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Sample records for cancer progression model

  1. Cancer progression modeling using static sample data.

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    Sun, Yijun; Yao, Jin; Nowak, Norma J; Goodison, Steve

    2014-01-01

    As molecular profiling data continues to accumulate, the design of integrative computational analyses that can provide insights into the dynamic aspects of cancer progression becomes feasible. Here, we present a novel computational method for the construction of cancer progression models based on the analysis of static tumor samples. We demonstrate the reliability of the method with simulated data, and describe the application to breast cancer data. Our findings support a linear, branching model for breast cancer progression. An interactive model facilitates the identification of key molecular events in the advance of disease to malignancy.

  2. Inferring tree causal models of cancer progression with probability raising.

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    Loes Olde Loohuis

    Full Text Available Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models.

  3. Progress against Prostate Cancer

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    ... 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 ...

  4. A stochastic model for identifying differential gene pair co-expression patterns in prostate cancer progression

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    Mao Yu

    2009-07-01

    Full Text Available Abstract Background The identification of gene differential co-expression patterns between cancer stages is a newly developing method to reveal the underlying molecular mechanisms of carcinogenesis. Most researches of this subject lack an algorithm useful for performing a statistical significance assessment involving cancer progression. Lacking this specific algorithm is apparently absent in identifying precise gene pairs correlating to cancer progression. Results In this investigation we studied gene pair co-expression change by using a stochastic process model for approximating the underlying dynamic procedure of the co-expression change during cancer progression. Also, we presented a novel analytical method named 'Stochastic process model for Identifying differentially co-expressed Gene pair' (SIG method. This method has been applied to two well known prostate cancer data sets: hormone sensitive versus hormone resistant, and healthy versus cancerous. From these data sets, 428,582 gene pairs and 303,992 gene pairs were identified respectively. Afterwards, we used two different current statistical methods to the same data sets, which were developed to identify gene pair differential co-expression and did not consider cancer progression in algorithm. We then compared these results from three different perspectives: progression analysis, gene pair identification effectiveness analysis, and pathway enrichment analysis. Statistical methods were used to quantify the quality and performance of these different perspectives. They included: Re-identification Scale (RS and Progression Score (PS in progression analysis, True Positive Rate (TPR in gene pair analysis, and Pathway Enrichment Score (PES in pathway analysis. Our results show small values of RS and large values of PS, TPR, and PES; thus, suggesting that gene pairs identified by the SIG method are highly correlated with cancer progression, and highly enriched in disease-specific pathways. From

  5. Multi-state relative survival modelling of colorectal cancer progression and mortality.

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    Gilard-Pioc, Séverine; Abrahamowicz, Michal; Mahboubi, Amel; Bouvier, Anne-Marie; Dejardin, Olivier; Huszti, Ella; Binquet, Christine; Quantin, Catherine

    2015-06-01

    Accurate identification of factors associated with progression of colorectal cancer remains a challenge. In particular, it is unclear which statistical methods are most suitable to separate the effects of putative prognostic factors on cancer progression vs cancer-specific and other cause mortality. To address these challenges, we analyzed 10 year follow-up data for patients who underwent curative surgery for colorectal cancer in 1985-2000. Separate analyses were performed in two French cancer registries. Results of three multivariable models were compared: Cox model with recurrence as a time-dependent variable, and two multi-state models, which separated prognostic factor effects on recurrence vs death, with or without recurrence. Conventional multi-state model analyzed all-cause mortality while new relative survival multi-state model focused on cancer-specific mortality. Among the 2517 and 2677 patients in the two registries, about 50% died without a recurrence, and 28% had a recurrence, of whom almost 90% died. In both multi-state models men had significantly increased risk of cancer recurrence in both registries (HR=0.79; 95% CI: 0.68-0.92 and HR=0.83; 95% CI: 0.71-0.96). However, the two multi-state models identified different prognostic factors for mortality without recurrence. In contrast to the conventional model, in the relative survival analyses gender had no independent association with cancer-specific mortality whereas patients diagnosed with stage III cancer had significantly higher risks in both registries (HR=1.67; 95% CI: 1.27-2.22 and HR=2.38; 95% CI: 1.29-3.27). In conclusion, relative survival multi-state model revealed that different factors may be associated with cancer recurrence vs cancer-specific mortality either after or without a recurrence.

  6. Multiscale Modelling of Cancer Progression and Treatment Control: The Role of Intracellular Heterogeneities in Chemotherapy Treatment

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    Chaplain, Mark A. J.; Powathil, Gibin G.

    Cancer is a complex, multiscale process involving interactions at intracellular, intercellular and tissue scales that are in turn susceptible to microenvironmental changes. Each individual cancer cell within a cancer cell mass is unique, with its own internal cellular pathways and biochemical interactions. These interactions contribute to the functional changes at the cellular and tissue scale, creating a heterogenous cancer cell population. Anticancer drugs are effective in controlling cancer growth by inflicting damage to various target molecules and thereby triggering multiple cellular and intracellular pathways, leading to cell death or cell-cycle arrest. One of the major impediments in the chemotherapy treatment of cancer is drug resistance driven by multiple mechanisms, including multi-drug and cell-cycle mediated resistance to chemotherapy drugs. In this article, we discuss two hybrid multiscale modelling approaches, incorporating multiple interactions involved in the sub-cellular, cellular and microenvironmental levels to study the effects of cell-cycle, phase-specific chemotherapy on the growth and progression of cancer cells.

  7. 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.

  8. Progress towards understanding heterotypic interactions in multi-culture models of breast cancer.

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    Regier, Mary C; Alarid, Elaine T; Beebe, David J

    2016-06-13

    Microenvironments in primary tumors and metastases include multiple cell types whose dynamic and reciprocal interactions are central to progression of the disease. However, the literature involving breast cancer studied in vitro is dominated by cancer cells in mono-culture or co-cultured with one other cell type. For in vitro studies of breast cancer the inclusion of multiple cell types has led to models that are more representative of in vivo behaviors and functions as compared to more traditional monoculture. Here, we review foundational co-culture techniques and their adaptation to multi-culture (including three or more cell types). Additionally, while macroscale methods involving conditioned media, direct contact, and indirect interactions have been informative, we examined many advances that have been made more recently using microscale systems with increased control over cellular and structural complexity. Throughout this discussion we consider the benefits and limitations of current multi-culture methods and the significant results they have produced.

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

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    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

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

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    Chiara Arrigoni

    2016-08-01

    Full Text Available 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.

  11. 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

  12. 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.

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

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    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...

  14. A Bayesian model for censored positive count data in evaluating breast cancer progression.

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    Yeh, Hung-Wen; Jiang, Yu; Garrard, Lili; Lei, Yang; Gajewski, Byron

    2013-01-01

    Basic science researchers transplant human cancer tissues from patients with ductal carcinoma in situ (DCIS) to animals and observe the progression of the disease. Successful transplants show invasion of human tissues across mammary ducts in animal fat pads and cause DCIS-like lesions in one or more ducts. In this work, we consider data from a recent publication of breast cancer research where positive counts of affected ducts may be subject to censoring. We fit the data with zero-truncated Poisson (ZTP) models with an informative prior of gamma. Due to the zero-truncation and right censoring, posterior distributions may not be conventional gamma and are estimated through Markov chain Monte Carlo and grid approximation. For each of the two cell lines, we fit a model with group-specific parameters for DCIS subtypes classified by the cell surface biomarkers, and another model with a homogeneous parameter across groups. Models are compared by the Deviance Information Criterion (DIC). For the chosen prior parameter values, Bayes estimates are comparative to the maximum likelihood estimates, and the DIC favors the simpler model in both cell lines. PMID:23997758

  15. 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...

  16. 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...

  17. Preventing Breast Cancer: Making Progress

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    Skip Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... inhibitor, can do an even better job of preventing breast cancer than the SERMs. Aromatase inhibitors stop an enzyme ...

  18. Targeting ECM Disrupts Cancer Progression

    DEFF Research Database (Denmark)

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

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the ex...... is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.......Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep 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 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...

  19. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions.

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    Pradeep, C-R; Zeisel, A; Köstler, W J; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

    2012-08-01

    The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.

  20. A growth model for primary cancer (II). New rules, progress curves and morphology transitions

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    Jr, S. C. Ferreira; Martins, M. L.; Vilela, M. J.

    1999-10-01

    In the present paper we extend the analysis of another model recently proposed to simulate the growth of carcinoma “in situ”, which includes cell proliferation, motility and death, as well as chemotactic interactions among cells. The tumour patterns generated by two distinct growth rules are characterised by its gyration radius, surface roughness, total number of cancer cells, and number of cells on tumour periphery. Our results indicate that very distinct morphological patterns follow Gompertz growth curves and their gyration radii increase linearly in time and scale, in the asymptotic limit, as a square root of the total number of tumour cells. In contrast, these distinct tumour patterns exhibit different scaling laws for their surfaces. Thus, some biological features of malignant behaviour seem to influence particularly the structure of the tumour border, while its gyration radius and progress curve are described by more robust functions. Finally, for both rules used, morphology transitions as well as a transient behaviour up to the onset of the phase of rapid growth in the Gompertz curves are observed.

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

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    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.

  2. 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.

  3. Ovine pulmonary adenocarcinoma as an animal model of progressive lung cancer and the impact of nutritional selenium supply.

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    Humann-Ziehank, Esther; Wolf, Petra; Renko, Kostja; Schomburg, Lutz; Ludwig Bruegmann, Michael; Andreae, Arnim; Brauer, Carsten; Ganter, Martin

    2011-01-01

    Jaagsiekte sheep retrovirus (JSRV) is known to induce ovine pulmonary adenocarcinoma (OPA). Several studies have suggested an influence of selenium (Se) status on cancer progression. Thus, combining OPA with a defined Se supply might serve as a suitable animal model to study the impact of Se on lung cancer progression. 16 naturally JSRV-infected sheep were divided into 2 treatment groups receiving (a) CT) was performed repeatedly and evaluated using a CT-OPA-score system. Liver biopsies were taken three-monthly, blood samples were collected biweekly to study treatment effects on Se concentrations and glutathione peroxidase (GPx) activity. Cell pellets from bronchoalveolar lavage fluid (BALF) were tested for JSRV by PCR to approve the infection. To date, four animals of the ongoing study have been euthanised. Autopsy and histopathology were performed and correlated to CT analysis. JSRV was detected in BALF cell pellets. Progression of lung tumours was monitored successfully by repeated CT examinations, enabling the detection of even small nodules or increased lung density. Histopathology revealed bronchioloalveolar adenocarcinoma in lung areas suspicious to be OPA from CT evaluation. Score-based analysis of CT images for quantifying tumour progression proved as a valuable tool. Se concentration and GPx activity increased in liver and serum of group b and verified the efficiency of different feeding regime. In conclusion, OPA along with CT, autopsy/histopathology, trace element and enzyme activity analysis provide a suitable large animal model to examine the impact of Se supply on lung tumourigenesis.

  4. Gabapentin, an Analgesic Used Against Cancer-Associated Neuropathic Pain: Effects on Prostate Cancer Progression in an In Vivo Rat Model.

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    Bugan, Ilknur; Karagoz, Zeynep; Altun, Seyhan; Djamgoz, Mustafa B A

    2016-03-01

    A major problem associated with clinical management of cancer is controlling the accompanying pain, and various analgesics are in common use for this purpose. Recent evidence suggests that some of the targets of analgesics, such as ion channels and receptors, may also be involved in the cancer process, thereby raising the possibility that such use of some analgesics may impact upon cancer itself. The main aim of this study was to determine whether gabapentin, a common adjuvant analgesic in current use against cancer-associated neuropathic pain, would affect tumour development and progression in vivo. The Dunning rat model of prostate cancer was used. Strongly metastatic Mat-LyLu cells were implanted subcutaneously into syngeneic Copenhagen rats which were then treated every other day with 4.6-16.8 μg/kg gabapentin by gavage. Primary tumourigenesis was monitored daily. Lung metastases were counted and measured after killing the rats 21 days later. Gabapentin had no effect on primary tumourigenesis but produced dose-dependent effects on lung metastasis. Whilst 4.6 μg/kg had no effect, 9.1 μg/kg gabapentin decreased the number of lung metastases significantly by 64%. In contrast, 16.8 μg/kg gabapentin promoted metastasis significantly by 112% and showed a strong tendency to shorten mean survival time. It is concluded that gabapentin prescribed to cancer patients against pain could impact upon the cancer process itself.

  5. Joint modelling of longitudinal and multi-state processes: application to clinical progressions in prostate cancer.

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    Ferrer, Loïc; Rondeau, Virginie; Dignam, James; Pickles, Tom; Jacqmin-Gadda, Hélène; Proust-Lima, Cécile

    2016-09-30

    Joint modelling of longitudinal and survival data is increasingly used in clinical trials on cancer. In prostate cancer for example, these models permit to account for the link between longitudinal measures of prostate-specific antigen (PSA) and time of clinical recurrence when studying the risk of relapse. In practice, multiple types of relapse may occur successively. Distinguishing these transitions between health states would allow to evaluate, for example, how PSA trajectory and classical covariates impact the risk of dying after a distant recurrence post-radiotherapy, or to predict the risk of one specific type of clinical recurrence post-radiotherapy, from the PSA history. In this context, we present a joint model for a longitudinal process and a multi-state process, which is divided into two sub-models: a linear mixed sub-model for longitudinal data and a multi-state sub-model with proportional hazards for transition times, both linked by a function of shared random effects. Parameters of this joint multi-state model are estimated within the maximum likelihood framework using an EM algorithm coupled with a quasi-Newton algorithm in case of slow convergence. It is implemented under R, by combining and extending mstate and JM packages. The estimation program is validated by simulations and applied on pooled data from two cohorts of men with localized prostate cancer. Thanks to the classical covariates available at baseline and the repeated PSA measurements, we are able to assess the biomarker's trajectory, define the risks of transitions between health states and quantify the impact of the PSA dynamics on each transition intensity. Copyright © 2016 John Wiley & Sons, Ltd.

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

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    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.

  7. 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.

  8. 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

  9. 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...

  10. 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.

  11. 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 ...

  12. Modeling of hypo/hyperglycemia and their impact on breast cancer progression related molecules.

    Directory of Open Access Journals (Sweden)

    Sirin A I Adham

    Full Text Available Breast cancer (BC arises commonly in women with metabolic dysfunction. The underlying mechanism by which glycemic load can exert its action on tumor metastasis is under investigated. In this study we showed that glycemic microenvironment alters the expression of three classes of proteins, VEGF and its receptors, cell to cell, and cell to extracellular matrix (ECM adhesion proteins in MDA-MB-231 parental cells and its two metastatic variants to the bone and brain (MDA-MB-231BO and MDA-MB-231BR, respectively. Using western blotting, we showed that VEGFR2 levels were higher in these variant cells and persisted in the cells under extreme hypoglycemia. Hypoglycemia did not alter VEGFR2 expression per se but rather suppressed its posttranslational glycosylation. This was reversed rapidly upon the restoration of glucose, and cyclohexamide (CHX treatment demonstrated that this deglycosylated VEGFR2 was not a product of de-novo protein synthesis. VEGFR2 co-receptor Neuropilin-1 was up-regulated four-fold in all MDA-MB-231 cells (parental and two variants compared to VEGFR2 expression, and was also susceptible to glycemic changes but resistant to CHX treatment for up to 72 hrs. Hypoglycemia also resulted in a significant decrease in specific catenin, cadherin, and integrin proteins, as well as cellular proliferation and colony forming ability. However, MDA-MB-231BR cells showed a unique sensitivity to hypo/hyperglycemia in terms of morphological changes, colony formation ability, integrin β3 expression and secreted VEGF levels. In conclusion, this study can be translated clinically to provide insight into breast cancer cell responses to glycemic levels relevant for our understanding of the interaction between diabetes and cancer.

  13. 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

  14. Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression

    Science.gov (United States)

    Saeed, Muhammad Tariq; Holowatyj, Andreana N.; Sheikh, Iftikhar A.; Zafar Paracha, Rehan; Shafi, Aamir; Siddiqa, Amnah; Bibi, Zurah; Khan, Mukaram

    2016-01-01

    The alteration of glucose metabolism, through increased uptake of glucose and glutamine addiction, is essential to cancer cell growth and invasion. Increased flux of glucose through the Hexosamine Biosynthetic Pathway (HBP) drives increased cellular O-GlcNAcylation (hyper-O-GlcNAcylation) and contributes to cancer progression by regulating key oncogenes. However, the association between hyper-O-GlcNAcylation and activation of these oncogenes remains poorly characterized. Here, we implement a qualitative modeling framework to analyze the role of the Biological Regulatory Network in HBP activation and its potential effects on key oncogenes. Experimental observations are encoded in a temporal language format and model checking is applied to infer the model parameters and qualitative model construction. Using this model, we discover step-wise genetic alterations that promote cancer development and invasion due to an increase in glycolytic flux, and reveal critical trajectories involved in cancer progression. We compute delay constraints to reveal important associations between the production and degradation rates of proteins. O-linked N-acetylglucosamine transferase (OGT), an enzyme used for addition of O-GlcNAc during O-GlcNAcylation, is identified as a key regulator to promote oncogenesis in a feedback mechanism through the stabilization of c-Myc. Silencing of the OGT and c-Myc loop decreases glycolytic flux and leads to programmed cell death. Results of network analyses also identify a significant cycle that highlights the role of p53-Mdm2 circuit oscillations in cancer recovery and homeostasis. Together, our findings suggest that the OGT and c-Myc feedback loop is critical in tumor progression, and targeting these mediators may provide a mechanism-based therapeutic approach to regulate hyper-O-GlcNAcylation in human cancer.

  15. Regulation of macrophage inhibitory factor (MIF) by epidermal growth factor receptor (EGFR) in the MCF10AT model of breast cancer progression.

    Science.gov (United States)

    Lim, Simin; Choong, Lee-Yee; Kuan, Chong Poh; Yunhao, Chen; Lim, Yoon-Pin

    2009-08-01

    Genetic aberration of EGFR is one of the major molecular characteristics of breast cancer. However, the molecular changes associated with EGFR signaling during different stages of breast cancer development have not been studied. In this study, complementary two-dimensional-DIGE and iTRAQ technologies were used to profile the expression level of proteins in 4 isogenic cell lines in the MCF10AT model of breast cancer progression following a time course of EGF stimulation. A total of 80 proteins (67 from iTRAQ, 15 from DIGE, 2 common in both) were identified to be up- or down-regulated by EGF treatment. Following EGF stimulation, the expression level of MIF, a cytokine that has been implicated in many human cancers, was decreased in MCF10A1 normal breast mammary epithelial cells, increased in MCF10AT1k preneoplastic and MCF10CA1h low grade breast cancer cells, but showed no obvious difference in the MCF10CA1a high grade cancer cells. The increase in MIF expression level following EGF treatment could also be observed in A431 cervical cancer cells. EGF-induced increases of MIF expression levels in CA1h breast cancer cells were abrogated when MEK, but not PIK3CA, was knocked down. In addition, silencing of MIF diminished the proliferation of EGF-stimulated CA1h cells when compared to control cells. Taken together, our data suggested an EGFR --> MEK --> MIF proliferative pathway that has never been reported previously and that this pathway "evolves" during disease progression as modeled by the MCF10AT system. Revelation of the novel relationship between MIF and EGF may contribute to an integrated understanding of the roles of these oncogenic factors during breast cancer development.

  16. 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; Barua, Animesh

    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. PMID:27579331

  17. 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.

  18. 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...

  19. 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.

  20. Bedtime misalignment and progression of breast cancer

    Science.gov (United States)

    Hahm, Bong-Jin; Jo, Booil; Dhabhar, Firdaus S.; Palesh, Oxana; Aldridge-Gerry, Arianna; Bajestan, Sepideh N.; Neri, Eric; Nouriani, Bita; Spiegel, David; Zeitzer, Jamie M.

    2016-01-01

    Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness–Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes (“going to bed at preferred bedtime”) (n=72), and 46.9 months for women with misaligned bedtimes (“going to bed later or earlier than the preferred bedtime”) (n=13) (log rank p=0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR=0.539, 95% CI=0.320–0.906, p=0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR=2.169, 95% CI=1.124–4.187, p=0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR=1.641, 95% CI=1.000–2.695, p=0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR=3.180, 95% CI=1.327–7.616, p=0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms. PMID:24156520

  1. 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.

