can be monitored by measuring changes in the spectrum of endogenous fluorophores such as reduced nicotinamide dinucleotide (NADH) and flavins. We believe this could act as a useful tool for the study of fluorescence dynamics of developing muscle invasive bladder cancer in patients. Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI. PMID:27446646

  15. The global state of palliative care-progress and challenges in cancer care.

    Science.gov (United States)

    Reville, Barbara; Foxwell, Anessa M

    2014-07-01

    All persons have a right to palliative care during cancer treatment and at the end-of-life. The World Health Organization (WHO) defines palliative care as a medical specialty that addresses physical, psychological, social, legal, and spiritual domains of care by an interdisciplinary team of professional and lay health care providers. Widespread adoption of this universal definition will aid policy development and educational initiatives on a national level. The need for palliative care is expanding due to the aging of the world's population and the increase in the rate of cancer in both developed and developing countries. However, in one third of the world there is no access to palliative care for persons with serious or terminal illness. Palliative care improves symptoms, most frequently pain, and improves quality of life for patients and their families, especially in the terminal disease phase. Accessibility to palliative care services, adequately trained health care professionals, availability of essential medicines, and gaps in education vary greatly throughout the world. Pain management is an integral concept in the practice of palliative care; however, opioiphobia, insufficient supply of opioids, and regulatory restrictions contribute to undue suffering for millions. Ongoing advocacy efforts call for increased awareness, palliative care integration with cancer care, and public and professional education. Enacting necessary change will require the engagement of health ministries and the recognition of the unique needs and resources of each country. The aim of this review is to examine progress in palliative care development and explore some of the barriers influencing cancer care across the globe. PMID:25841689

  16. Net Platelet Angiogenic Activity (NPAA) Correlates with Progression and Prognosis of Non-Small Cell Lung Cancer

    OpenAIRE

    Lijuan Yao; Hang Dong; Yiqin Luo; Jianping Du; Wen Hu

    2014-01-01

    Circulating platelets are abundant sources of angiogensis molecules for the tumor vasculature affecting tumor growth and metastasis. The relationship between non-small cell lung cancer (NSCLC) and intra-platelet levels of VEGF, TSP-1 and net platelet angiogenic activity (NPAA) is unclear. The aim of this study was to better understand the role of these factors in the progression of NSCLC cancer and to assess its clinical significance. Platelet VEGF and TSP-1 and NPAA were measured preoperativ...

  17. A stochastic model for immunotherapy of cancer.

    Science.gov (United States)

    Baar, Martina; Coquille, Loren; Mayer, Hannah; Hölzel, Michael; Rogava, Meri; Tüting, Thomas; Bovier, Anton

    2016-01-01

    We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different actors, T-cells, cytokines or cancer cells, are modelled as single particles (individuals) in the stochastic system. The main expansions of the model are distinguishing cancer cells by phenotype and genotype, including environment-dependent phenotypic plasticity that does not affect the genotype, taking into account the effects of therapy and introducing a competition term which lowers the reproduction rate of an individual in addition to the usual term that increases its death rate. We illustrate the new setup by using it to model various phenomena arising in immunotherapy. Our aim is twofold: on the one hand, we show that the interplay of genetic mutations and phenotypic switches on different timescales as well as the occurrence of metastability phenomena raise new mathematical challenges. On the other hand, we argue why understanding purely stochastic events (which cannot be obtained with deterministic models) may help to understand the resistance of tumours to therapeutic approaches and may have non-trivial consequences on tumour treatment protocols. This is supported through numerical simulations. PMID:27063839

  18. Breast Cancer Risk Assessment SAS Macro (Gail Model)

    Science.gov (United States)

    A SAS macro (commonly referred to as the Gail Model) that projects absolute risk of invasive breast cancer according to NCI’s Breast Cancer Risk Assessment Tool (BCRAT) algorithm for specified race/ethnic groups and age intervals.

  19. Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression

    International Nuclear Information System (INIS)

    Genomic and transcriptomic alterations affecting key cellular processes such us cell proliferation, differentiation and genomic stability are considered crucial for the development and progression of cancer. Most invasive breast carcinomas are known to derive from precursor in situ lesions. It is proposed that major global expression abnormalities occur in the transition from normal to premalignant stages and further progression to invasive stages. Serial analysis of gene expression (SAGE) was employed to generate a comprehensive global gene expression profile of the major changes occurring during breast cancer malignant evolution. In the present study we combined various normal and tumor SAGE libraries available in the public domain with sets of breast cancer SAGE libraries recently generated and sequenced in our laboratory. A recently developed modified t test was used to detect the genes differentially expressed. We accumulated a total of approximately 1.7 million breast tissue-specific SAGE tags and monitored the behavior of more than 25,157 genes during early breast carcinogenesis. We detected 52 transcripts commonly deregulated across the board when comparing normal tissue with ductal carcinoma in situ, and 149 transcripts when comparing ductal carcinoma in situ with invasive ductal carcinoma (P < 0.01). A major novelty of our study was the use of a statistical method that correctly accounts for the intra-SAGE and inter-SAGE library sources of variation. The most useful result of applying this modified t statistics beta binomial test is the identification of genes and gene families commonly deregulated across samples within each specific stage in the transition from normal to preinvasive and invasive stages of breast cancer development. Most of the gene expression abnormalities detected at the in situ stage were related to specific genes in charge of regulating the proper homeostasis between cell death and cell proliferation. The comparison of in situ lesions

  20. Prediction Model for Gastric Cancer Incidence in Korean Population

    OpenAIRE

    Eom, Bang Wool; Joo, Jungnam; Kim, Sohee; Shin, Aesun; Yang, Hye-Ryung; Park, Junghyun; Choi, Il Ju; Kim, Young-Woo; Kim, Jeongseon; Nam, Byung-Ho

    2015-01-01

    Background Predicting high risk groups for gastric cancer and motivating these groups to receive regular checkups is required for the early detection of gastric cancer. The aim of this study is was to develop a prediction model for gastric cancer incidence based on a large population-based cohort in Korea. Method Based on the National Health Insurance Corporation data, we analyzed 10 major risk factors for gastric cancer. The Cox proportional hazards model was used to develop gender specific ...