  2. 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...

  3. 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

  4. 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.

  5. 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

  6. 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...

  7. 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.

  8. A joint model for the dependence between clustered times to tumour progression and deaths: A meta-analysis of chemotherapy in head and neck cancer.

    Science.gov (United States)

    Rondeau, Virginie; Pignon, Jean-Pierre; Michiels, Stefan

    2015-12-01

    The observation of time to tumour progression (TTP) or progression-free survival (PFS) may be terminated by a terminal event. In this context, deaths may be due to tumour progression, and the time to the major failure event (death) may be correlated with the TTP. The usual assumption of independence between the TTP process and death, required by many commonly used statistical methods, can be violated. Furthermore, although the relationship between TTP and time to death is most relevant to the anti-cancer drug development or to evaluation of TTP as a surrogate endpoint, statistical models that try to describe the dependence structure between these two characteristics are not frequently used. We propose a joint frailty model for the analysis of two survival endpoints, TTP and time to death, or PFS and time to death, in the context of data clustering (e.g. at the centre or trial level). This approach allows us to simultaneously evaluate the prognostic effects of covariates on the two survival endpoints, while accounting both for the relationship between the outcomes and for data clustering. We show how a maximum penalized likelihood estimation can be applied to a nonparametric estimation of the continuous hazard functions in a general joint frailty model with right censoring and delayed entry. The model was motivated by a large meta-analysis of randomized trials for head and neck cancers (Meta-Analysis of Chemotherapy in Head and Neck Cancers), in which the efficacy of chemotherapy on TTP or PFS and overall survival was investigated, as adjunct to surgery or radiotherapy or both.

  9. 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.

  10. Membrane potential and cancer progression

    Directory of Open Access Journals (Sweden)

    Ming eYang

    2013-07-01

    Full Text Available Membrane potential (Vm, the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm is a key biophysical signal in non-excitable cells, modulating important cellular activities, such as proliferation and differentiation. Therefore, the multiplicities of various ion channels/transporters expressed on different cells are finely tuned in order to regulate the Vm. It is well established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm has functional roles in cancer cell migration. In addition, hyperpolarization is necessary for stem cell differentiation. For example, both osteogenesis and adipogenesis are hindered in human mesenchymal stem cells under depolarizing conditions. Therefore, in the context of cancer, membrane depolarization might be important for the emergence and maintenance of cancer stem cells, giving rise to sustained tumor growth. This review aims to provide a broad understanding of the Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration and differentiation will be discussed. In the long term, Vm might be a valuable clinical marker for tumor detection with prognostic value, and could even be artificially modified in order to inhibit tumor growth and metastasis.

  11. 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

  12. Monitoring of Tumor Promotion and Progression in a Mouse Model of Inflammation-Induced Colon Cancer with Magnetic Resonance Colonography

    Directory of Open Access Journals (Sweden)

    Matthew R. Young

    2009-03-01

    Full Text Available Early detection of precancerous tissue has significantly improved survival of most cancers including colorectal cancer (CRC. Animal models designed to study the early stages of cancer are valuable for identifying molecular events and response indicators that correlate with the onset of disease. The goal of this work was to investigate magnetic resonance (MR colonography in a mouse model of CRC on a clinical MR imager. Mice treated with azoxymethane and dextran sulfate sodium were imaged by serial MR colonography (MRC from initiation to euthanasia. Magnetic resonance colonography was obtained with both T1- and T2-weighted images after administration of a Fluorinert enema to remove residual luminal signal and intravenous contrast to enhance the colon wall. Individual tumor volumes were calculated and validated ex vivo. The Fluorinert enema provided a clear differentiation of the lumen of the colon from the mucosal lining. Inflammation was detected 3 days after dextran sulfate sodium exposure and subsided during the next week. Tumors as small as 1.2 mm3 were detected and as early as 29 days after initiation. Individual tumor growths were followed over time, and tumor volumes were measured by MR imaging correlated with volumes measured ex vivo. The use of a Fluorinert enema during MRC in mice is critical for differentiating mural processes from intraluminal debris. Magnetic resonance colonography with Fluorinert enema and intravenous contrast enhancement will be useful in the study of the initial stages of colon cancer and will reduce the number of animals needed for preclinical trials of prevention or intervention.

  13. Interleukin-8 in breast cancer progression.

    Science.gov (United States)

    Todorović-Raković, Nataša; Milovanović, Jelena

    2013-10-01

    Interleukin-8 (IL-8) is a chemokine that has an autocrine and/or paracrine tumor-promoting role and significant potential as a prognostic and/or predictive cancer biomarker. In breast cancer, which is mostly determined by expression of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), IL-8 could play a specific role. IL-8 is highly expressed in ER- breast cancers, but it increases invasiveness and metastatic potential of both ER- and ER+ breast cancer cells. It is also highly expressed in HER2+ breast cancers. Because of the complex crosstalk between these receptors and IL-8, its role is mainly determined by delicate balance in their signaling pathways. Therefore, the main point of this review was to analyze the possible influence of IL-8 in breast cancer progression related to its interaction with ER and HER2 and the consequent therapeutic implications of these relations.

  14. 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 ...

  15. Current progress in immunotherapy for pancreatic cancer.

    Science.gov (United States)

    Foley, Kelly; Kim, Victoria; Jaffee, Elizabeth; Zheng, Lei

    2016-10-10

    Pancreatic cancer remains one of the most lethal cancers with few treatment options. Immune-based strategies to treat pancreatic cancer, such as immune checkpoint inhibitors, therapeutic vaccines, and combination immunotherapies, are showing promise where other approaches have failed. Immune checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, are effective as single agents in immune sensitive cancers like melanoma, but lack efficacy in immune insensitive cancers including pancreatic cancer. However, these inhibitors are showing clinical activity, even in traditionally non-immunogenic cancers, when combined with other interventions, including chemotherapy, radiation therapy, and therapeutic vaccines. Therapeutic vaccines given together with immune modulating agents are of particular interest because vaccines are the most efficient way to induce effective anti-tumor T cell responses, which is required for immunotherapies to be effective. In pancreatic cancer, early studies suggest that vaccines can induce T cells that have the potential to recognize and kill pancreatic cancer cells, but the tumor microenvironment inhibits effective T cell trafficking and function. While progress has been made in the development of immunotherapies for pancreatic cancer over the last several years, additional trials are needed to better understand the signals within the tumor microenvironment that are formidable barriers to T cell infiltration and function. Additionally, as more pancreatic specific antigens are identified, immunotherapies will continue to be refined to provide the most significant clinical benefit.

  16. Differential expression proteomics of human colorectal cancer based on a syngeneic cellular model for the progression of adenoma to carcinoma.

    Science.gov (United States)

    Roth, Udo; Razawi, Hanieh; Hommer, Julia; Engelmann, Katja; Schwientek, Tilo; Müller, Stefan; Baldus, Stephan E; Patsos, Georgios; Corfield, Anthony P; Paraskeva, Christos; Hanisch, Franz-Georg

    2010-01-01

    This is the first differential expression proteomics study on a human syngeneic cellular in vitro progression model of the colorectal adenoma-to-carcinoma sequence, the anchorage-dependent non-tumorigenic adenoma derived cell line AA/C1 and the derived anchorage-independent and tumorigenic carcinoma cell line AA/C1/SB10C. The study is based on quantitative 2-DE and is complemented by Western blot validation. Excluding redundancies due to proteolysis and post-translational modified isoforms of over 2000 protein spots, 13 proteins were revealed as regulated with statistical variance being within the 95th confidence level and were identified by peptide mass fingerprinting in MALDI MS. Progression-associated proteins belong to the functional complexes of anaerobic glycolysis/gluconeogenesis, steroid biosynthesis, prostaglandin biosynthesis, the regulation and maintenance of the cytoskeleton, protein biosynthesis and degradation, the regulation of apoptosis or other functions. Partial but significant overlap was revealed with previous proteomics and transcriptomics studies in colorectal carcinoma. Among upregulated proteins we identified 3-HMG-CoA synthase, protein phosphatase 1, prostaglandin E synthase 2, villin 1, annexin A1, triosephosphate isomerase, phosphoserine aminotransferase 1, fumarylacetoacetate hydrolase and pyrroline-5-carboxylate reductase 1 (PYCR1), while glucose-regulated protein 78, cathepsin D, lamin A/C and quinolate phosphoribosyltransferase were downregulated.

  17. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    Science.gov (United States)

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  18. 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.

  19. 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

  20. Embryonic morphogen nodal promotes breast cancer growth and progression.

    Directory of Open Access Journals (Sweden)

    Daniela F Quail

    Full Text Available Breast cancers expressing human embryonic stem cell (hESC-associated genes are more likely to progress than well-differentiated cancers and are thus associated with poor patient prognosis. Elevated proliferation and evasion of growth control are similarly associated with disease progression, and are classical hallmarks of cancer. In the current study we demonstrate that the hESC-associated factor Nodal promotes breast cancer growth. Specifically, we show that Nodal is elevated in aggressive MDA-MB-231, MDA-MB-468 and Hs578t human breast cancer cell lines, compared to poorly aggressive MCF-7 and T47D breast cancer cell lines. Nodal knockdown in aggressive breast cancer cells via shRNA reduces tumour incidence and significantly blunts tumour growth at primary sites. In vitro, using Trypan Blue exclusion assays, Western blot analysis of phosphorylated histone H3 and cleaved caspase-9, and real time RT-PCR analysis of BAX and BCL2 gene expression, we demonstrate that Nodal promotes expansion of breast cancer cells, likely via a combinatorial mechanism involving increased proliferation and decreased apopotosis. In an experimental model of metastasis using beta-glucuronidase (GUSB-deficient NOD/SCID/mucopolysaccharidosis type VII (MPSVII mice, we show that although Nodal is not required for the formation of small (<100 cells micrometastases at secondary sites, it supports an elevated proliferation:apoptosis ratio (Ki67:TUNEL in micrometastatic lesions. Indeed, at longer time points (8 weeks, we determined that Nodal is necessary for the subsequent development of macrometastatic lesions. Our findings demonstrate that Nodal supports tumour growth at primary and secondary sites by increasing the ratio of proliferation:apoptosis in breast cancer cells. As Nodal expression is relatively limited to embryonic systems and cancer, this study establishes Nodal as a potential tumour-specific target for the treatment of breast cancer.

  1. Motesanib diphosphate in progressive differentiated thyroid cancer

    DEFF Research Database (Denmark)

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

    2008-01-01

    point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma......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...

  2. 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...

  3. 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.

  4. Cancer stem cells: progress and challenges in lung cancer.

    Science.gov (United States)

    Templeton, Amanda K; Miyamoto, Shinya; Babu, Anish; Munshi, Anupama; Ramesh, Rajagopal

    2014-01-01

    The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called "cancer stem cells" (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs. PMID:27358855

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. Salivary Protein Profiles among HER2/neu-Receptor-Positive and -Negative Breast Cancer Patients: Support for Using Salivary Protein Profiles for Modeling Breast Cancer Progression

    Directory of Open Access Journals (Sweden)

    Charles F. Streckfus

    2012-01-01

    Full Text Available Purpose. The objective of this study was to compare the salivary protein profiles from individuals diagnosed with breast cancer that were either HER2/neu receptor positive or negative. Methods. Two pooled saliva specimens underwent proteomic analysis. One pooled specimen was from women diagnosed with stage IIa HER2/neu-receptor-positive breast cancer patients (n=10 and the other was from women diagnosed with stage IIa HER2/neu-receptor-negative cancer patients (n=10. The pooled samples were trypsinized and the peptides labeled with iTRAQ reagent. Specimens were analyzed using an LC-MS/MS mass spectrometer. Results. The results yielded approximately 71 differentially expressed proteins in the saliva specimens. There were 34 upregulated proteins and 37 downregulated proteins.

  10. Dietary energy balance modulates ovarian cancer progression and metastasis.

    Science.gov (United States)

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

    2014-08-15

    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 surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.

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

    NARCIS (Netherlands)

    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 demonstra

  12. The mathematics of cancer: integrating quantitative models.

    Science.gov (United States)

    Altrock, Philipp M; Liu, Lin L; Michor, Franziska

    2015-12-01

    Mathematical modelling approaches have become increasingly abundant in cancer research. The complexity of cancer is well suited to quantitative approaches as it provides challenges and opportunities for new developments. In turn, mathematical modelling contributes to cancer research by helping to elucidate mechanisms and by providing quantitative predictions that can be validated. The recent expansion of quantitative models addresses many questions regarding tumour initiation, progression and metastases as well as intra-tumour heterogeneity, treatment responses and resistance. Mathematical models can complement experimental and clinical studies, but also challenge current paradigms, redefine our understanding of mechanisms driving tumorigenesis and shape future research in cancer biology.

  13. 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.

  14. 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.

  15. 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.

  16. Relating Single Cell Heterogeneity To Genotype During Cancer Progression

    Science.gov (United States)

    Rajaram, Satwik

    2013-03-01

    Progression of normal cells towards cancer is driven by a series of genetic changes. Traditional population-averaged measurements have found that cell signalling activities are increasingly altered during this progression. Despite the fact that cancer cells are known to be highly heterogeneous, the response of individual pathways to specific genetic changes remains poorly characterized at a single cell level. Do signalling alterations in a pathway reflect a shift of the whole population, or changes to specific subpopulations? Are alterations to pathways independent, or are cells with alterations in one pathway more likely to be abnormal in another due to crosstalk? We are building a computational framework that analyzes immunofluorescence microscopy images of cells to identify alterations in individual pathways at a single-cell level. A primary novelty of our approach is a ``change of basis'' that allows us to understand signalling in cancer cells in terms of the much better understood patterns of signalling in normal cells. This allows us to model heterogeneous populations of cancer cells as a mixture of distinct subpopulations, each with a specific combination of signalling pathways altered beyond the normal baseline. We used this framework to analyze human bronchial epithelial cell lines containing a series of genetic modifications commonly seen in lung cancer. We confirmed expected trends (such as a population-wide epithelial mesenchymal transition following the last of our series of modifications) and are presently studying the relation between the mutational profiles of cancer cells and pathway crosstalk. Our framework will help establish a more natural basis for future investigations into the phenotype-genotype relationship in heterogeneous populations.

  17. 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.

  18. 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...

  19. Targeting clotting proteins in cancer therapy - progress and challenges.

    Science.gov (United States)

    Ruf, Wolfram; Rothmeier, Andrea S; Graf, Claudine

    2016-04-01

    Cancer-associated thrombosis remains a significant complication in the clinical management of cancer and interactions of the hemostatic system with cancer biology continue to be elucidated. Here, we review recent progress in our understanding of tissue factor (TF) regulation and procoagulant activation, TF signaling in cancer and immune cells, and the expanding roles of the coagulation system in stem cell niches and the tumor microenvironment. The extravascular functions of coagulant and anti-coagulant pathways have significant implications not only for tumor progression, but also for the selection of appropriate target specific anticoagulants in the therapy of cancer patients. PMID:27067961

  20. 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

  1. 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.

  2. 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.

  3. 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...

  4. CXCL5 Promotes Prostate Cancer Progression

    Directory of Open Access Journals (Sweden)

    Lesa A Begley

    2008-03-01

    Full Text Available CXCL5 is a proangiogenic CXC-type chemokine that is an inflammatory mediator and a powerful attractant for granulocytic immune cells. Unlike many other chemokines, CXCL5 is secreted by both immune (neutrophil, monocyte, and macrophage and nonimmune (epithelial, endothelial, and fibroblastic cell types. The current study was intended to determine which of these cell types express CXCL5 in normal and malignant human prostatic tissues, whether expression levels correlated with malignancy and whether CXCL5 stimulated biologic effects consistent with a benign or malignant prostate epithelial phenotype. The results of these studies show that CXCL5 protein expression levels are concordant with prostate tumor progression, are highly associated with inflammatory infiltrate, and are frequently detected in the lumens of both benign and malignant prostate glands. Exogenous administration of CXCL5 stimulates cellular proliferation and gene transcription in both nontransformed and transformed prostate epithelial cells and induces highly aggressive prostate cancer cells to invade through synthetic basement membrane in vitro. These findings suggest that the inflammatory mediator, CXCL5, may play multiple roles in the etiology of both benign and malignant proliferative diseases in the prostate.

  5. 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...

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. Progress in Systems Biological Modeling of Cancer%癌症的系统生物学模型研究进展

    Institute of Scientific and Technical Information of China (English)

    周建平

    2014-01-01

    Systems biology is a biology-based inter-disciplinary field which focuses on complex interactions within biological systems. Systems biological study can integrate multi-dimensional data describing the target biological system at different levels, and establish mathematical models of the system to study the characteristic behaviors of the system by virtual simulation, interference and forecasts. As complex biological systems, cancers have been extensively studied in systems biology. Systems biology models of cancers,including statistics-based models,signaling and metabolic bio-chemical models and tissue-level models,are valuable supplement to traditional animal models in cancer research. In this review, some valuable mathematical modeling efforts made in cancer systems biology were overviewed.%系统生物学研究采用的是系统性的研究方法,即获取并整合目标系统不同层次的生物学信息,构建适用于该生物系统的数学模型,对该系统的特征性行为进行系统性研究。癌症是一种复杂的生物系统,已成为系统生物学研究的热点领域。癌症的系统生物学模型是对传统的癌症动物模型的补充,主要包括:统计推断模型、生化网络模型、以及组织水平模型等。本文综述了这些系统模型方法在癌症研究中的应用情况及其取得的重要研究成果。

  11. Liver cancer stem cell markers: Progression and therapeutic implications

    Science.gov (United States)

    Sun, Jing-Hui; Luo, Qing; Liu, Ling-Ling; Song, Guan-Bin

    2016-01-01

    Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets. PMID:27053846

  12. 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

  13. 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

  14. 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.

  15. Role of glutathione in cancer progression and chemoresistance.

    Science.gov (United States)

    Traverso, Nicola; Ricciarelli, Roberta; Nitti, Mariapaola; Marengo, Barbara; Furfaro, Anna Lisa; Pronzato, Maria Adelaide; Marinari, Umberto Maria; Domenicotti, Cinzia

    2013-01-01

    Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

  16. 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...

  17. 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...

  18. Histone Demethylase RBP2 Is Critical for Breast Cancer Progression and Metastasis

    Directory of Open Access Journals (Sweden)

    Jian Cao

    2014-03-01

    Full Text Available Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that aberrant epigenetic modifications contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene-expression data sets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes, including TNC. In addition, RBP2 loss suppresses tumor formation in MMTV-neu transgenic mice. These results suggest that therapeutic targeting of RBP2 is a potential strategy for inhibition of tumor progression and metastasis.

  19. 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, ...

  20. 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

  1. A tissue biomarker panel predicting systemic progression after PSA recurrence post-definitive prostate cancer therapy.

    Directory of Open Access Journals (Sweden)

    Tohru Nakagawa

    Full Text Available BACKGROUND: Many men develop a rising PSA after initial therapy for prostate cancer. While some of these men will develop a local or metastatic recurrence that warrants further therapy, others will have no evidence of disease progression. We hypothesized that an expression biomarker panel can predict which men with a rising PSA would benefit from further therapy. METHODOLOGY/PRINCIPAL FINDINGS: A case-control design was used to test the association of gene expression with outcome. Systemic (SYS progression cases were men post-prostatectomy who developed systemic progression within 5 years after PSA recurrence. PSA progression controls were matched men post-prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years. Using expression arrays optimized for paraffin-embedded tissue RNA, 1021 cancer-related genes were evaluated-including 570 genes implicated in prostate cancer progression. Genes from 8 previously reported marker panels were included. A systemic progression model containing 17 genes was developed. This model generated an AUC of 0.88 (95% CI: 0.84-0.92. Similar AUCs were generated using 3 previously reported panels. In secondary analyses, the model predicted the endpoints of prostate cancer death (in SYS cases and systemic progression beyond 5 years (in PSA controls with hazard ratios 2.5 and 4.7, respectively (log-rank p-values of 0.0007 and 0.0005. Genes mapped to 8q24 were significantly enriched in the model. CONCLUSIONS/SIGNIFICANCE: Specific gene expression patterns are significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence.

  2. 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

  3. 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.

  4. 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.

  5. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  6. Targeted Cancer Therapy: Vital Oncogenes and a New Molecular Genetic Paradigm for Cancer Initiation Progression and Treatment

    Science.gov (United States)

    Willis, Rudolph E.

    2016-01-01

    It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis. PMID:27649156

  7. 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...

  8. 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...

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. Epithelial-mesenchymal transition in breast cancer progression and metastasis

    Institute of Scientific and Technical Information of China (English)

    Yifan Wang; Binhua P. Zhou

    2011-01-01

    Breast cancer is the most common cancer in women,and approximately 90% of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells.Epithelial-mesenchymal transition (EMT) is a vital process for large-scale cell movement during morphogenesis at the time of embryonic development.Tumor cells usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis.Several transcription factors and signals are involved in these events.In this review,we summarize recent advances in breast cancer researches that have provided new insights in the molecular mechanisms underlying EMT regulation during breast cancer progression and metastasis.We especially focus on the molecular pathways that control EMT.

  15. 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.

  16. 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

  17. Dynamics of cancer progression and suppression: A novel evolutionary game theory based approach.

    Science.gov (United States)

    Banerjee, Jeet; Ranjan, Tanvi; Layek, Ritwik Kumar

    2015-01-01

    In this paper, a novel mathematical approach is proposed for the dynamics of progression and suppression of cancer. We define mutant cell density, ρ(μ) (μ × ρ), as a primary factor in cancer dynamics, and use logistic growth model and replicator equation for defining the dynamics of total cell density (ρ) and mutant fraction (μ), respectively. Furthermore, in the proposed model, we introduce an analytical expression for a control parameter D (drug), to suppress the proliferation of mutants with extra fitness level σ. Lastly, we present a comparison of the proposed model with some existing models of tumour growth.

  18. 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

  19. 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.

  20. Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer.

    Science.gov (United States)

    Ding, Lin; El Zaatari, Mohamad; Merchant, Juanita L

    2016-01-01

    This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model. PMID:27573785

  1. 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

  2. Progress in animal models for predicting the results of clinical trials of cancer drugs%预测肿瘤药物临床试验效果的动物模型新进展

    Institute of Scientific and Technical Information of China (English)

    余飞; 丁慧

    2015-01-01

    基于人体试验的实际应用及伦理方面的考虑,合适的动物模型对于肿瘤药物研发至关重要。制药公司和研究机构在肿瘤治疗新药的开发过程中消耗大量资源,最佳动物体内模型的选择可以改进或缩短研发进程。在技术复杂性方面,肿瘤遗传工程小鼠模型( GEMM)已逐步完善,并且GEMM能够准确重建人类肿瘤的同源发生,为加快肿瘤药物的开发提供机遇。本文主要综合比较预测肿瘤药物临床试验效果的不同类型动物模型,探讨其优劣,并对体内模型的评估方法及与临床转化等进行简述,为肿瘤药物临床前试验提供参考。%Due to practical and ethical concerns associated with human experiments, animal models have been essential in cancer research.Vast resources are expended during the development of new cancer therapeutics, and selection of optimal in vivo models should improve this process.Genetically engineered mouse models ( GEMM) of cancer have progressively improved in technical sophistication and, accurately recapitulating the human cognate condition, have provided opportunities to accelerate the development of cancer drugs.In this article we consider the different types of animal models used for predicting the results of clinical trials of cancer drugs, and discuss the strengths and weaknesses of each in this regard.In addition, the methods of predicting in vivo models and clinical translation are discussed.

  3. 前列腺癌体内实验模型的研究进展%Research progress of in vivo animal models of prostate cancer

    Institute of Scientific and Technical Information of China (English)

    聂迪森; 秦卫军; 温伟红; 赵宁宁; 师长宏

    2015-01-01

    Prostate cancer is one of the most common malignant tumors in men and related studies have achieved great breakthrough in recent years.But because of the lack of effective in vivo animal models, the process to translate basic research into clinical application has been severely hampered.Patient derived prostate tumor xenograft ( PDPTX) model is an ideal animal model in which freshly isolated tumor tissues from patients were inoculated into immunodeficient mice.This model can duplicate the heterogeneity of primary tumor in a better way and keep the tumor complexity at molecular, genetic and pathological levels.Particularly, the PDPTX model, in which the isolated tumor tissue is inoculated under the renal capsule, is even better, because it solves the clrawbacks of traditional subcutaneous inoculation model.In traditional mod-els, the success rate is low, it’s not easy for lower grade tumor to form xenograft, and it’s not easy to reconstruct metasta-sis, etc.PDPTX provides a more ideal in vivo model for prostate cancer studies.It has irreplaceable advantages, especially in target therapy, new drug screening and individualized tumor treatment.%前列腺癌是男性最为常见的恶性肿瘤之一。近年来有关前列腺癌的相关研究取得了较大突破,但由于缺少有效的体内实验模型,导致研究成果向临床应用的转化受到严重阻碍。人源性前列腺癌移植( patient de-rived prostate tumor xenograft,PDPTX)模型是将患者新鲜的肿瘤组织移植于免疫缺陷小鼠而建立的体内模型,该模型能较好地复制原发肿瘤的异质性,保持肿瘤在分子学、基因学和病理学的复杂性。特别是采用肾包膜移植建立PDPTX模型的方法较好地解决了传统皮下移植建模成功率低、低级别肿瘤成瘤难、无法实现移植瘤转移等缺点,为前列腺癌研究提供了更为理想的体内模型。尤其是在靶向治疗、新型药物筛选、个体化治疗等方面具有不可取代的优势。

  4. Progression and metastasis of lung cancer.

    Science.gov (United States)

    Popper, Helmut H

    2016-03-01

    Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the "foreign" stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

  5. Progress in Immunotherapy for Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yan XU

    2014-01-01

    Full Text Available In recent years, the five-year survival rate of patients with advanced stage non-small cell lung cancer (NSCLC remains low despite recent advances in surgery, irradiation, chemotherapy, and targeted therapy. Immunotherapy which utilizes the immune system to control and eradicate cancer is a viable treatment approach for malignancy. Immunotherapy in patients with lung cancer has made breakthrough progress recently. Novel immunotherapeutic agents, such as antigen-specific tumour vaccines, checkpoint inhibitors, etc, have all been evaluated in lung cancer, and some have shown prolonged survival time in phase II trials and III trails. The immune-related response criteria for the evaluation of antitumor responses with immunotherapeutic agents have been made. Now, immunotherapy will likely be a fundamentally new concept for the treatment of NSCLC.

  6. 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...

  7. Dual role of GRK5 in cancer development and progression.

    Science.gov (United States)

    Gambardella, J; Franco, A; Giudice, C Del; Fiordelisi, A; Cipolletta, E; Ciccarelli, M; Trimarco, B; Iaccarino, G; Sorriento, D

    2016-05-01

    GRK5 is a multifunctional protein that is able to move within the cell in response to various stimuli to regulate key intracellular signaling from receptor activation, on plasmamembrane, to gene transcription, in the nucleus. Thus, GRK5 is involved in the development and progression of several pathological conditions including cancer. Several reports underline the involvement of GRK5 in the regulation of tumor growth even if they appear controversial. Indeed, depending on its subcellular localization and on the type of cancer, GRK5 is able to both inhibit cancer progression, through the desensitization of GPCR and non GPCR-receptors (TSH, PGE2R, PDGFR), and induce tumor growth, acting on non-receptor substrates (p53, AUKA and NPM1). All these findings suggest that targeting GRK5 could be an useful anti-cancer strategy, for specific tumor types. In this review, we will discuss the different effects of this kinase in the induction and progression of tumorigenesis, the molecular mechanisms by which GRK5 exerts its effects, and the potential therapeutic strategies to modulate them.

  8. 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.

  9. 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

  10. 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

  11. The Cancer Genome Anatomy Project: EST Sequencing and the Genetics of Cancer Progression

    Directory of Open Access Journals (Sweden)

    David B. Krizman

    1999-06-01

    Full Text Available As the process of tumor progression proceeds from the normal cellular state to a preneoplastic condition and finally to the fully invasive form, the molecular characteristics of the cell change as well. These characteristics can be considered a molecular fingerprint of the cell at each stage of progression and, analogous to fingerprinting a criminal, can be used as markers of the progression process. Based on this premise, the Cancer Genome Anatomy Project was initiated with the broad goal of determining the comprehensive molecular characterization of normal, premalignant, and malignant tumor cells, thus making a reality the identification of all major cellular mechanisms leading to tumor initiation and progression ([Strausberg, R.L., Dahl, C.A., and Klausner, R.D. (1997. “New opportunities for uncovering the molecular basis of cancer.” Nat. Genet., 16: 415-516.], www.ncbi.nlm.nih.gov/ncicgap/. The expectation of determining the genetic fingerprints of cancer progression will allow for 1 correlation of disease progression with therapeutic outcome; 2 improved evaluation of disease treatment; 3 stimulation of novel approaches to prevention, detection, and therapy; and 4 enhanced diagnostic tools for clinical applications. Whereas acquiring the comprehensive molecular analysis of cancer progression may take years, results from initial, short-term goals are currently being realized and are proving very fruitful.

  12. 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

  13. Daxx regulates mitotic progression and prostate cancer predisposition.

    Science.gov (United States)

    Kwan, Pak Shing; Lau, Chi Chiu; Chiu, Yung Tuen; Man, Cornelia; Liu, Ji; Tang, Kai Dun; Wong, Yong Chuan; Ling, Ming-Tat

    2013-04-01

    Mitotic progression of mammalian cells is tightly regulated by the E3 ubiquitin ligase anaphase promoting complex (APC)/C. Deregulation of APC/C is frequently observed in cancer cells and is suggested to contribute to chromosome instability and cancer predisposition. In this study, we identified Daxx as a novel APC/C inhibitor frequently overexpressed in prostate cancer. Daxx interacts with the APC/C coactivators Cdc20 and Cdh1 in vivo, with the binding of Cdc20 dependent on the consensus destruction boxes near the N-terminal of the Daxx protein. Ectopic expression of Daxx, but not the D-box deleted mutant (DaxxΔD-box), inhibited the degradation of APC/Cdc20 and APC/Cdh1 substrates, leading to a transient delay in mitotic progression. Daxx is frequently upregulated in prostate cancer tissues; the expression level positively correlated with the Gleason score and disease metastasis (P = 0.027 and 0.032, respectively). Furthermore, ectopic expression of Daxx in a non-malignant prostate epithelial cell line induced polyploidy under mitotic stress. Our data suggest that Daxx may function as a novel APC/C inhibitor, which promotes chromosome instability during prostate cancer development.

  14. 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.

  15. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

    DEFF Research Database (Denmark)

    Wang, Zhipeng; Jin, Haifeng; Xu, Ruodan;

    2009-01-01

    ability to block progress of colitis to colon cancer, and its molecular mechanism of action are investigated. A mouse model for colitis-induced colorectal cancer was used to test the effect of triptolide on cancer progression. Treatment of mice with triptolide decreased the incidence of colon cancer...... formation, and increased survival rate. Moreover, triptolide decreased the incidence of tumors in nude mice inoculated with cultured colon cancer cells dose-dependently. In vitro, triptolide inhibited the proliferation, migration and colony formation of colon cancer cells. Secretion of IL6 and levels of JAK....... This suggests that triptolide might be a candidate for prevention of colitis induced colon cancer because it reduces inflammation and prevents tumor formation and development....

  16. 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)

  17. 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...

  18. Cancer Metabolism: A Modeling Perspective

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    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...... 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....... 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...

  19. 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

  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. The ghrelin axis--does it have an appetite for cancer progression?

    Science.gov (United States)

    Chopin, Lisa K; Seim, Inge; Walpole, Carina M; Herington, Adrian C

    2012-12-01

    Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHSR), is a peptide hormone with diverse physiological roles. Ghrelin regulates GH release, appetite and feeding, gut motility, and energy balance and also has roles in the cardiovascular, immune, and reproductive systems. Ghrelin and the GHSR are expressed in a wide range of normal and tumor tissues, and a fluorescein-labeled, truncated form of ghrelin is showing promise as a biomarker for prostate cancer. Plasma ghrelin levels are generally inversely related to body mass index and are unlikely to be useful as a biomarker for cancer, but may be useful as a marker for cancer cachexia. Some single nucleotide polymorphisms in the ghrelin and GHSR genes have shown associations with cancer risk; however, larger studies are required. Ghrelin regulates processes associated with cancer, including cell proliferation, apoptosis, cell migration, cell invasion, inflammation, and angiogenesis; however, the role of ghrelin in cancer is currently unclear. Ghrelin has predominantly antiinflammatory effects and may play a role in protecting against cancer-related inflammation. Ghrelin and its analogs show promise as treatments for cancer-related cachexia. Further studies using in vivo models are required to determine whether ghrelin has a role in cancer progression.

  2. 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

  3. 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.

  4. 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...

  5. Progress in adjuvant chemotherapy for breast cancer: an overview.

    Science.gov (United States)

    Anampa, Jesus; Makower, Della; Sparano, Joseph A

    2015-01-01

    Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy.

  6. Tumor-Derived Exosomes and Their Role in Cancer Progression.

    Science.gov (United States)

    Whiteside, Theresa L

    2016-01-01

    Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation.

  7. Potential Biomarker of L type Amino Acid Transporter 1 in Breast Cancer Progression

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Zhongxing; Cho, Heidi T.; Williams, Larry; Zhu, Aizhi; Liang, Ke; Huang, Ke; Wu, Hui; Jiang, Chunsu; Hong, Samuel; Crowe, Ronald; Goodman, Mark M.; Shim, Hyunsuk [Emory Univ. School of Medicine, Atlanta (United States)

    2011-06-15

    L type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer. LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with 1 amino 3 [{sup 18F}]fluorocyclo butane 1 carboxylic acid ([{sup 18F}]FACBC) PET was assessed for its diagnostic biomarker potential. Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced stage breast cancer. Furtermore, the blockade of LAT1 with its inhibitor, 2 amino bicyclo[2.2.1]heptane 2 carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, [{sup 18F}]FACBC, has been demonstrated to be an excellent PET tracer for the non invasive imaging og malignant breast cancer using an orthotopic animal model. The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. [{sup 18F}]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging.

  8. 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.

  9. 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.

  10. 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.

  11. 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...

  12. 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

  13. 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.

  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. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Bladder Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing bladder 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.

  20. Esophageal Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing esophageal 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.

  1. 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.

  2. Testicular Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of testicular 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.

  3. 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.

  4. 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.

  5. Preclinical fluorescent mouse models of pancreatic cancer

    Science.gov (United States)

    Bouvet, Michael; Hoffman, Robert M.

    2007-02-01

    Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

  6. 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

  7. 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.

  8. Recent progress on countercurrent chromatography modeling

    OpenAIRE

    Wang, Fengkang; Ito, Yoichiro; Wei, Yun

    2014-01-01

    As countercurrent chromatography is becoming an established method in chromatography for many kinds of products, it is becoming increasingly important to model the process and to be able to predict the peaks for a given process. The CCC industries are looking for rapid methods to analyze the processes of countercurrent chromatography and select suitable solvent system. In this paper, recent progress is reviewed in the development and demonstration of several types of models of countercurrent ...

  9. Chemokines in Cancer Development and Progression and Their Potential as Targeting Molecules for Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Naofumi Mukaida

    2014-01-01

    Full Text Available Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer.

  10. 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

  11. 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...

  12. Spontaneous initiation, promotion and progression of colorectal cancer in the novel A/J Min/+ mouse.

    Science.gov (United States)

    Sødring, Marianne; Gunnes, Gjermund; Paulsen, Jan Erik

    2016-04-15

    The C57BL/6J multiple intestinal neoplasia (Min/+) mouse is a widely used murine model for familial adenomatous polyposis, a hereditary form of human colorectal cancer. However, it is a questionable model partly because the vast majority of tumors arise in the small intestine, and partly because the fraction of tumors that progress to invasive carcinomas is minuscule. A/J mice are typically more susceptible to carcinogen-induced colorectal cancer than C57BL/6J mice. To investigate whether the novel Min/+ mouse on the A/J genetic background could be a better model for colorectal cancer, we examined the spontaneous intestinal tumorigenesis in 81 A/J Min/+ mice ranging in age from 4 to 60 weeks. The A/J Min/+ mouse exhibited a dramatic increase in number of colonic lesions when compared to what has been reported for the conventional Min/+ mouse; however, an increase in small intestinal lesions did not occur. In addition, this novel mouse model displayed a continual development of colonic lesions highlighted by the transition from early lesions (flat ACF) to tumors over time. In mice older than 40 weeks, 13 colonic (95% CI: 8.7-16.3) and 21 small intestinal (95% CI: 18.6-24.3) tumors were recorded. Notably, a considerable proportion of those lesions progressed to carcinomas in both the colon (21%) and small intestine (51%). These findings more closely reflect aspects of human colorectal carcinogenesis. In conclusion, the novel A/J Min/+ mouse may be a relevant model for initiation, promotion and progression of colorectal cancer.

  13. Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.

    Science.gov (United States)

    Rachagani, Satyanarayana; Macha, Muzafar A; Menning, Melanie S; Dey, Parama; Pai, Priya; Smith, Lynette M; Mo, Yin-Yuan; Batra, Surinder K

    2015-11-24

    Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets. PMID:26516699

  14. 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.

  15. 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

  16. 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.

  17. Imaging in Colorectal Cancer: Progress and Challenges for the Clinicians

    Science.gov (United States)

    Van Cutsem, Eric; Verheul, Henk M. W.; Flamen, Patrik; Rougier, Philippe; Beets-Tan, Regina; Glynne-Jones, Rob; Seufferlein, Thomas

    2016-01-01

    The use of imaging in colorectal cancer (CRC) has significantly evolved over the last twenty years, establishing important roles in surveillance, diagnosis, staging, treatment selection and follow up. The range of modalities has broadened with the development of novel tracer and contrast agents, and the fusion of technologies such as positron emission tomography (PET) and computed tomography (CT). Traditionally, the most widely used modality for assessing treatment response in metastasised colon and rectal tumours is CT, combined with use of the RECIST guidelines. However, a growing body of evidence suggests that tumour size does not always adequately correlate with clinical outcomes. Magnetic resonance imaging (MRI) is a more versatile technique and dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted (DW)-MRI may be used to evaluate biological and functional effects of treatment. Integrated fluorodeoxyglucose (FDG)-PET/CT combines metabolic and anatomical imaging to improve sensitivity and specificity of tumour detection, and a number of studies have demonstrated improved diagnostic accuracy of this modality in a variety of tumour types, including CRC. These developments have enabled the progression of treatment strategies in rectal cancer and improved the detection of hepatic metastatic disease, yet are not without their limitations. These include technical, economical and logistical challenges, along with a lack of robust evidence for standardisation and formal guidance. In order to successfully apply these novel imaging techniques and utilise their benefit to provide truly personalised cancer care, advances need to be clinically realised in a routine and robust manner. PMID:27589804

  18. 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.

  19. 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

  20. Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene

    OpenAIRE

    Schayek, Hagit; Bentov, Itay; Sun, Shihua; Plymate, Stephen R; Werner, Haim

    2010-01-01

    The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF1R) expression. DNA methylation of CpG islands is an epigenetic mechanism associated with gene silencing. Recent studies have demonstrated that methylation occurs early in prostate carcinogenesis and, furthermore, may contribute to androgen ind...

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    Fleshner Neil E

    2010-06-01

    Full Text Available Abstract Background 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. Methods 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. Results 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 Conclusion 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.

  9. In situ quantification of genomic instability in breast cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Ortiz de Solorzano, Carlos; Chin, Koei; Gray, Joe W.; Lockett, Stephen J.

    2003-05-15

    Genomic instability is a hallmark of breast and other solid cancers. Presumably caused by critical telomere reduction, GI is responsible for providing the genetic diversity required in the multi-step progression of the disease. We have used multicolor fluorescence in situ hybridization and 3D image analysis to quantify genomic instability cell-by-cell in thick, intact tissue sections of normal breast epithelium, preneoplastic lesions (usual ductal hyperplasia), ductal carcinona is situ or invasive carcinoma of the breast. Our in situ-cell by cell-analysis of genomic instability shows an important increase of genomic instability in the transition from hyperplasia to in situ carcinoma, followed by a reduction of instability in invasive carcinoma. This pattern suggests that the transition from hyperplasia to in situ carcinoma corresponds to telomere crisis and invasive carcinoma is a consequence of telomerase reactivation afertelomere crisis.

  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. A progress report on seismic model studies

    Science.gov (United States)

    Healy, J.H.; Mangan, G.B.

    1963-01-01

    The value of seismic-model studies as an aid to understanding wave propagation in the Earth's crust was recognized by early investigators (Tatel and Tuve, 1955). Preliminary model results were very promising, but progress in model seismology has been restricted by two problems: (1) difficulties in the development of models with continuously variable velocity-depth functions, and (2) difficulties in the construction of models of adequate size to provide a meaningful wave-length to layer-thickness ratio. The problem of a continuously variable velocity-depth function has been partly solved by a technique using two-dimensional plate models constructed by laminating plastic to aluminum, so that the ratio of plastic to aluminum controls the velocity-depth function (Healy and Press, 1960). These techniques provide a continuously variable velocity-depth function, but it is not possible to construct such models large enough to study short-period wave propagation in the crust. This report describes improvements in our ability to machine large models. Two types of models are being used: one is a cylindrical aluminum tube machined on a lathe, and the other is a large plate machined on a precision planer. Both of these modeling techniques give promising results and are a significant improvement over earlier efforts.

  12. Correlation of DNA Ploidy with Progression of Cervical Cancer

    Directory of Open Access Journals (Sweden)

    M. Singh

    2008-01-01

    Full Text Available The majority of squamous cell carcinomas of cervix are preceded by visible changes in the cervix, most often detected by cervical smear. As cervical cancer is preceded by long precancerous stages, identification of the high-risk population through detection of DNA ploidy may be of importance in effective management of this disease. Here we attempted to correlate aneuploid DNA patterns and their influence on biological behavior of flow-cytometry analysis of DNA ploidy which was carried out in cytologically diagnosed cases of mild (79, moderate (36, and severe (12 dysplasia, as well as “atypical squamous cells of unknown significance (ASCUS” (57 along with controls (69, in order to understand its importance in malignant progression of disease. Cytologically diagnosed dysplasias, which were employed for DNA ploidy studies, 39 mild, 28 moderate, and 11 severe dysplasia cases were found to be aneuploid. Out of the 69 control subjects, 6 cases showed aneuploidy pattern and the rest 63 subjects were diploid. An aneuploidy pattern was observed in 8 out of 57 cases of cytologically evaluated ASCUS. The results of the followup studies showed that aberrant DNA content reliably predicts the occurrence of squamous cell carcinoma in cervical smear. Flow cytometric analysis of DNA ploidy may provide a strategic diagnostic tool for early detection of carcinoma cervix. Therefore, it is a concept of an HPV screening with reflex cytology in combination with DNA flow cytometry to detect progressive lesions with the greatest possible sensitivity and specificity.

  13. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Y. H.; Nam, K. S.; Oh, Y. H.; Kim, M. K.; Kim, M. Y.; Jang, J. S. [Dongguk University, Seoul (Korea, Republic of)

    2008-04-15

    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. 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.

  16. 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.

  17. Progress in Modeling and Simulation of Batteries

    Energy Technology Data Exchange (ETDEWEB)

    Turner, John A [ORNL

    2016-01-01

    Modeling and simulation of batteries, in conjunction with theory and experiment, are important research tools that offer opportunities for advancement of technologies that are critical to electric motors. The development of data from the application of these tools can provide the basis for managerial and technical decision-making. Together, these will continue to transform batteries for electric vehicles. This collection of nine papers presents the modeling and simulation of batteries and the continuing contribution being made to this impressive progress, including topics that cover: * Thermal behavior and characteristics * Battery management system design and analysis * Moderately high-fidelity 3D capabilities * Optimization Techniques and Durability As electric vehicles continue to gain interest from manufacturers and consumers alike, improvements in economy and affordability, as well as adoption of alternative fuel sources to meet government mandates are driving battery research and development. Progress in modeling and simulation will continue to contribute to battery improvements that deliver increased power, energy storage, and durability to further enhance the appeal of electric vehicles.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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...

  7. 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.

  8. 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...

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

    Directory of Open Access Journals (Sweden)

    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.

  10. 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

  11. 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.

  12. 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

  13. 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...

  14. 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

  15. 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.

  16. Nano-mechanical Phenotype as a Promising Biomarker to Evaluate Cancer Development, Progression, and Anti-cancer Drug Efficacy.

    Science.gov (United States)

    Park, Soyeun

    2016-06-01

    Since various bio-mechanical assays have been introduced for studying mechanical properties of biological samples, much progress has been made in cancer biology. It has been noted that enhanced mechanical deformability can be used as a marker for cancer diagnosis. The relation between mechanical compliances and the metastatic potential of cancer cells has been suggested to be a promising prognostic marker. Although it is yet to be conclusive about its clinical application due to the complexity in the tissue integrity, the nano-mechanical compliance of human cell samples has been evaluated by several groups as a promising marker in diagnosing cancer development and anticipating its progression. In this review, we address the mechanical properties of diverse cancer cells obtained by atomic force microscopy-based indentation experiments and reiterate prognostic relations between the nano-mechanical compliance and cancer progression. We also review the nano-mechanical responses of cancer cells to the anti-cancer drug treatment in order to interrogate a possible use of nano-mechanical compliance as a means to evaluate the effectiveness of anti-cancer drugs.

  17. 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.

  18. Prostatic and dietary omega-3 fatty acids and prostate cancer progression during active surveillance.

    Science.gov (United States)

    Moreel, Xavier; Allaire, Janie; Léger, Caroline; Caron, André; Labonté, Marie-Ève; Lamarche, Benoît; Julien, Pierre; Desmeules, Patrice; Têtu, Bernard; Fradet, Vincent

    2014-07-01

    The association between omega-3 (ω-3) fatty acids and prostate cancer has been widely studied. However, little is known about the impact of prostate tissue fatty acid content on prostate cancer progression. We hypothesized that compared with the estimated dietary ω-3 fatty acids intake and the ω-3 fatty acids levels measured in red blood cells (RBC), the prostate tissue ω-3 fatty acid content is more strongly related to prostate cancer progression. We present the initial observations from baseline data of a phase II clinical trial conducted in a cohort of 48 untreated men affected with low-risk prostate cancer, managed under active surveillance. These men underwent a first repeat biopsy session within 6 months after the initial diagnosis of low-risk prostate cancer, at which time 29% of the men had progressed from a Gleason score of 6 to a Gleason score of 7. At the first repeat biopsy session, fatty acid levels were assessed with a food-frequency questionnaire, and determined in the RBC and in the prostate tissue biopsy. We found that eicosapentaenoic acid (EPA) was associated with a reduced risk of prostate cancer progression when measured directly in the prostate tissue. Thus, this initial interim study analysis suggests that prostate tissue ω-3 fatty acids, especially EPA, may be protective against prostate cancer progression in men with low-risk prostate cancer.

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. Kidney cancer progression linked to shifts in tumor metabolism

    Science.gov (United States)

    Investigators in The Cancer Genome Atlas Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma.

  5. 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...

  6. 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

  7. 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 ...

  8. Progress towards a Venus reference cloud model

    Science.gov (United States)

    Wilson, Colin; Ignatiev, Nikolay; Marcq, Emmanuel

    Venus is completely enveloped by clouds. The main cloud layers stretch from altitudes of 48 - 75 km, with additional tenuous hazes found at altitudes 30 - 100 km. Clouds play a crucial role in governing atmospheric circulation, chemistry and climate on all planets, but particularly so on Venus due to the optical thickness of the atmosphere. The European Space Agency’s Venus Express (VEx) satellite has carried out a wealth of observations of Venus clouds since its arrival at Venus in April 2006. Many VEx observations are relevant to cloud science - from imagers and spectrometers to solar, stellar and radio occultation - each covering different altitude ranges, spectral ranges and atmospheric constituents. We have formed an International Team at the International Space Science Institute to bring together scientists from each of the relevant Venus Express investigation teams as well as from previous missions, as well as those developing computational and analytical models of clouds and hazes. The aims of the project are (1) to create self-consistent reference cloud/haze models which capture not only a mean cloud structure but also its main modes of variability; and (2) to bring together modelers and observers, to reach an understanding of clouds and hazes on Venus which matches all observables and is physically consistent. Our approach is to first to assemble an averaged cloud profile for low latitudes, showing how cloud number abundances and other observables vary as a function of altitude, consistent with all available observations. In a second step, we will expand this work to produce a reference cloud profile which varies with latitude and local solar time, as well as optical thickness of the cloud. We will present our status in progressing towards this goal. We acknowledge the support of the International Space Science Institute of Berne, Switzerland, in hosting our Team’s meetings.

  9. 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

  10. 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.

  11. miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer.

    Science.gov (United States)

    Mühlberg, Leonie; Kühnemuth, Benjamin; Costello, Eithne; Shaw, Victoria; Sipos, Bence; Huber, Magdalena; Griesmann, Heidi; Krug, Sebastian; Schober, Marvin; Gress, Thomas M; Michl, Patrick

    2016-06-01

    Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu. PMID:27471627

  12. Progress against cancer in the Netherlands since the late 1980s: an epidemiological evaluation.

    NARCIS (Netherlands)

    Karim-Kos, H.E.; Kiemeney, L.A.L.M.; Louwman, M.W.; Coebergh, J.W.W.; Vries, E. de

    2012-01-01

    Progress against cancer through prevention and treatment is often measured by survival statistics only instead of analyzing trends in incidence, survival and mortality simultaneously because of interactive influences. This study combines these parameters of major cancers to provide an overview of th

  13. 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.

  14. 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...

  15. 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.)

  16. 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...

  17. 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...

  18. [Research progression of translational medicine in gastric cancer].

    Science.gov (United States)

    Li, Maoran; Zhao, Gang; Zhu, Chunchao

    2014-02-01

    Gastric cancer is one of the most common malignant tumors which is a great threat to human health. In recent years, the reform of surgical mordalities and the optimization of radiation and chemotherapy is still far from reducing morbidity and mortality of gastric cancer. As a new research pattern, translational medicine has emerged in various clinical subjects, which leads to remarkable effects. In this paper, the definition and development of translational medicine, molecular markers and drug treatment of gastric cancer will be discussed and the feasibility of translational medicine in the treatment of gastric cancer will be explained. In our opinion, the intervention of translational medicine could change the current situation that scientific researches is severely disconnected with clinical practice and increase the detection rate of gastric cancer and the effective rate of adjuvant therapy after surgery to improve the prognosis of patients with gastric cancer.

  19. Neural Cell Adhesion Protein CNTN1 Promotes the Metastatic Progression of Prostate Cancer.

    Science.gov (United States)

    Yan, Judy; Ojo, Diane; Kapoor, Anil; Lin, Xiaozeng; Pinthus, Jehonathan H; Aziz, Tariq; Bismar, Tarek A; Wei, Fengxiang; Wong, Nicholas; De Melo, Jason; Cutz, Jean-Claude; Major, Pierre; Wood, Geoffrey; Peng, Hao; Tang, Damu

    2016-03-15

    Prostate cancer metastasis is the main cause of disease-related mortality. Elucidating the mechanisms underlying prostate cancer metastasis is critical for effective therapeutic intervention. In this study, we performed gene-expression profiling of prostate cancer stem-like cells (PCSC) derived from DU145 human prostate cancer cells to identify factors involved in metastatic progression. Our studies revealed contactin 1 (CNTN1), a neural cell adhesion protein, to be a prostate cancer-promoting factor. CNTN1 knockdown reduced PCSC-mediated tumor initiation, whereas CNTN1 overexpression enhanced prostate cancer cell invasion in vitro and promoted xenograft tumor formation and lung metastasis in vivo. In addition, CNTN1 overexpression in DU145 cells and corresponding xenograft tumors resulted in elevated AKT activation and reduced E-cadherin (CDH1) expression. CNTN1 expression was not readily detected in normal prostate glands, but was clearly evident on prostate cancer cells in primary tumors and lymph node and bone metastases. Tumors from 637 patients expressing CNTN1 were associated with prostate cancer progression and worse biochemical recurrence-free survival following radical prostatectomy (P prostate cancer progression and metastasis, prompting further investigation into the mechanisms that enable neural proteins to become aberrantly expressed in non-neural malignancies.

  20. 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.

  1. 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...

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. Quantitative assessment of smoking-induced emphysema progression in longitudinal CT screening for lung cancer

    Science.gov (United States)

    Suzuki, H.; Mizuguchi, R.; Matsuhiro, M.; Kawata, Y.; Niki, N.; Nakano, Y.; Ohmatsu, H.; Kusumoto, M.; Tsuchida, T.; Eguchi, K.; Kaneko, M.; Moriyama, N.

    2015-03-01

    Computed tomography has been used for assessing structural abnormalities associated with emphysema. It is important to develop a robust CT based imaging biomarker that would allow quantification of emphysema progression in early stage. This paper presents effect of smoking on emphysema progression using annual changes of low attenuation volume (LAV) by each lung lobe acquired from low-dose CT images in longitudinal screening for lung cancer. The percentage of LAV (LAV%) was measured after applying CT value threshold method and small noise reduction. Progression of emphysema was assessed by statistical analysis of the annual changes represented by linear regression of LAV%. This method was applied to 215 participants in lung cancer CT screening for five years (18 nonsmokers, 85 past smokers, and 112 current smokers). The results showed that LAV% is useful to classify current smokers with rapid progression of emphysema (0.2%/year, plung cancer.

  7. 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.

  8. 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.

  9. 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

  10. Proportion cured models applied to 23 cancer sites in Norway.

    Science.gov (United States)

    Cvancarova, Milada; Aagnes, Bjarte; Fosså, Sophie D; Lambert, Paul C; Møller, Bjørn; Bray, Freddie

    2013-04-01

    Statistical cure is reached when a group of patients has the same mortality as cancer-free individuals. Cure models predict the cured proportion and the median survival of fatal cases. Cure models have seldom been applied and tested systematically across all major cancer sites. Incidence and follow-up data on 23 cancer sites recorded at the Cancer Registry of Norway 1963-2007 were obtained. Mixture cure models were fitted to obtain trends and up-to-date estimates (based on period approach) assuming cured and uncured groups exist. The model converged for cancers of the mouth and pharynx, oesophagus, stomach, colon, rectum, liver, gallbladder, pancreas, lung and trachea, ovary, kidney, bladder, CNS, non-Hodgkin lymphoma (only for males) and leukemia. The proportion of cured patients increased 1963-2002 for both sexes, with the largest changes (in percent) seen for leukemia (46.4 and 46.7) and CNS (35.9, 42.0), males given first. Median survival time for the uncured cases increased for colon and rectal cancer, and there was a three- fold increase in median survival time for patients with fatal ovarian cancers. Cancers of bladder and CNS had the highest up-to-date proportion cured (in percent), 67.4 and 64.0, respectively, pancreas and liver were amongst the lowest (5.7 and 9.9, respectively). Cure models are useful when monitoring progress in cancer care, but must be applied and interpreted with caution. The absolute estimates of the cure proportion are speculative and should not be calculated where cure is not medically anticipated. PMID:22927104

  11. 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)

  12. 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.

  13. Strategies and resources for coping with fear of disease progression in women with reproductive system cancer

    Directory of Open Access Journals (Sweden)

    Moskovchenko, Denis V.

    2016-06-01

    Full Text Available Fear of disease progression is one of the most common sources of psychological distress in patients suffering from chronic diseases. Fear of disease progression is a situationspecific and fully discernible (reportable emotion based on personal experience of a life-threatening disease. This article presents the results of a study of cancer patients’ coping behavior according to the levels of fear of disease progression experienced. The presence of pronounced fear of disease progression reflects a negative cognitive-affective response to one’s expectations for one’s own future; this response is related to a decrease in adaptive capacity. To determine the particular characteristics of coping strategies and coping resources in women with reproductive-system cancers according to the level of fear of disease progression. A total of 177 women with reproductive-system cancers were examined, among them 59 with breast cancer and 118 with gynecological cancers. Women with reproductive-system cancers have varying sets of coping strategies and coping resources according to their level of fear of disease progression. For each of the differentiated groups, specific characteristics of the strategies of coping with difficult life situations are described, along with cognitive self-regulation strategies specific to the illness and to coping resources. The women exhibiting moderate fear of disease progression significantly more often adhered to problem-oriented strategies of coping with difficult life situations and illness and had an internal locus of control regarding treatment. Patients with a low level of fear of disease progression tended to use strategies of positive reinterpretation of difficult life situations and illness; an external locus of control regarding treatment prevailed in this group. Patients found to have a dysfunctional level of fear of disease progression displayed significantly higher rates of using cognitive-regulation strategies

  14. 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.

  15. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer

    DEFF Research Database (Denmark)

    Antonio, Nicole; Bønnelykke-Behrndtz, Marie Louise; Ward, Laura Chloe;

    2015-01-01

    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......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...... 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...

  16. 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.

  17. Genomic and genetic alterations influence the progression of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Stefania Nobili; Lorenzo Bruno; Ida Landini; Cristina Napoli; Paolo Bechi; Francesco Tonelli; Carlos A Rubio; Enrico Mini; Gabriella Nesi

    2011-01-01

    Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Twomain gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.

  18. Ensemble Modeling of Cancer Metabolism

    Directory of Open Access Journals (Sweden)

    Tahmineh eKhazaei

    2012-05-01

    Full Text Available The metabolic behaviour of cancer cells is adapted to meet their proliferative needs, with notable changes such as enhanced lactate secretion and glucose uptake rates. In this work, we use the Ensemble Modeling (EM framework to gain insight and predict potential drug targets for tumour cells. EM generates a set of models which span the space of kinetic parameters that are constrained by thermodynamics. Perturbation data based on known targets are used to screen the entire ensemble of models to obtain a sub-set, which is increasingly predictive. EM allows for incorporation of regulatory information and captures the behaviour of enzymatic reactions at the molecular level by representing reactions in the elementary reaction form. In this study, a metabolic network consisting of 58 reactions is considered and accounts for glycolysis, the pentose phosphate pathway, lipid metabolism, amino acid metabolism, and includes allosteric regulation of key enzymes. Experimentally measured intracellular and extracellular metabolite concentrations are used for developing the ensemble of models along with information on established drug targets. The resulting models predicted transaldolase (TALA and succinyl-CoA ligase (SUCOAS1m to cause a significant reduction in growth rate when repressed, relative to currently known drug targets. Furthermore, the results suggest that the synergetic repression of transaldolase and glycine hydroxymethyltransferase (GHMT2r will lead to a three-fold decrease in growth rate compared to the repression of single enzyme targets.

  19. [Biology of cancer cell-stroma interaction in carcinogenesis and cancer progression].

    Science.gov (United States)

    Fujita, S; Sugihara, H; Ito, R; Tsuchihashi, Y

    1984-03-01

    Cancer cells are dependent on physical and chemical supports of stroma no less than non-cancerous cells and tissues are. The role of stroma should, therefore, be important in genesis and progression of cancers growing in vivo. But this aspect underlying carcinogenesis and manifestation of human cancers has long been neglected or attracted less attention in the investigations of oncology. Focusing particular attention on parenchyma-stromal interaction in gastrointestinal mucosa, the authors have found that, quite unexpectedly, in normal gastric as well as intestinal mucosa of all the animal species so for studied, vascularity is always poorly developed in the generative cell zones. Cross-sectional area of vascular bed is markedly reduced in this zone. Application of Hagen-Poiseulle law revealed that the reduced total cross-sectional area, resulting in a rapid drop in hydrostatic pressure, creates here a situation particularly favorable for proliferating cell population. Since the transport of water soluble material together with tissue fluid through the capillary wall is driven by the hydrostatic pressure, the generative cell zones are found to be present at the site where the turnover of the material is the most active. Before the zone of the rapid pressure drop, there appears zone of relatively high intravascular hydrostatic pressure, where secretory function seems to be facilitated. This zone, as is well known, corresponds to glandular portion of the mucosa. After the zone of the rapid pressure drop (in surface of the mucosa), zone of a low intravascular hydrostatic pressure appears, where absorptive function is to be facilitated. Within such zones, in gastric mucosa surface epithelium and in intestinal mucosa absorptive villi cells are located. It is likely that architecture of gastrointestinal epithelium and vascular pattern in the stroma is closely correlated and that the former is determined, at least partly, by the latter. When human gastric mucosa shows

  20. Safety and chemopreventive effect of Polyphenon E in preventing early and metastatic progression of prostate cancer in TRAMP mice.

    Science.gov (United States)

    Kim, Seung Joon; Amankwah, Ernest; Connors, Shahnjayla; Park, Hyun Y; Rincon, Maria; Cornnell, Heather; Chornokur, Ganna; Hashim, Arig Ibrahim; Choi, Junsung; Tsai, Ya-Yu; Engelman, Robert W; Kumar, Nagi; Park, Jong Y

    2014-04-01

    Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer.

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression

    Science.gov (United States)

    Cohen-Dvashi, Hadas; Ben-Chetrit, Nir; Russell, Roslin; Carvalho, Silvia; Lauriola, Mattia; Nisani, Sophia; Mancini, Maicol; Nataraj, Nishanth; Kedmi, Merav; Roth, Lee; Köstler, Wolfgang; Zeisel, Amit; Yitzhaky, Assif; Zylberg, Jacques; Tarcic, Gabi; Eilam, Raya; Wigelman, Yoav; Will, Rainer; Lavi, Sara; Porat, Ziv; Wiemann, Stefan; Ricardo, Sara; Schmitt, Fernando; Caldas, Carlos; Yarden, Yosef

    2015-01-01

    Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells. PMID:25678558

  6. 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

  7. The progress of study on pathogenesis in ovarian cancer

    Institute of Scientific and Technical Information of China (English)

    JI Yu-bin; LI Hai-jiao; YU Lei; LIU Guang-da; PANG Lin-lin; YANG Hai-fan

    2008-01-01

    Ovarian cancer is one of the three malignant tumors in female reproductive system, the death rate locates in the first place of gynecological cancer. Most patients are already at the advanced stage when examine their bodies, five-year survival rate are only about 20 % to 30 %. So gynecological cancer has bedome one of tumor which the most waiting to be considered. It happens refer to the incidence of chromosomal abnormalities, cancer gene change. The inactivation of tumor suppressor gene, inhibitor of apoptosis and other genetic changes, the imbalance in the regulatory network due to the interaction of multiple genes and their product. Chromosomal abnormalities play an important role in the development of ovarian cancer, the chromosomes of common characteristic and non-random changes are 1,3, 5, 6, 7, 8, 11, 12, 15, 17, 18, 20, 22 etc. Cancer gene including K-ras, c-erb-B2/HER-2, D1 (CyclinD1), AIB1 etc. K-ras coded protein p21 is activated through point mutation, cause the enzyme activity deprivation of GMP, slowed down the speed of GTP degrdn into GMP, activate target molecule persistently, make cells proliferate persistently, then leading to cancer. HER-2 gene amplification result in the over expression of HER-2 protein, made cells over proliferate,Protein over expression convey the strong signal of proliferation, over activate the early transcription factor and certain gene in the nuclear, then promote the occurrence of cancer. Cyclin D1 promote cells enter from S to Gl phase, thus contribute to the proliferation of cell division, then canceration. AIB1 gene over express, will cause tumor cells immortalized. Tumor suppressor gene, such as BRCA1, p53, p73, p16 etc. The expression depl of BRCA1 protein in ovarian Cystadenocarcinoma prompt that the reduction of BRCA1 protein synthesis, resulting in apoptosis decreased, the cell proliferation disinhibit, then disorder and proliferate, thus leading to cancer, p53 mutation happened in about 30 percents to 80 percents

  8. 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.

  9. Hypoxia in models of lung cancer

    DEFF Research Database (Denmark)

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

    2010-01-01

    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...

  10. 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.

  11. 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...

  12. 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.

  13. 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...

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. [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

  20. 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

  1. 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.

  2. miR-340 and ZEB1 negative feedback loop regulates TGF-β- mediated breast cancer progression

    Science.gov (United States)

    Xie, Ye-Gong; Wang, Jie; Mao, Jie-Fei; Zhang, Bin; Wang, Xin; Cao, Xu-Chen

    2016-01-01

    MicroRNAs act as key regulators in carcinogenesis and progression in various cancers. In present study, we explored the role of miR-340 in the breast cancer progression. Our results showed that overexpression of miR-340 inhibits breast cancer cell proliferation and invasion, whereas depletion of miR-340 promotes breast cancer progression. Molecularly, ZEB1 was identified as a target gene of miR-340 and miR-340 suppressed the expression of ZEB1 by directly binding to the 3′-UTR of ZEB1. Furthermore, ZEB1 transcriptionally suppresses miR-340 expression. The negative feedback loop regulated TGF-β-mediated breast cancer progression. In conclusion, our data suggested that miR-340 acted as a tumor suppressor in breast cancer progression. PMID:27036021

  3. 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 ...

  4. 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...

  5. 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.

  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. 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....

  8. 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.

  9. 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

  10. The role of activated protein C in cancer progression

    NARCIS (Netherlands)

    G.L. van Sluis; H.R. Büller; C.A. Spek

    2010-01-01

    Activated protein C (APC) is best known as a natural anticoagulant that also has direct cell signaling properties which (among others) enhance vascular barrier function. We recently established the relevance of APC-induced barrier enhancement by showing that endogenous APC limits cancer cell extrava

  11. 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".

  12. 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.

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

    Institute of Scientific and Technical Information of China (English)

    Ze-Hua Wang; Cong-Jian Xu

    2015-01-01

    Objective: This review aimed to update the progress ofmicroRNA (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 ofnanoscience and technology, analysis methods ofmiRNA 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.

  14. Evaluation of bioluminescent imaging for noninvasive monitoring of colorectal cancer progression in the liver and its response to immunogene therapy

    Directory of Open Access Journals (Sweden)

    Gonzalez-Aparicio Manuela

    2009-01-01

    Full Text Available Abstract Background Bioluminescent imaging (BLI is based on the detection of light emitted by living cells expressing a luciferase gene. Stable transfection of luciferase in cancer cells and their inoculation into permissive animals allows the noninvasive monitorization of tumor progression inside internal organs. We have applied this technology for the development of a murine model of colorectal cancer involving the liver, with the aim of improving the pre-clinical evaluation of new anticancer therapies. Results A murine colon cancer cell line stably transfected with the luciferase gene (MC38Luc1 retains tumorigenicity in immunocompetent C57BL/6 animals. Intrahepatic inoculation of MC38Luc1 causes progressive liver infiltration that can be monitored by BLI. Compared with ultrasonography (US, BLI is more sensitive, but accurate estimation of tumor mass is impaired in advanced stages. We applied BLI to evaluate the efficacy of an immunogene therapy approach based on the liver-specific expression of the proinflammatory cytokine interleukin-12 (IL-12. Individualized quantification of light emission was able to determine the extent and duration of antitumor responses and to predict long-term disease-free survival. Conclusion We show that BLI is a rapid, convenient and safe technique for the individual monitorization of tumor progression in the liver. Evaluation of experimental treatments with complex mechanisms of action such as immunotherapy is possible using this technology.

  15. Maspin expression and its clinicopathological significance in tumorigenesis and progression of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Meng-Chun Wang; Yan-Min Yang; Xiao-Han Li; Fang Dong; Yan Li

    2004-01-01

    AIM: To investigate maspin expression in tumorigenesis and progression of gastric cancer and to explore its relevant molecular mechanisms.METHODS: Formalin-fixed and paraffin-embedded tissues from normal mucosa (n=182), dysplasia (n=69), cancer (n=113) of the stomach were studied for maspin expression by immunohistochemistry. Microvessel density (MVD) in gastric cancer was labeled using anti-CD34 antibody. Maspin expression was compared with clinical parameters and MVD of tumors. Caspase-3 expression was also detected in gastric carcinoma by immunohistochemistry. The relationship between Caspase-3 and maspin expression was concerned as well.RESULTS: The positive rates of maspin expression were 79.8%(145/182), 75.4%(52/69) and 50.4%(57/113) in normal mucosa, dysplasia and cancer of the stomach,respectively. Cancer less frequently expressed maspin than normal mucosa and dysplasia (P<0.05). Maspin expression showed a significantly negative association with invasive depth, metastasis, Lauren's and Nakamura's classification (P<0.05), but not with tumor size, Borrmann's classification,growth pattern or TNM staging (P>0.05). The positive rate of Caspase-3 was significantly lower in gastric cancer than in normal gastric mucosa (P<0.05,32.7% vs 50.4%). It was noteworthy that maspin expression was negatively correlated with MVD, but positively correlated with expression of Caspase-3 in gastric cancer (P<0.05).CONCLUSION: Down-regulated maspin expression is a late molecular event in gastric carcinogenesis. Reduced expression of maspin contributes to progression of gastric cancer probably by inhibiting cell adhesion, enhancing cell mobility,decreasing cell apoptosis and facilitating angiogenesis.Additionally altered expression of maspin underlies the molecular mechanism of differentiation of gastric cancer and supports the different histogenetic pathways of intestinal and diffuse gastric cancers. Maspin expression can be considered as an effective and objective

  16. 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.

  17. Tissue-engineered models of human tumors for cancer research

    Science.gov (United States)

    Villasante, Aranzazu; Vunjak-Novakovic, Gordana

    2015-01-01

    Introduction Drug toxicity often goes undetected until clinical trials, which are the most costly and dangerous phase of drug development. Both the cultures of human cells and animal studies have limitations that cannot be overcome by incremental improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. An area that could greatly benefit from these models is cancer research. Areas covered In this review, the authors first describe the engineered tumor systems, using Ewing's sarcoma as an example of human tumor that cannot be predictably studied in cell culture and animal models. Then, they discuss the importance of the tissue context for cancer progression and outline the biomimetic principles for engineering human tumors. Finally, they discuss the utility of bioengineered tumor models for cancer research and address the challenges in modeling human tumors for use in drug discovery and testing. Expert opinion While tissue models are just emerging as a new tool for cancer drug discovery, they are already demonstrating potential for recapitulating, in vitro, the native behavior of human tumors. Still, numerous challenges need to be addressed before we can have platforms with a predictive power appropriate for the pharmaceutical industry. Some of the key needs include the incorporation of the vascular compartment, immune system components, and mechanical signals that regulate tumor development and function. PMID:25662589

  18. 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...

  19. 20 Years of Progress in Radiation Oncology: Prostate Cancer.

    Science.gov (United States)

    Lanciano; Thomas; Eifel

    1997-04-01

    Carcinoma of the cervix remains of special interest to the Patterns of Care Study (PCS) because of the prominent role that radiotherapy plays in the definitive management of all stages and extents of disease. Five PCS surveys have been conducted for squamous cell cancer of the uterine cervix beginning in 1973 and repeated thereafter at 5-year intervals. The records of over 2,700 women have been reviewed for these surveys. Changes in the pretreatment investigations of cervical cancer patients have occurred during these years, with an increase in the use of computed tomography (CT) and a decrease in the use of intravenous pyelography and cystoscopy. A marked increase in the use of linear accelerators has also occurred, with 98% of all facilities having a linear accelerator as the highest energy treatment machine in the 1988 survey. There has been a change in brachytherapy prescription over the time of the surveys, with most institutions reporting point dose calculations and dose distributions instead of milligram hours. Mean point A dose has increased to approximately 80cGy, reflecting the PCS recommendations of dose intensity to the paracentral point through use of brachytherapy. The outcome for stage I and II cervical cancer has remained stable over the time of the surveys, while the results have improved for stage III disease. This improvement in survival and local control for stage III cervical cancer is due in part to the PCS, which has developed standards of treatment with the goal of radiation dose intensity. A number of patient, tumor, and treatment factors significant in multivariate analysis have been described by the PCS with large cohorts of patients. The most important treatment factors associated with a decrease in pelvic failure and improved survival are the use of brachytherapy and higher paracentral dose. A significant dose response has been described for stage III cervical cancer and optimal pelvic control has been demonstrated with point A doses

  20. 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

  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. 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.

  3. The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention

    Science.gov (United States)

    Vahora, Huzefa; Khan, Munawwar Ali; Alalami, Usama; Hussain, Arif

    2016-01-01

    Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment. PMID:27051643

  4. 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.

  5. 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.

  6. 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.

  7. Recent progress in 8igenomic research of liver cancer

    Institute of Scientific and Technical Information of China (English)

    HAN ZeGuang

    2009-01-01

    Along the course of occurrence and development of liver cancer, the corresponding somatic cells ac-cumulate 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 re-search in this field.

  8. 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

  9. 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...

  10. 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...

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

    Directory of Open Access Journals (Sweden)

    Serena Bonomi

    2013-01-01

    Full Text Available 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 might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.

  12. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

    Science.gov (United States)

    Chaudhary, Belal; Elkord, Eyad

    2016-01-01

    Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID:27509527

  13. 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.

  14. 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....

  15. PTEN Deficiency Contributes to the Development and Progression of Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Cristiane H Squarize

    2013-05-01

    Full Text Available The sequencing of the head and neck cancer has provided a blueprint of the most frequent genetic alterations in this cancer type. They include inactivating mutations in Notch, p53, and p16ink4a tumor suppressor genes, in addition to nonoverlapping activating mutations of the PIK3CA and RAS oncogenes or inactivation of the tumor suppressor gene PTEN. Notably, these genetic alterations, along with epigenetic changes, result in increased activity of phosphoinositide 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR pathway, which is present in most head and neck squamous cell carcinomas (HNSCCs. Moreover, we show here that approximately 30% of HNSCCs exhibit reduced PTEN expression. We challenged the biologic relevance of this finding by combining the intraoral administration of a tobacco surrogate, 4-nitroquinoline 1-oxide, with a genetically defined animal model displaying reduced PTEN expression, achieved by the conditional deletion of Pten using the keratin promoter 14 CRE-lox system. This provided a specific genetic and environmentally defined animal model for HNSCC that resulted in the rapid development of oral-specific carcinomas. Under these experimental conditions, control mice did not develop HNSCC lesions. In contrast, most mice harboring Pten deficiency developed multiple SCC lesions in the lateral border and ventral part of the tongue and floor of the mouth, which are the preferred anatomic sites for human HNSCC. Overall, our study highlights the likely clinical relevance of reduced PTEN expression and/or inactivation in HNSCC progression, while the combined Pten deletion with exposure to tobacco carcinogens or their surrogates may provide a unique experimental model system to study novel molecular targeted treatments for HNSCC patients.

  16. Genetically engineered mouse models of prostate cancer

    NARCIS (Netherlands)

    Nawijn, Martijn C.; Bergman, Andreas M.; van der Poel, Henk G.

    2008-01-01

    Objectives: Mouse models of prostate cancer are used to test the contribution of individual genes to the transformation process, evaluate the collaboration between multiple genetic lesions observed in a single tumour, and perform preclinical intervention studies in prostate cancer research. Methods:

  17. A Weibull multi-state model for the dependence of progression-free survival and overall survival.

    Science.gov (United States)

    Li, Yimei; Zhang, Qiang

    2015-07-30

    In oncology clinical trials, overall survival, time to progression, and progression-free survival are three commonly used endpoints. Empirical correlations among them have been published for different cancers, but statistical models describing the dependence structures are limited. Recently, Fleischer et al. proposed a statistical model that is mathematically tractable and shows some flexibility to describe the dependencies in a realistic way, based on the assumption of exponential distributions. This paper aims to extend their model to the more flexible Weibull distribution. We derived theoretical correlations among different survival outcomes, as well as the distribution of overall survival induced by the model. Model parameters were estimated by the maximum likelihood method and the goodness of fit was assessed by plotting estimated versus observed survival curves for overall survival. We applied the method to three cancer clinical trials. In the non-small-cell lung cancer trial, both the exponential and the Weibull models provided an adequate fit to the data, and the estimated correlations were very similar under both models. In the prostate cancer trial and the laryngeal cancer trial, the Weibull model exhibited advantages over the exponential model and yielded larger estimated correlations. Simulations suggested that the proposed Weibull model is robust for data generated from a range of distributions.

  18. State-Space Size Considerations for Disease-Progression Models

    OpenAIRE

    Regnier, Eva D.; Shechter, Steven M.

    2013-01-01

    The article of record as published may be found at http://dx.doi.org/10.1002/sim.5808 Markov models of disease progression are widely used to model transitions in patients’ health state over time. Usually, patients’ health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number...

  19. Research Progress in the Use of Drugs for Breast Cancer Targeted Therapy

    Institute of Scientific and Technical Information of China (English)

    Shun'e Yang; Bing Zhao

    2008-01-01

    In recent years,many significant advances have been made on molecular target therapy to aim directly at epidermal growth factor receptors and vascular endothelial growth factor in breast cancers.Clinical studies of such agents as trastuzumab,lapatinib,erlotinib and bevacituzumab have been widely conducted.This paper will review the recent research progress related to targeted therapy.

  20. 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 ...

  1. 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 ...

  2. 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

  3. 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

    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 fina...

  4. Dual Roles of RNF2 in Melanoma Progression | Office of Cancer Genomics

    Science.gov (United States)

    Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and prometastatic.

  5. Nanochips of Tantalum Oxide Nanodots as artificial-microenvironments for monitoring Ovarian cancer progressiveness

    Science.gov (United States)

    Dhawan, Udesh; Wang, Ssu-Meng; Chu, Ying Hao; Huang, Guewha S.; Lin, Yan Ren; Hung, Yao Ching; Chen, Wen Liang

    2016-08-01

    Nanotopography modulates cell characteristics and cell behavior. Nanotopological cues can be exploited to investigate the in-vivo modulation of cell characteristics by the cellular microenvironment. However, the studies explaining the modulation of tumor cell characteristics and identifying the transition step in cancer progressiveness are scarce. Here, we engineered nanochips comprising of Tantalum oxide nanodot arrays of 10, 50, 100 and 200 nm as artificial microenvironments to study the modulation of cancer cell behavior. Clinical samples of different types of Ovarian cancer at different stages were obtained, primary cultures were established and then seeded on different nanochips. Immunofluorescence (IF) was performed to compare the morphologies and cell characteristics. Indices corresponding to cell characteristics were defined. A statistical comparison of the cell characteristics in response to the nanochips was performed. The cells displayed differential growth parameters. Morphology, Viability, focal adhesions, microfilament bundles and cell area were modulated by the nanochips which can be used as a measure to study the cancer progressiveness. The ease of fabrication of nanochips ensures mass-production. The ability of the nanochips to act as artificial microenvironments and modulate cell behavior may lead to further prospects in the markerless monitoring of the progressiveness and ultimately, improving the prognosis of Ovarian cancer.

  6. Copper and angiogenesis: unravelling a relationship key to cancer progression.

    Science.gov (United States)

    Finney, Lydia; Vogt, Stefan; Fukai, Tohru; Glesne, David

    2009-01-01

    1. Angiogenesis, the formation of new capillaries from existing vasculature, is a critical process in normal physiology as well as several physiopathologies. A desire to curb the supportive role angiogenesis plays in the development and metastasis of cancers has driven exploration into anti-angiogenic strategies as cancer therapeutics. Key to this, angiogenesis additionally displays an exquisite sensitivity to bioavailable copper. Depletion of copper has been shown to inhibit angiogenesis in a wide variety of cancer cell and xenograft systems. Several clinical trials using copper chelation as either an adjuvant or primary therapy have been conducted. Yet, the biological basis for the sensitivity of angiogenesis remains unclear. Numerous molecules important to angiogenesis regulation have been shown to be either directly or indirectly influenced by copper, yet a clear probative answer to the connection remains elusive. 2. Measurements of copper in biological systems have historically relied on techniques that, although demonstrably powerful, provide little or no information as to the spatial distribution of metals in a cellular context. Therefore, several new approaches have been developed to image copper in a biological context. One such approach relies on synchrotron-derived X-rays from third-generation synchrotrons and the technique of high resolution X-ray fluorescence microprobe (XFM) analysis. 3. Recent applications of XFM approaches to the role of copper in regulating angiogenesis have provided unique insight into the connection between copper and cellular behaviour. Using XFM, copper has been shown to be highly spatially regulated, as it is translocated from perinuclear areas of the cell towards the tips of extending filopodia and across the cell membrane into the extracellular space during angiogenic processes. Such findings may explain the heightened sensitivity of this cellular process to this transition metal and set a new paradigm for the kinds of

  7. A MULTISCALE, CELL-BASED FRAMEWORK FOR MODELING CANCER DEVELOPMENT

    Energy Technology Data Exchange (ETDEWEB)

    JIANG, YI [Los Alamos National Laboratory

    2007-01-16

    Cancer remains to be one of the leading causes of death due to diseases. We use a systems approach that combines mathematical modeling, numerical simulation, in vivo and in vitro experiments, to develop a predictive model that medical researchers can use to study and treat cancerous tumors. The multiscale, cell-based model includes intracellular regulations, cellular level dynamics and intercellular interactions, and extracellular level chemical dynamics. The intracellular level protein regulations and signaling pathways are described by Boolean networks. The cellular level growth and division dynamics, cellular adhesion and interaction with the extracellular matrix is described by a lattice Monte Carlo model (the Cellular Potts Model). The extracellular dynamics of the signaling molecules and metabolites are described by a system of reaction-diffusion equations. All three levels of the model are integrated through a hybrid parallel scheme into a high-performance simulation tool. The simulation results reproduce experimental data in both avasular tumors and tumor angiogenesis. By combining the model with experimental data to construct biologically accurate simulations of tumors and their vascular systems, this model will enable medical researchers to gain a deeper understanding of the cellular and molecular interactions associated with cancer progression and treatment.

  8. 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.

  9. 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.

  10. Progress in Global Multicompartmental Modelling of DDT

    Science.gov (United States)

    Stemmler, I.; Lammel, G.

    2009-04-01

    Dichlorophenyltrichloroethane, DDT, and its major metabolite dichlorophenyldichloroethylene, DDE, are long-lived in the environment (persistent) and circulate since the 1950s. They accumulate along food chains, cause detrimental effects in marine and terrestrial wild life, and pose a hazard for human health. DDT was widely used as an insecticide in the past and is still in use in a number of tropical countries to combat vector borne diseases like malaria and typhus. It is a multicompartmental substance with only a small mass fraction residing in air. A global multicompartment chemistry transport model (MPI-MCTM; Semeena et al., 2006) is used to study the environmental distribution and fate of dichlorodiphenyltrichloroethane (DDT). For the first time a horizontally and vertically resolved global model was used to perform a long-term simulation of DDT and DDE. The model is based on general circulation models for the ocean (MPIOM; Marsland et al., 2003) and atmosphere (ECHAM5). In addition, an oceanic biogeochemistry model (HAMOCC5.1; Maier-Reimer et al., 2005 ) and a microphysical aerosol model (HAM; Stier et al., 2005 ) are included. Multicompartmental substances are cycling in atmosphere (3 phases), ocean (3 phases), top soil (3 phases), and vegetation surfaces. The model was run for 40 years forced with historical agricultural application data of 1950-1990. The model results show that the global environmental contamination started to decrease in air, soil and vegetation after the applications peaked in 1965-70. In some regions, however, the DDT mass had not yet reached a maximum in 1990 and was still accumulating mass until the end of the simulation. Modelled DDT and DDE concentrations in atmosphere, ocean and soil are evaluated by comparison with observational data. The evaluation of the model results indicate that degradation of DDE in air was underestimated. Also for DDT, the discrepancies between model results and observations are related to uncertainties of

  11. 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...... not be familiar with GIS analytical tools like Query Languages, can still understand technical discussions on flood analysis through the use of 3D models, which are close to reality....

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer.

    Science.gov (United States)

    Xu, J; Li, Y; Wang, F; Wang, X; Cheng, B; Ye, F; Xie, X; Zhou, C; Lu, W

    2013-02-21

    MicroRNAs (miRNAs) act as important gene regulators in human genomes and their aberrant expression links to many malignancies. We previously identified a different characteristic miRNA expression profile in cervical cancer from that in cervical normal tissues, including the downregulated miR-424. However, the role and mechanism of miR-424 in cervical cancer still remain unknown. Here, we focused on identifying the tumor-suppressive function and clinical significance of miR-424 and exploring the mechanistic relevance by characterizing its target. We showed a significantly decreased expression of miR-424 in 147 cervical cancer tissues versus 74 cervical normal tissues by performing quantitative RT-PCR. In 147 cervical cancer tissue samples, low-level expression of miR-424 was positively correlated with poor tumor differentiation, advanced clinical stage, lymph node metastasis and other poor prognostic clinicopathological parameters. Further in vitro observations showed that enforced expression of miR-424 inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, and suppressed cell migration and invasion in two human cervical cancer cell lines, SiHa and CaSki, implying that miR-424 functions as a tumor suppressor in the progression of cervical cancer. Interestingly, overexpression of miR-424 inhibited the expression of protein checkpoint kinase 1 (Chk1) and phosphorylated Chk1 (p-Chk1) at residues Ser345 and decreased the activity of luciferase-reporter containing the 3'-untranslated region (UTR) of Chk1 with predicted miR-424-binding site. Moreover, miR-424 expression levels were inversely correlated with Chk1 and p-Chk1 protein levels in both cervical cancer and normal tissues. Furthermore, RNAi-mediated knockdown of Chk1 decreased matrix metalloproteinase 9 expression and phenocopied the tumor suppressive effects of miR-424 in cell models. Taken together, our results identify a crucial tumor suppressive role of miR-424 in the progression of

  17. The significance of dynamin 2 expression for prostate cancer progression, prognostication, and therapeutic targeting.

    Science.gov (United States)

    Xu, Bin; Teng, Liang Hong; Silva, Sabrina Daniela da; Bijian, Krikor; Al Bashir, Samir; Jie, Su; Dolph, Michael; Alaoui-Jamali, Moulay A; Bismar, Tarek A

    2014-02-01

    Dynamin 2 (Dyn2) is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. In this study, we investigated the implication of Dyn2 as a prognostic marker and therapeutic target for progressive prostate cancer (PCA). We evaluated Dyn2 protein expression by immunohistochemistry in two cohorts: men with localized PCA treated by retropubic radical prostatectomy (n = 226), and men with advanced/castrate-resistant PCA (CRPC) treated by transurethral resection of prostate (TURP) (n = 253). The role of Dyn2 in cell invasiveness was assessed by in vitro and in vivo experiments using androgen-responsive and refractory PCA preclinical models. Dyn2 expression was significantly increased across advanced stages of PCA compared to benign prostate tissue (P size and lymph node metastases in vivo. In isolated PCA cells, Dyn2 was found to regulate focal adhesion turnover, which is critical for cell migration; this mechanism requires full Dyn2 compared to mutants deficient in GTPase activity. In conclusion, Dyn2 overexpression is associated with neoplastic prostate epithelium and is associated with poor prognosis. Inhibition of Dyn2 prevents cell invasiveness in androgen-responsive and -refractory PCA models, supporting the potential benefit of Dyn2 to serve as a therapeutic target for advanced PCA.

  18. SOME PROGRESS IN THE LATTICE BOLTMANN MODEL

    Institute of Scientific and Technical Information of China (English)

    FENG SHI-DE; TSUTAHARA MICHIHISA; JI ZHONG-ZHEN

    2001-01-01

    A lattice Boltzmann equation model has been developed by using the equilibrium distribution function of the Maxwell-Boltzmann-like form, which is third order in fluid velocity uα. The criteria of energy conservation between the macroscopic physical quantities and the microscopic particles are introduced into the model, thus the thermal hydrodynamic equations containing the effect of buoyancy force can be recovered in terms of the Taylor and ChapmanEnskog asymptotic expansion methods. The two-dimensional thermal convection phenomena in a square cavity and between two concentric cylinders have been calculated by implementing a heat flux boundary condition. Both numerical results are in good agreement with the conventional numerical results.

  19. State-space size considerations for disease-progression models.

    Science.gov (United States)

    Regnier, Eva D; Shechter, Steven M

    2013-09-30

    Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix. PMID:23609629

  20. 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

  1. 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.

  2. 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...

  3. 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.

  4. A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.

    Directory of Open Access Journals (Sweden)

    Feixiong Cheng

    2015-09-01

    Full Text Available Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network. We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes. This functional consequence is often generated by the combined effect of genetic and epigenetic (e.g., chromatin regulation alterations. By quantifying cancer genome evolution using the gene gravity model, we identified six putative cancer genes (AHNAK, COL11A1, DDX3X, FAT4, STAG2, and SYNE1. The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups. Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes. In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Chu, Tian-Li [Department of General Surgery, The People’s Hospital of Wuqing, Tianjin (China); Zhao, Hong-Meng [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Li, Yue [Department of Respiration, Affiliated Hospital of Medical College of Chinese People’s Armed Police Force, Tianjin (China); Chen, Ao-Xiang; Sun, Xuan [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Ge, Jie, E-mail: gejie198003@163.com [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)

    2014-04-04

    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.

  14. 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.

  15. 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.

  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. A Bayesian nonlinear mixed-effects disease progression model

    OpenAIRE

    Kim, Seongho; Jang, Hyejeong; Wu, Dongfeng; Abrams, Judith

    2015-01-01

    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 meth...

  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. 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...

  1. 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 ...

  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. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism.

    Science.gov (United States)

    Wang, Zhi-Qiang; Faddaoui, Adnen; Bachvarova, Magdalena; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Guillemette, Chantal; Gobeil, Stéphane; Macdonald, Elizabeth; Vanderhyden, Barbara; Bachvarov, Dimcho

    2015-10-13

    Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs). Moreover, BCAT1 suppression resulted in downregulation of numerous genes implicated in lipid production and protein synthesis, suggesting its important role in controlling EOC metabolism. Further metabolomic analyses were indicative for significant depletion of most amino acids and different phospho- and sphingolipids following BCAT1 knockdown. Finally, BCAT1 suppression led to significantly prolonged survival time in xenograft model of advanced peritoneal EOC. Taken together, our findings provide new insights about the functional role of BCAT1 in ovarian carcinogenesis and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.

  4. 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

  5. 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

  6. Context Sensitive Modeling of Cancer Drug Sensitivity

    Science.gov (United States)

    Chen, Bo-Juen; Litvin, Oren; Ungar, Lyle; Pe’er, Dana

    2015-01-01

    Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression), an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should—and should not—be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features. PMID:26274927

  7. Context Sensitive Modeling of Cancer Drug Sensitivity.

    Directory of Open Access Journals (Sweden)

    Bo-Juen Chen

    Full Text Available Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression, an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should-and should not-be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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...

  13. 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...

  14. 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...

  15. 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 ...

  16. STAT5A/B Gene Locus Undergoes Amplification during Human Prostate Cancer Progression

    OpenAIRE

    Haddad, Bassem R.; Gu, Lei; Mirtti, Tuomas; Dagvadorj, Ayush; Vogiatzi, Paraskevi; Hoang, David T.; Bajaj, Renu; Leiby, Benjamin; Ellsworth, Elyse; Blackmon, Shauna; Ruiz, Christian; Curtis, Mark; Fortina, Paolo; Ertel, Adam; Liu, Chengbao

    2013-01-01

    The molecular mechanisms underlying progression of prostate cancer (PCa) to castrate-resistant (CR) and metastatic disease are poorly understood. Our previous mechanistic work shows that inhibition of transcription factor Stat5 by multiple alternative methods induces extensive rapid apoptotic death of Stat5-positive PCa cells in vitro and inhibits PCa xenograft tumor growth in nude mice. Furthermore, STAT5A/B induces invasive behavior of PCa cells in vitro and in vivo, suggesting involvement ...

  17. 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.

  18. 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

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

    Directory of Open Access Journals (Sweden)

    Francesca Cammarota

    2016-01-01

    Full Text Available 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 vascular permeability and ending to remodeling of desmoplastic loosely vascularized stromal ECM. The constant bidirectional interaction of epithelial cancer cells with the surrounding microenvironment allows damaged stromal cell usage as a source of nutrients for cancer cells, maintains the stroma renewal thus resembling a wound that does not heal, and affects the characteristics of tumor mesenchymal stem/stromal cells (MSCs. Although MSCs have been shown to coordinate tumor cell growth, dormancy, migration, invasion, metastasis, and drug resistance, recently they have been successfully used in treatment of hematopoietic malignancies to enhance the effect of total body irradiation-hematopoietic stem cell transplantation therapy. Hence, targeting the stromal elements in combination with conventional chemotherapeutics and usage of MSCs to attenuate graft-versus-host disease may offer new strategies to overcome cancer treatment failure and relapse of the disease.

  20. Re-organisation of oesophago-gastric cancer care in England: progress and remaining challenges

    Directory of Open Access Journals (Sweden)

    Greenaway Kimberley

    2009-11-01

    Full Text Available Abstract Background Oesophago-gastric cancer services in England have been extensively reorganised since 2001 to deliver a centralised, specialist-led service. Our aim was to assess how well the National Health Service (NHS in England met organisational standards for oesophago-gastric cancer care. Methods Questionnaires that asked about the provision of staging investigations, curative and palliative treatments and key personnel were sent in September 2007 to the lead clinician for oesophago-gastric cancer at all 30 cancer networks and 156 NHS acute trusts in England. Results Responses were received from all networks and 81% of NHS trusts. All networks provided essential staging investigations and a range of endoscopic palliative therapies. Only 16 of the 30 cancer networks discussed all patients at the specialist multi-disciplinary team meeting and 11 networks had not fully centralised curative surgery. There was also variation between NHS trusts in the integration of the palliative care team, the availability of nurse specialists and the use of dieticians to provide nutritional support. Conclusion There has been considerable progress in reforming oesophago-gastric cancer services but the process of reorganisation is still incomplete and regional differences in service provision exist that may lead to variation in patient outcomes.

  1. 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

  2. Assessing the role of IL-35 in colorectal cancer progression and prognosis.

    Science.gov (United States)

    Zeng, Jin-Cheng; Zhang, Zhi; Li, Tian-Yu; Liang, Yan-Fang; Wang, Hong-Mei; Bao, Jing-Jing; Zhang, Jun-Ai; Wang, Wan-Dang; Xiang, Wen-Yu; Kong, Bin; Wang, Zhi-Yong; Wu, Bin-Hua; Chen, Xiao-Dong; He, Long; Zhang, Shu; Wang, Cong-Yi; Xu, Jun-Fa

    2013-01-01

    Despite the recent realization of Interleukin (IL)-35 in tumorigenesis, its exact impact on colorectal cancer (CRC) progression and prognosis, however, is yet to be elucidated clearly. We thus in the present report conducted comparative analysis of IL-35 levels between CRC patients and matched control subjects. IL-35 is highly expressed in all CRC tissues, which can be detected in vast majority of colorectal cancer cells. IL-35 levels in CRC lysates and serum samples are highly correlated to the severity of malignancy and the clinical stage of tumor. Particularly, a significant reduction for serum IL-35 was noted in patients after surgical resection, indicating that IL-35 promotes CRC progression associated with poor prognosis. Mechanistic study demonstrated a significant correlation between serum IL-35 levels and the number of peripheral regulatory T (Treg) cells in CRC patients, suggesting that IL-35 implicates in CRC pathogenesis probably by inducing Treg cells, while cancer cell-derived IL-35 may also recruit Treg cells into the tumor microenvironment in favor of tumor growth. Together, our data support that IL-35 could be a valuable biomarker for assessing CRC progression and prognosis in clinical settings.

  3. 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

  4. 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

  5. Nano-encapsulated chlorophyllin significantly delays progression of lung cancer both in in vitro and in vivo models through activation of mitochondrial signaling cascades and drug-DNA interaction.

    Science.gov (United States)

    Das, Jayeeta; Samadder, Asmita; Mondal, Jesmin; Abraham, Suresh K; Khuda-Bukhsh, Anisur Rahman

    2016-09-01

    Chlorophyllin (CHL), a sodium-copper-salt derived from chlorophyll, has been widely used as a food-dye, also reportedly having some anti-cancer effect. We tested if PLGA-loaded CHL (NCHL) could have additional protective abilities through its faster and targeted drug delivery in cancer cells. Physico-chemical characterization of NCHL was done through atomic-force microscopy and UV-spectroscopy. NCHL demonstrated greater ability of drug uptake and strong anti-cancer potentials in non-small cell lung cancer cells, A549, as revealed from data of% cell viability, generation of reactive-oxygen-species and expression of bax, bcl2, caspase3, p53 and cytochrome c proteins. Circular dichroic spectral data indicated strong binding of NCHL with calf-thymus-DNA, causing a conformational/structural change in DNA. Further, NCHL could cross the blood-brain-barrier in mice and showed greater efficacy in recovery process of tissue damage, reduction in chromosomal aberrations and% of micronuclei in co-mutagens (Sodiumarsenite+Benzo[a]Pyrene)-treated mice at a much reduced dose, indicating its use in therapeutic oncology.

  6. Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis

    Institute of Scientific and Technical Information of China (English)

    Guocan Wang; Chia-Hsin Chan; Yuan Gao; Hui-Kuan Lin

    2012-01-01

    S-phase kinase-associated protein 2 (Skp2) belongs to the F-box protein family.It is a component of the SCF E3 ubiquitin ligase complex.Skp2 has been shown to regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation,including cyclin-dependent kinase inhibitor p27.Skp2 has also been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers.This review discusses the recent discoveries on the novel roles of Skp2 in regulating cellular senescence,cancer progression,and metastasis,as well as the therapeutic potential of targeting Skp2 for human cancer treatment.

  7. 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.

  8. Probiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis.

    Science.gov (United States)

    Konishi, Hiroaki; Fujiya, Mikihiro; Tanaka, Hiroki; Ueno, Nobuhiro; Moriichi, Kentaro; Sasajima, Junpei; Ikuta, Katsuya; Akutsu, Hiroaki; Tanabe, Hiroki; Kohgo, Yutaka

    2016-01-01

    Previous reports have suggested that some probiotics inhibit tumorigenesis and cancer progression. However, the molecules involved have not yet been identified. Here, we show that the culture supernatant of Lactobacillus casei ATCC334 has a strong tumour-suppressive effect on colon cancer cells. Using mass spectrometry, we identify ferrichrome as a tumour-suppressive molecule produced by L. casei ATCC334. The tumour-suppressive effect of ferrichrome is greater than that of cisplatin and 5-fluorouracil, and ferrichrome has less of an effect on non-cancerous intestinal cells than either of those agents. A transcriptome analysis reveals that ferrichrome treatment induces apoptosis, which is mediated by the activation of c-jun N-terminal kinase (JNK). Western blotting indicates that the induction of apoptosis by ferrichrome is reduced by the inhibition of the JNK signalling pathway. This we demonstrate that probiotic-derived ferrichrome exerts a tumour-suppressive effect via the JNK signalling pathway. PMID:27507542

  9. 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).

  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. 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

  12. 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.

  13. 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

  14. Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression

    Science.gov (United States)

    Zhai, Hui-yuan; Sui, Ming-hua; Yu, Xiao; Qu, Zhen; Hu, Jin-chen; Sun, Hai-qing; Zheng, Hai-tao; Zhou, Kai; Jiang, Li-xin

    2016-01-01

    Background Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. Material/Methods qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. Results Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. Conclusions LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells. PMID:27634385

  15. 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.

  16. 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.

  17. 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.

  18. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.

    Science.gov (United States)

    Chen, W-T; Zhu, G; Pfaffenbach, K; Kanel, G; Stiles, B; Lee, A S

    2014-10-16

    Glucose-regulated protein 78 (GRP78), a molecular chaperone widely elevated in human cancers, is critical for endoplasmic reticulum (ER) protein folding, stress signaling and PI3K/AKT activation. Genetic knockout models of GRP78 revealed that GRP78 maintains homeostasis of metabolic organs, including liver, pancreas and adipose tissues. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common liver cancers. There is a lack of effective therapeutics for HCC and CC, highlighting the need to further understand liver tumorigenic mechanisms. PTEN (phosphatase and tenson homolog deleted on chromosome 10), a tumor suppressor that antagonizes the PI3K/AKT pathway, is inactivated in a wide range of tumors, including 40-50% of human liver cancers. To elucidate the role of GRP78 in liver cancer, we created a mouse model with biallelic liver-specific deletion of Pten and Grp78 mediated by Albumin-Cre-recombinase (cP(f/f)78(f/f)). Interestingly, in contrast to PTEN, deletion of GRP78 was progressive but incomplete. At 3 months, cP(f/f)78(f/f) livers showed hepatomegaly, activation of lipogenic genes, exacerbated steatosis and liver injury, implying that GRP78 protects the liver against PTEN-null-mediated pathogenesis. Furthermore, in response to liver injury, we observed increased proliferation and expansion of bile duct and liver progenitor cells in cP(f/f)78(f/f) livers. Strikingly, bile duct cells in cP(f/f)78(f/f) livers maintained wild-type (WT) GRP78 level, whereas adjacent areas showed GRP78 reduction. Analysis of signaling pathways revealed selective JNK activation, β-catenin downregulation, along with PDGFRα upregulation, which was unique to cP(f/f)78(f/f) livers at 6 months. Development of both HCC and CC was accelerated and was evident in cP(f/f)78(f/f) livers at 8-9 months, coinciding with intense GRP78 expression in the cancer lesions, and GRP78 expression in adjacent normal areas reverted back to the WT level. In contrast, c78(f/f) livers

  19. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    Science.gov (United States)

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer 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. gems: An R Package for Simulating from Disease Progression Models

    Directory of Open Access Journals (Sweden)

    Nello Blaser

    2015-03-01

    Full Text Available Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The R package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death, displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application.

  2. 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.

  3. 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

  4. 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

  5. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer

    Science.gov (United States)

    Chattopadhyay, Esita; Singh, Richa; Ray, Anindita; Roy, Roshni; de Sarkar, Navonil; Paul, Ranjan Rashmi; Pal, Mousumi; Aich, Ritesh; Roy, Bidyut

    2016-09-01

    Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions.

  6. [Apropos of the studies of Lewis, Nusslein-Volhard and Wieschaus, 1995 Nobel prize winners, on the genetic mechanisms of embryonic development of drosophila. A model for human cancer progression].

    Science.gov (United States)

    Cillo, C

    1996-07-01

    EB Lewis, C Nusslein-Volhard and E Wieschaus were the winners of the Nobel prize in 1995 for the discovery of genes controling the embryonic development in drosophila. Drosophila development is dependent on sequential activities of three types of genes: the maternal genes, the segmentation genes, and the homeotic genes which are responsible for the segment identity and finally for the building of the body. Mutations of these genes are spectacular because they affect the body structure formed from individual segments. Therefore, the molecular processes regulating the development of inferior organisms such as yeast or more complex as the vertebrates were elucidated by these three researchers. These early biological mechanisms regulate the cell life through interactions with neighbouring cells. We speculate that any alteration of these processes might be implicated in cancer. Understanding of these molecular mechanisms which control cell interactions in cancer constitutes a basis for definition of new prognostic markers and putatively novel therapeutic approaches.

  7. Nonparametric inference and uniqueness for periodically observed progressive disease models.

    Science.gov (United States)

    Griffin, Beth Ann; Lagakos, Stephen W

    2010-04-01

    In many studies examining the progression of HIV and other chronic diseases, subjects are periodically monitored to assess their progression through disease states. This gives rise to a specific type of panel data which have been termed "chain-of-events data"; e.g. data that result from periodic observation of a progressive disease process whose states occur in a prescribed order and where state transitions are not observable. Using a discrete time semi-Markov model, we develop an algorithm for nonparametric estimation of the distribution functions of sojourn times in a J state progressive disease model. Issues of uniqueness for chain-of-events data are not well-understood. Thus, a main goal of this paper is to determine the uniqueness of the nonparametric estimators of the distribution functions of sojourn times within states. We develop sufficient conditions for uniqueness of the nonparametric maximum likelihood estimator, including situations where some but not all of its components are unique. We illustrate the methods with three examples. PMID:19629683

  8. 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.

  9. Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Prostate Cancer Progression

    Directory of Open Access Journals (Sweden)

    Yixuan Gong

    2014-06-01

    Full Text Available Matrix metalloproteinases (MMPs, a group of zinc-dependent endopeptidases involved in the degradation of the extracellular matrix, play an important role in tissue remodeling associated with various physiological processes such as morphogenesis, angiogenesis, and tissue repair, as well as pathological processes including cirrhosis, arthritis and cancer. The MMPs are well established as mediators of tumor invasion and metastasis by breaking down connective tissue barriers. Although there has been a vast amount of literature on the role of MMPs in invasion, metastasis and angiogenesis of various cancers, the role of these endopeptidases in prostate cancer progression has not been systematically reviewed. This overview summarizes findings on the tissue and blood expression of MMPs, their function, regulation and prognostic implication in human prostate cancer, with a focus on MMP-2, -7, -9, MT1-MMP and tissue inhibitor of metalloproteinase 1 (TIMP-1. This review also summarizes the efficacy and failure of early-generation matrix metalloproteinase inhibitors (MMPIs in the treatment of metastatic prostate cancer and highlights the lessons and challenges for next generation MMPIs.

  10. 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 

  11. The progress and promise of zebrafish as a model to study mast cells.

    Science.gov (United States)

    Prykhozhij, Sergey V; Berman, Jason N

    2014-09-01

    Immunological and hematological research using the zebrafish (Danio rerio) has significantly advanced our understanding of blood lineage ontology, cellular functions and mechanisms, and provided opportunities for disease modeling. Mast cells are an immunological cell type involved in innate and adaptive immune systems, hypersensitivity reactions and cancer progression. The application of zebrafish to study mast cell biology exploits the developmental and imaging opportunities inherent in this model system to enable detailed genetic and molecular studies of this lineage outside of traditional mammalian models. In this review, we first place the importance of mast cell research in zebrafish into the context of comparative studies of mast cells in other fish species and highlight its advantages due to superior experimental tractability and direct visualization in transparent embryos. We discuss current and future tools for mast cell research in zebrafish and the notable results of using zebrafish for understanding mast cell fate determination and our development of a systemic mastocytosis model.

  12. 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.)

  13. 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...

  14. Purine nucleoside analog--sulfinosine modulates diverse mechanisms of cancer progression in multi-drug resistant cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Mirjana Dačević

    progression qualify SF as multi-potent anti-cancer agent, which use must be considered, in particular for resistant malignancies.

  15. Cancer immunotherapy : insights from transgenic animal models

    NARCIS (Netherlands)

    McLaughlin, PMJ; Kroesen, BJ; Harmsen, MC; de Leij, LFMH

    2001-01-01

    A wide range of strategies in cancer immunotherapy has been developed in the last decade, some of which are currently being used in clinical settings. The development of these immunotherapeutical strategies has been facilitated by the generation of relevant transgenic animal models. Since the differ

  16. 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.

  17. 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

  18. 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.

  19. Role of interleukin-8 in the progression of estrogen receptor-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    YAO Chen; LIN Ying; YE Cai-sheng; BI Jiong; ZHU Yi-fan; WANG Shen-ming

    2007-01-01

    Background Estrogen receptor (ER) is a very important biomarker of breast cancer. ER deletion has been consistently associated with tumor progression, recurrence, metastasis and poor prognosis, but the biological mechanism is still unclear. ER negative breast cancer expresses high levels of interieukin-8 (IL-8). ER expression can downregulate IL-8 promotor activity. As a multifunctional cytokine, IL-8 has many important biological activities in tumor genesis and development. With the goal of investigating the role of IL-8 in ER-negative breast cancer progression, we applied RNA interference technology to specifically knockdown the IL-8 expression in ER-negative breast cancer cell line MDA-MB-231.Methods Interfering pRNA-IL-8 and the control was transfected into ER(-) MDA-MB-231. The proliferation, cell apotosis,and invasive ability were recorded in transfected, untransfected and negative transfected cells. These cells were injected into nude mice to assess tumorigenicity, proliferation, metastasis and microvessel density (MVD).Results In vitro, decreased expression of IL-8 was associated with reduced cell invasion (P<0.001), but had no effect on cell proliferation (P>0.05). In vivo, neutrophils infiltration was significantly inhibited in pRNA-IL-8 transfected cells compared with untransfected and negatively transfected cells (P=0.001, P<0.001). Less metastasis was found in transfected cells compared with negatively transfected cells (0% vs 80%, P=0.048). Nevertheless, we observed less MVD in transfected cells compared with control in nude mice (P<0.001).Conclusions IL-8 inhibits ER-negative breast cancer cell growth and promotes its metastasis in vivo, which may be correlated with neutrophils infiltration induced by IL-8.

  20. 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 ...

  1. DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage

    Directory of Open Access Journals (Sweden)

    DeGeest Koen

    2008-09-01

    Full Text Available Abstract Background Hypermethylation of promoter CpG islands with associated loss of gene expression, and hypomethylation of CpG-rich repetitive elements that may destabilize the genome are common events in most, if not all, epithelial cancers. Methods The methylation of 6,502 CpG-rich sequences spanning the genome was analyzed in 137 ovarian samples (ten normal, 23 low malignant potential, 18 stage I, 16 stage II, 54 stage III, and 16 stage IV ranging from normal tissue through to stage IV cancer using a sequence-validated human CpG island microarray. The microarray contained 5' promoter-associated CpG islands as well as CpG-rich satellite and Alu repetitive elements. Results Results showed a progressive de-evolution of normal CpG methylation patterns with disease progression; 659 CpG islands showed significant loss or gain of methylation. Satellite and Alu sequences were primarily associated with loss of methylation, while promoter CpG islands composed the majority of sequences with gains in methylation. Since the majority of ovarian tumors are late stage when diagnosed, we tested whether DNA methylation profiles could differentiate between normal and low malignant potential (LMP compared to stage III ovarian samples. We developed a class predictor consisting of three CpG-rich sequences that was 100% sensitive and 89% specific when used to predict an independent set of normal and LMP samples versus stage III samples. Bisulfite sequencing confirmed the NKX-2-3 promoter CpG island was hypermethylated with disease progression. In addition, 5-aza-2'-deoxycytidine treatment of the ES2 and OVCAR ovarian cancer cell lines re-expressed NKX-2-3. Finally, we merged our CpG methylation results with previously published ovarian expression microarray data and identified correlated expression changes. Conclusion Our results show that changes in CpG methylation are cumulative with ovarian cancer progression in a sequence-type dependent manner, and that Cp

  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. 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.

  4. Model-theoretical foundation of action and progression

    Institute of Scientific and Technical Information of China (English)

    田启家; 史忠植

    1997-01-01

    Action is one of the most important concepts in computer science, and situation calculus is the standard formalism for representing and reasoning about actions and their effects. Situation calculus essentially could be presented in a logic framework. Based on the framework LR, such a logic framework is given. Minimal action theory is proposed and studied from the point of view of model theory. By theorems of mathematical logic, some results about the definability about the progression in minimal action theory are obtained.

  5. 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

  6. In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Che-Ming Liu

    Full Text Available Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4 expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1, which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.

  7. 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

  8. 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.

  9. Towards a multiscale model of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Ingeborg MM van Leeuwen; Carina M Edwards; Mohammad Ilyas; Helen M Byrne

    2007-01-01

    Colorectal cancer (CRC) is one of the best characterised cancers, with extensive data documenting the sequential gene mutations that underlie its development.Complementary datasets are also being generated describing changes in protein and RNA expression,tumour biology and clinical outcome. Both the quantity and the variety of information are inexorably increasing and there is now an accompanying need to integrate these highly disparate datasets. In this article we aim to explain why we believe that mathematical modelling represents a natural tool or language with which to integrate these data and, in so doing, to provide insight into CRC.

  10. Role of deregulated microRNAs in breast cancer progression using FFPE tissue.

    Directory of Open Access Journals (Sweden)

    Liang Chen

    Full Text Available MicroRNAs (miRNAs contribute to cancer initiation and progression by silencing the expression of their target genes, causing either mRNA molecule degradation or translational inhibition. Intraductal epithelial proliferations of the breast are histologically and clinically classified into normal, atypical ductal hyperplasia (ADH, ductal carcinoma in situ (DCIS and invasive ductal carcinoma (IDC. To better understand the progression of ductal breast cancer development, we attempt to identify deregulated miRNAs in this process using Formalin-Fixed, Paraffin-Embedded (FFPE tissues from breast cancer patients. Following tissue microdissection, we obtained 8 normal, 4 ADH, 6 DCIS and 7 IDC samples, which were subject to RNA isolation and miRNA expression profiling analysis. We found that miR-21, miR-200b/c, miR-141, and miR-183 were consistently up-regulated in ADH, DCIS and IDC compared to normal, while miR-557 was uniquely down-regulated in DCIS. Interestingly, the most significant miRNA deregulations occurred during the transition from normal to ADH. However, the data did not reveal a step-wise miRNA alteration among discrete steps along tumor progression, which is in accordance with previous reports of mRNA profiling of different stages of breast cancer. Furthermore, the expression of MSH2 and SMAD7, two important molecules involving TGF-β pathway, was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells. In this study, we have not only identified a number of potential candidate miRNAs for breast cancer, but also found that deregulation of miRNA expression during breast tumorigenesis might be an early event since it occurred significantly during normal to ADH transition. Consequently, we have demonstrated the feasibility of miRNA expression profiling analysis using archived FFPE tissues, typically with rich clinical information, as a means of miRNA biomarker discovery.

  11. 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.

  12. 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.

  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. Ski regulates Hippo and TAZ signaling to suppress breast cancer progression.

    Science.gov (United States)

    Rashidian, Juliet; Le Scolan, Erwan; Ji, Xiaodan; Zhu, Qingwei; Mulvihill, Melinda M; Nomura, Daniel; Luo, Kunxin

    2015-02-10

    Ski, the transforming protein of the avian Sloan-Kettering retrovirus, inhibits transforming growth factor-β (TGF-β)/Smad signaling and displays both pro-oncogenic and anti-oncogenic activities in human cancer. Inhibition of TGF-β signaling is likely responsible for the pro-oncogenic activity of Ski. We investigated the mechanism(s) underlying the tumor suppressor activity of Ski and found that Ski suppressed the activity of the Hippo signaling effectors TAZ and YAP to inhibit breast cancer progression. TAZ and YAP are transcriptional coactivators that can contribute to cancer by promoting proliferation, tumorigenesis, and cancer stem cell expansion. Hippo signaling activates the the Lats family of kinases, which phosphorylate TAZ and YAP, resulting in cytoplasmic retention and degradation and inhibition of their transcriptional activity. We showed that Ski interacted with multiple components of the Hippo pathway to facilitate activation of Lats2, resulting in increased phosphorylation and subsequent degradation of TAZ. Ski also promoted the degradation of a constitutively active TAZ mutant that is not phosphorylated by Lats, suggesting the existence of a Lats2-independent degradation pathway. Finally, we showed that Ski repressed the transcriptional activity of TAZ by binding to the TAZ partner TEAD and recruiting the transcriptional co-repressor NCoR1 to the TEAD-TAZ complex. Ski effectively reversed transformation and epithelial-to-mesenchyme transition in cultured breast cancer cells and metastasis in TAZ-expressing xenografted tumors. Thus, Ski inhibited the function of TAZ through multiple mechanisms in human cancer cells.

  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. 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.

  19. Recent progress in the identification of BRAF inhibitors as anti-cancer agents.

    Science.gov (United States)

    El-Nassan, Hala Bakr

    2014-01-24

    The "RAS/BRAF/MEK/ERK" pathway has been associated with human cancers due to the frequent oncogenic mutations identified in its members. In particular, BRAF is mutated at high frequency in many cancers especially melanoma. This mutation leads to activation of the MAPK signaling pathway, inducing uncontrolled cell proliferation, and facilitating malignant transformation. All these facts make BRAF an ideal target for antitumor therapeutic development. Many BRAF inhibitors have been discovered during the last decade and most of them exhibit potent antitumor activity especially on tumors that harbor BRAF(V600E) mutations. Some of these compounds have entered clinical trials and displayed encouraged results. The present review highlights the progress in identification and development of BRAF inhibitors especially during the last five years.

  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. The role of miRNA regulation in cancer progression and drug resistance

    DEFF Research Database (Denmark)

    Joshi, Tejal

    RNAs in the context of cancer biology, drug resistance and disease progression. The first project described in Chapter 6 addresses the problem of tamoxifen resistance, an anti-estrogen drug that is generally highly effective in the treatment of ER-positive breast cancers. The underlying molecular mechanisms......This PhD thesis presents the work carried out at Center for Biological Sequence Analysis, Technical University of Denmark. The projects presented in this thesis are a purely bioinformatic in nature. Included in this thesis are the two projects that focus on the gene regulatory events mediated by mi...... for the acquired resistance to tamoxifen are not very well understood. Therefore, with the aid of miRNA and gene expression profiles for MCF7/S0.5 (tamoxifen sensitive) and three MCF7/S0.5 derived tamoxifen resistant cell lines, we obtained several miRNA-mediated regulatory events in the tamoxifen resistant cell...

  2. Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression.

    Science.gov (United States)

    Barras, David; Lorusso, Girieca; Lhermitte, Benoît; Viertl, David; Rüegg, Curzio; Widmann, Christian

    2014-07-01

    The p120 RasGAP protein negatively regulates Ras via its GAP domain. RasGAP carries several other domains that modulate several signaling molecules such as Rho. RasGAP is also a caspase-3 substrate. One of the caspase-3-generated RasGAP fragments, corresponding to amino acids 158-455 and called fragment N2, was previously reported to specifically sensitize cancer cells to death induced by various anticancer agents. Here, we show that fragment N2 inhibits migration in vitro and that it impairs metastatic progression of breast cancer to the lung. Hence, stress-activated caspase-3 might contribute to the suppression of metastasis through the generation of fragment N2. These results indicate that the activity borne by fragment N2 has a potential therapeutic relevance to counteract the metastatic process.

  3. Recent progress in development of siRNA delivery vehicles for cancer therapy.

    Science.gov (United States)

    Kim, Hyun Jin; Kim, Ahram; Miyata, Kanjiro; Kataoka, Kazunori

    2016-09-01

    Recent progress in RNA biology has broadened the scope of therapeutic targets of RNA drugs for cancer therapy. However, RNA drugs, typically small interfering RNAs (siRNAs), are rapidly degraded by RNases and filtrated in the kidney, thereby requiring a delivery vehicle for efficient transport to the target cells. To date, various delivery formulations have been developed from cationic lipids, polymers, and/or inorganic nanoparticles for systemic delivery of siRNA to solid tumors. This review describes the current status of clinical trials related to siRNA-based cancer therapy, as well as the remaining issues that need to be overcome to establish a successful therapy. It, then introduces various promising design strategies of delivery vehicles for stable and targeted siRNA delivery, including the prospects for future design.

  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. 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.

  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. 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. 

  8. 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

  9. 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.

  10. 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

  11. Real-time motion analysis reveals cell directionality as an indicator of breast cancer progression.

    Directory of Open Access Journals (Sweden)

    Michael C Weiger

    Full Text Available Cancer cells alter their migratory properties during tumor progression to invade surrounding tissues and metastasize to distant sites. However, it remains unclear how migratory behaviors differ between tumor cells of different malignancy and whether these migratory behaviors can be utilized to assess the malignant potential of tumor cells. Here, we analyzed the migratory behaviors of cell lines representing different stages of breast cancer progression using conventional migration assays or time-lapse imaging and particle image velocimetry (PIV to capture migration dynamics. We find that the number of migrating cells in transwell assays, and the distance and speed of migration in unconstrained 2D assays, show no correlation with malignant potential. However, the directionality of cell motion during 2D migration nicely distinguishes benign and tumorigenic cell lines, with tumorigenic cell lines harboring less directed, more random motion. Furthermore, the migratory behaviors of epithelial sheets observed under basal conditions and in response to stimulation with epidermal growth factor (EGF or lysophosphatitic acid (LPA are distinct for each cell line with regard to cell speed, directionality, and spatiotemporal motion patterns. Surprisingly, treatment with LPA promotes a more cohesive, directional sheet movement in lung colony forming MCF10CA1a cells compared to basal conditions or EGF stimulation, implying that the LPA signaling pathway may alter the invasive potential of MCF10CA1a cells. Together, our findings identify cell directionality as a promising indicator for assessing the tumorigenic potential of breast cancer cell lines and show that LPA induces more cohesive motility in a subset of metastatic breast cancer cells.

  12. A role of autophagy in PTP4A3-driven cancer progression.

    Science.gov (United States)

    Huang, Yu-Han; Al-Aidaroos, Abdul Qader O; Yuen, Hiu-Fung; Zhang, Shu-Dong; Shen, Han-Ming; Rozycka, Ewelina; McCrudden, Cian M; Tergaonkar, Vinay; Gupta, Abhishek; Lin, You Bin; Thiery, Jean Paul; Murray, James T; Zeng, Qi

    2014-10-01

    Autophagy, a "self-eating" cellular process, has dual roles in promoting and suppressing tumor growth, depending on cellular context. PTP4A3/PRL-3, a plasma membrane and endosomal phosphatase, promotes multiple oncogenic processes including cell proliferation, invasion, and cancer metastasis. In this study, we demonstrate that PTP4A3 accumulates in autophagosomes upon inhibition of autophagic degradation. Expression of PTP4A3 enhances PIK3C3-BECN1-dependent autophagosome formation and accelerates LC3-I to LC3-II conversion in an ATG5-dependent manner. PTP4A3 overexpression also enhances the degradation of SQSTM1, a key autophagy substrate. These functions of PTP4A3 are dependent on its catalytic activity and prenylation-dependent membrane association. These results suggest that PTP4A3 functions to promote canonical autophagy flux. Unexpectedly, following autophagy activation, PTP4A3 serves as a novel autophagic substrate, thereby establishing a negative feedback-loop that may be required to fine-tune autophagy activity. Functionally, PTP4A3 utilizes the autophagy pathway to promote cell growth, concomitant with the activation of AKT. Clinically, from the largest ovarian cancer data set (GSE 9899, n = 285) available in GEO, high levels of expression of both PTP4A3 and autophagy genes significantly predict poor prognosis of ovarian cancer patients. These studies reveal a critical role of autophagy in PTP4A3-driven cancer progression, suggesting that autophagy could be a potential Achilles heel to block PTP4A3-mediated tumor progression in stratified patients with high expression of both PTP4A3 and autophagy genes.

  13. Relevance of the neuropeptide Y system in the biology of cancer progression.

    Science.gov (United States)

    Ruscica, M; Dozio, E; Motta, M; Magni, P

    2007-01-01

    The peptides pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY) share a similar structure, known as PP-fold. Within this family of peptides, NPY, a highly conserved 36-aminoacid residue peptide, is involved in the regulation of a wide range of physiological functions, such as food intake and energy metabolism, as well as in the promotion of some remarkable aspects of tumor progression, including cell proliferation, matrix invasion, metastatization, and angiogenesis. NPY exerts its biological effects through five G-protein coupled receptors, named Y1-, Y2-, Y4-, Y5-, and y6-R, which appear associated with different aspects of oncogenesis. Y1-R seems involved in the modulation of cancer cell proliferation, whereas Y2-R activation appears to promote angiogenesis. The development of NPY receptor subtype selective analogs has helped to elucidate the physiological and pathophysiological role and localization of each receptor and may contribute to a better understanding of the receptor-ligand interaction. The NPY system appears to be variously associated with specific tumors, including neural crest-derived tumors, breast and prostate cancers. In addition to NPY, PYY is also able to affect cancer cell growth in a dose-dependent manner and through Y-Rs. In conclusion, peptides of the NPY family and the related receptors play an important role in the progression of different cancer types, with some molecular specificity according to each step of this process. On this basis, future studies may be directed to the implementation of novel diagnostic and therapeutic approaches targeting this system.

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.)

  20. 自噬与甲状腺癌的研究进展%Autophagy and its research progress in thyroid cancer

    Institute of Scientific and Technical Information of China (English)

    张思林; 罗庆; 余杰情

    2016-01-01

    To summarize the autophagy and its research progress in thyroid cancer.In combination with available literatures published in recent years involving the relationship between autophagy and thyroid cancer,the characteristics of autophagy,the role in thyroid cancer were reviewed.The changes of autophagy level will directly or indirectly participate in the pathogenesis and progression of thyroid cancer.Reagents regulating autophagy will have broad prospect of application in thyroid cancer therapy.The autophagy in the thyroid cancer is still poorly understood,and to clarify the molecular mechanism of autophagy and kill thyroid cancer cells by reasonable regulation of autophagy still needs more further studies.

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. Mouse models for BRAF-induced cancers.

    Science.gov (United States)

    Pritchard, C; Carragher, L; Aldridge, V; Giblett, S; Jin, H; Foster, C; Andreadi, C; Kamata, T

    2007-11-01

    Oncogenic mutations in the BRAF gene are detected in approximately 7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine-->glutamate mutation at residue 600 ((V600E)BRAF). In cells cultured in vitro, (V600E)BRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that (V600E)BRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.

  8. Early decline in cancer antigen 125 as a surrogate for progression-free survival in recurrent ovarian cancer

    DEFF Research Database (Denmark)

    Lee, Chee K; Friedlander, Michael; Brown, Chris;

    2011-01-01

    [38.7%], P = .14) compared with CP patients. The PFS for CPLD patients did not change statistically significantly after adjustment for early decline (adjusted HR = 0.80, 95% CI = 0.68 to 0.94, P = .007). These findings are opposite to what would be expected if these markers were good surrogates......We used data from 886 patients from the CAELYX in Platinum Sensitive Ovarian Patients (CALYPSO) trial, recruited between April 2005 and September 2007, to examine the role of early decline in cancer antigen 125 (CA125) and early tumor response as prognostic factors and surrogates for superiority...... response as surrogates for CPLD treatment benefit compared with CP. All statistical tests were two-sided. Early decline (defined as rate of CA125 decrease of at least 50% per month) was associated with improved PFS (adjusted hazard ratio [HR] for progression = 0.81, 95% confidence interval [CI] = 0.67 to 0...

  9. SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis.

    Science.gov (United States)

    Tseng, Ruo-Chia; Lee, Shih-Hua; Hsu, Han-Shui; Chen, Ben-Han; Tsai, Wan-Ching; Tzao, Ching; Wang, Yi-Ching

    2010-01-15

    Chromosome 4p15.3 is frequently deleted in late-stage lung cancer. We investigated the significance of the SLIT2 gene located in this region to lung cancer progression. SLIT2 encodes an extracellular glycoprotein that can suppress breast cancer by regulating beta-catenin. In this study, we examined alterations in the structure or expression of SLIT2, its receptor ROBO1, and beta-catenin, along with the AKT/glycogen synthase kinase 3beta (GSK3beta)/beta-transducin repeat-containing protein (betaTrCP) pathway in lung cancer cell lines and patients. Low SLIT2 expression correlated with an upward trend of pathological stage and poorer survival in lung cancer patients. Importantly, SLIT2, betaTrCP, and beta-catenin expression levels predicted postoperative recurrence of lung cancer in patients. Stimulating SLIT2 expression by various methods increased the level of E-cadherin caused by attenuation of its transcriptional repressor SNAI1. Conversely, knocking down SLIT2 expression increased cell migration and reduced cell adhesion through coordinated deregulation of beta-catenin and E-cadherin/SNAI1 in the AKT/GSK3beta/betaTrCP pathway. Our findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel "theranostic" factor with potential as a therapeutic target and prognostic predictor in lung cancer. Cancer Res; 70(2); 543-51.

  10. 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

  11. 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

  12. A Stochastic Model for the Progression of Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Noura Anwar

    2014-11-01

    Full Text Available Multistate Markov models are well-established methods for estimating rates of transition between stages of chronic diseases. The objective of this study is to propose a stochastic model that describes the progression process of chronic kidney disease; CKD, estimate the mean time spent in each stage of disease stages that precedes developing end-stage renal failure and to estimate the life expectancy of a CKD patient. Continuoustime Markov Chain is appropriate to model CKD. Explicit expressions of transition probability functions are derived by solving system of forward Kolmogorov differential equations. Besides, the mean sojourn time, the state probability distribution, life expectancy of a CKD patient and expected number of patients in each state of the system are presented in the study. A numerical example is provided. Finally, concluding remarks and discussion are presented.

  13. The Role of Pulmonary Veins in Cancer Progression from a Computed Tomography Viewpoint

    Science.gov (United States)

    Chang, Hung; Liao, Tzu-Yao; Wen, Ming-Sheng; Yu, Chih-Teng

    2016-01-01

    Background. We studied the role of pulmonary veins in cancer progression using computed tomography (CT) scans. Methods. We obtained data from 260 patients with pulmonary vein obstruction syndrome (PVOS). We used CT scans to investigate pulmonary lesions in relation to pulmonary veins. We divided the lesions into central and peripheral lesions by their anatomical location: in the lung parenchymal tissue or pulmonary vein; in the superior or inferior pulmonary vein; and by unilateral or bilateral presence in the lungs. Results. Of the 260 PVOS patients, 226 (87%) had central lesions, 231 (89%) had peripheral lesions, and 190 (75%) had mixed central and peripheral lesions. Among the 226 central lesions, 93% had lesions within the superior pulmonary vein, either bilaterally or unilaterally. Among the 231 peripheral lesions, 65% involved bilateral lungs, 70% involved lesions within the inferior pulmonary veins, and 23% had obvious metastatic extensions into the left atrium. All patients exhibited nodules within their pulmonary veins. The predeath status included respiratory failure (40%) and loss of consciousness (60%). Conclusion. CT scans play an important role in following tumor progression within pulmonary veins. Besides respiratory distress, PVOS cancer cells entering centrally can result in cardiac and cerebral events and loss of consciousness or can metastasize peripherally from the pulmonary veins to the lungs.

  14. 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.

  15. Validating and Optimizing the Effects of Model Progression in Simulation-Based Inquiry Learning

    Science.gov (United States)

    Mulder, Yvonne G.; Lazonder, Ard W.; de Jong, Ton; Anjewierden, Anjo; Bollen, Lars

    2012-01-01

    Model progression denotes the organization of the inquiry learning process in successive phases of increasing complexity. This study investigated the effectiveness of model progression in general, and explored the added value of either broadening or narrowing students' possibilities to change model progression phases. Results showed that…

  16. The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration.

    Science.gov (United States)

    Fraga, Avelino; Ribeiro, Ricardo; Príncipe, Paulo; Lobato, Carlos; Pina, Francisco; Maurício, Joaquina; Monteiro, Cátia; Sousa, Hugo; Calais da Silva, F; Lopes, Carlos; Medeiros, Rui

    2014-01-01

    The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

  17. Mouse Models of Breast Cancer: Platforms for Discovering Precision Imaging Diagnostics and Future Cancer Medicine.

    Science.gov (United States)

    Manning, H Charles; Buck, Jason R; Cook, Rebecca S

    2016-02-01

    Representing an enormous health care and socioeconomic challenge, breast cancer is the second most common cancer in the world and the second most common cause of cancer-related death. Although many of the challenges associated with preventing, treating, and ultimately curing breast cancer are addressable in the laboratory, successful translation of groundbreaking research to clinical populations remains an important barrier. Particularly when compared with research on other types of solid tumors, breast cancer research is hampered by a lack of tractable in vivo model systems that accurately recapitulate the relevant clinical features of the disease. A primary objective of this article was to provide a generalizable overview of the types of in vivo model systems, with an emphasis primarily on murine models, that are widely deployed in preclinical breast cancer research. Major opportunities to advance precision cancer medicine facilitated by molecular imaging of preclinical breast cancer models are discussed.

  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. 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.

  20. 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.

  1. 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.

  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. KAP1 promotes proliferation and metastatic progression of breast cancer cells.

    Science.gov (United States)

    Addison, Joseph B; Koontz, Colton; Fugett, James H; Creighton, Chad J; Chen, Dongquan; Farrugia, Mark K; Padon, Renata R; Voronkova, Maria A; McLaughlin, Sarah L; Livengood, Ryan H; Lin, Chen-Chung; Ruppert, J Michael; Pugacheva, Elena N; Ivanov, Alexey V

    2015-01-15

    KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here, we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers. KAP1 silencing in breast cancer cells reduced proliferation and inhibited the growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. In cells where KAP1 was silenced, we identified multiple downregulated genes linked to tumor progression and metastasis, including EREG/epiregulin, PTGS2/COX2, MMP1, MMP2, and CD44, along with downregulation of multiple KRAB-ZNF proteins. KAP1-dependent stabilization of KRAB-ZNF required direct interactions with KAP1. Together, our results show that KAP1-mediated stimulation of multiple KRAB-ZNF contributes to the growth and metastasis of breast cancer.

  4. 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

  5. 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.

  6. Progress in gastric cancer surgery in Japan%日本胃癌外科治疗的进展

    Institute of Scientific and Technical Information of China (English)

    丸山圭一; 陈雨信

    2008-01-01

    The.progress in diagnosis and surgical treatment of gastric cancer contributes to the raised diagnosis rate and 5-year survival rate of gastric cancer patients in Japan. According to the clinical data of 273 142 Japanese gastric cancer patients from 1962 to 1991, the proportion of patients with stage I gastric cancer was increased from 22.5% to 58.1%, and the accumulative 5-year survival rate from 37.5% to 68.8%. The improvement of the accumulative 5-year survival rate was remarkable for patients with stage Ⅱ gastric cancer (from 47.7% to 70.3%) and stage Ⅲ gastric cancer (from 26.4% to 45.0%).

  7. HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells.

    Directory of Open Access Journals (Sweden)

    Amy Belton

    Full Text Available BACKGROUND: Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES cells to facilitate an epithelial-mesenchymal transition (EMT, invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood. METHODS/PRINCIPAL FINDINGS: To determine how HMGA1 functions in metastatic colon cancer, we manipulated HMGA1 expression in transgenic mice and colon cancer cells. We discovered that HMGA1 drives proliferative changes, aberrant crypt formation, and intestinal polyposis in transgenic mice. In colon cancer cell lines from poorly differentiated, metastatic tumors, knock-down of HMGA1 blocks anchorage-independent cell growth, migration, invasion, xenograft tumorigenesis and three-dimensional colonosphere formation. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the knock-down cells. Knock-down of HMGA1 also inhibits metastatic progression to the liver in vivo. In metastatic colon cancer cells, HMGA1 induces expression of Twist1, a gene involved in embryogenesis, EMT, and tumor progression, while HMGA1 represses E-cadherin, a gene that is down-regulated during EMT and metastatic progression. In addition, HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa. CONCLUSIONS: Our findings demonstrate for the first time that HMGA1 drives proliferative changes and polyp formation in the intestines of transgenic mice and induces metastatic progression and stem-like properties in colon cancer cells. These findings indicate that HMGA1 is a key regulator, both in metastatic

  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...... on 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. 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.

  10. 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

  11. A Stochastic Markov Chain Model to Describe Lung Cancer Growth and Metastasis

    OpenAIRE

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

    2012-01-01

    A stochastic Markov chain model for metastatic progression is developed for primary lung cancer based on a network construction of metastatic sites with dynamics modeled as an ensemble of random walkers on the network. We calculate a transition matrix, with entries (transition probabilities) interpreted as random variables, and use it to construct a circular bi-directional network of primary and metastatic locations based on postmortem tissue analysis of 3827 autopsies on untreated patients d...

  12. 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...

  13. Models and correlations of the DEBRIS Late-Phase Melt Progression Model

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, R.C.; Gasser, R.D. [Sandia National Labs., Albuquerque, NM (United States). Reactor Safety Experiments Dept.

    1997-09-01

    The DEBRIS Late Phase Melt Progression Model is an assembly of models, embodied in a computer code, which is designed to treat late-phase melt progression in dry rubble (or debris) regions that can form as a consequence of a severe core uncover accident in a commercial light water nuclear reactor. The approach is fully two-dimensional, and incorporates a porous medium modeling framework together with conservation and constitutive relationships to simulate the time-dependent evolution of such regions as various physical processes act upon the materials. The objective of the code is to accurately model these processes so that the late-phase melt progression that would occur in different hypothetical severe nuclear reactor accidents can be better understood and characterized. In this report the models and correlations incorporated and used within the current version of DEBRIS are described. These include the global conservation equations solved, heat transfer and fission heating models, melting and refreezing models (including material interactions), liquid and solid relocation models, gas flow and pressure field models, and the temperature and compositionally dependent material properties employed. The specific models described here have been used in the experiment design analysis of the Phebus FPT-4 debris-bed fission-product release experiment. An earlier DEBRIS code version was used to analyze the MP-1 and MP-2 late-phase melt progression experiments conducted at Sandia National Laboratories for the US Nuclear Regulatory Commission.

  14. The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAFV600E-Positive Papillary and Anaplastic Thyroid Carcinoma

    OpenAIRE

    Vanden Borre, Pierre; McFadden, David G.; Gunda, Viswanath; Sadow, Peter M.; Varmeh, Shohreh; Bernasconi, Maria; Jacks, Tyler; Parangi, Sareh

    2014-01-01

    Background: While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient m...

  15. 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

  16. Models for prevention and treatment of cancer: problems vs promises.

    Science.gov (United States)

    Aggarwal, Bharat B; Danda, Divya; Gupta, Shan; Gehlot, Prashasnika

    2009-11-01

    Current estimates from the American Cancer Society and from the International Union Against Cancer indicate that 12 million cases of cancer were diagnosed last year, with 7 million deaths worldwide; these numbers are expected to double by 2030 (27 million cases with 17 million deaths). Despite tremendous technological developments in all areas, and President Richard Nixon's initiative in the 1974 "War against Cancer", the US cancer incidence is the highest in the world and the cancer death rate has not significantly changed in the last 50 years (193.9 per 100,000 in 1950 vs 193.4 per 100,000 in 2002). Extensive research during the same time, however, has revealed that cancer is a preventable disease that requires major changes in life style; with one third of all cancers assigned to Tobacco, one third to diet, and remaining one third to the environment. Approximately 20 billion dollars are spent annually to find a cure for cancer. We propose that our inability to find a cure to cancer lies in the models used. Whether cell culture or animal studies, no model has yet been found that can reproduce the pathogenesis of the disease in the laboratory. Mono-targeted therapies, till know in most cases, have done a little to make a difference in cancer treatment. Similarly, molecular signatures/predictors of the diagnosis of the disease and response are also lacking. This review discusses the pros and cons of current cancer models based on cancer genetics, cell culture, animal models, cancer biomarkers/signature, cancer stem cells, cancer cell signaling, targeted therapies, therapeutic targets, clinical trials, cancer prevention, personalized medicine, and off-label uses to find a cure for cancer and demonstrates an urgent need for "out of the box" approaches. PMID:19481061

  17. Models for prevention and treatment of cancer: problems vs promises.

    Science.gov (United States)

    Aggarwal, Bharat B; Danda, Divya; Gupta, Shan; Gehlot, Prashasnika

    2009-11-01

    Current estimates from the American Cancer Society and from the International Union Against Cancer indicate that 12 million cases of cancer were diagnosed last year, with 7 million deaths worldwide; these numbers are expected to double by 2030 (27 million cases with 17 million deaths). Despite tremendous technological developments in all areas, and President Richard Nixon's initiative in the 1974 "War against Cancer", the US cancer incidence is the highest in the world and the cancer death rate has not significantly changed in the last 50 years (193.9 per 100,000 in 1950 vs 193.4 per 100,000 in 2002). Extensive research during the same time, however, has revealed that cancer is a preventable disease that requires major changes in life style; with one third of all cancers assigned to Tobacco, one third to diet, and remaining one third to the environment. Approximately 20 billion dollars are spent annually to find a cure for cancer. We propose that our inability to find a cure to cancer lies in the models used. Whether cell culture or animal studies, no model has yet been found that can reproduce the pathogenesis of the disease in the laboratory. Mono-targeted therapies, till know in most cases, have done a little to make a difference in cancer treatment. Similarly, molecular signatures/predictors of the diagnosis of the disease and response are also lacking. This review discusses the pros and cons of current cancer models based on cancer genetics, cell culture, animal models, cancer biomarkers/signature, cancer stem cells, cancer cell signaling, targeted therapies, therapeutic targets, clinical trials, cancer prevention, personalized medicine, and off-label uses to find a cure for cancer and demonstrates an urgent need for "out of the box" approaches.

  18. 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

  19. 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...

  20. NDRG1 expression is related to the progression and prognosis of gastric cancer patients through modulating proliferation, invasion and cell cycle of gastric cancer cells.

    Science.gov (United States)

    Chang, Xiaojing; Xu, Xiaoyang; Ma, Jinguo; Xue, Xiaoying; Li, Zhenhua; Deng, Peng; Zhang, Shuanglong; Zhi, Yu; Chen, Jing; Dai, Dongqiu

    2014-09-01

    N-myc downstream-regulated gene 1 (NDRG1) has been proposed as a tumor suppressor gene in many different types of tumors, but its potential function and corresponding mechanism are not yet fully elucidated. This study aims to detect the possible function of NDRG1 in gastric cancer progression. In this study, 112 paired gastric cancer tissues and corresponding nonmalignant gastric tissues were utilized to identify the differential protein expression of NDRG1 by immunohistochemistry and its clinical significance was analyzed. Furthermore, 49 of 112 paired gastric specimens were used to detect the differential mRNA expression by real-time PCR. The over expression of NDRG1 in human gastric cancer cell line AGS by PcDNA3.1-NDRG1 transfection was utilized to detect the role of NDRG1 in regulating the biological behavior of gastric cancer.