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‣ Polycyclic Aromatic Hydrocarbons May Contibute for Prostate Cancer Progression

Freitas, Mariana; Alves, Vera; Sarmento-Ribeiro, Ana; Mota-Pinto, Anabela
Fonte: Scientific Research Publicador: Scientific Research
Tipo: Artigo de Revista Científica
Português
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57.09782%
Prostate cancer is the most common form of cancer affecting men in the Western world. Risk factors include ageing, genetics, recurrent inflammation, lifestyle and diet intake, related to an increase of oxidative stress. Prostate cancer risk is also associated with exposure to carcinogen such as polycyclic aromatic hydrocarbons (PAHs), originated from the incomplete combustion of carbon-containing fuels like tobacco, wood, diesel, or charbroiled meat. Although numerous studies have associated the effect of PAHs to tumour development, few investigations have associated its effects to cancer progression. Considering that prostate cancer patients don’t die from localized prostate cancer but from advanced disease, we are interested in investigating whether PAHs may potentially influence prostate cancer progression and how this could be related to an increase in oxidative stress. Likewise we evaluated the effect of PAHs (pyrene, benzo(a) pyrene, chrysene and benzo(k)fluoranthene) on cell growth and in the expression of molecules involved in cancer me- tastization such as the vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF) using prostate- derived cell lines from localized adenocarcinoma (HPV10), bone metastasis (PC3) and in non-neoplastic prostate epi- thelium cells. Moreover...

‣ A new proposed rodent model of chemically induced prostate carcinogenesis: Distinct time-course prostate cancer progression in the dorsolateral and ventral lobes

Gonçalves, Bianca F.; De Campos, Silvana G.P.; Zanetoni, Cristiani; Scarano, Wellerson R.; Falleiros Jr., Luiz R.; Amorim, Reneé L.; Gões, Rejane M.; Taboga, Sebastião R.
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 1202-1213
Português
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56.98242%
Background. Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes. We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes. Methods. Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment. Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle α-actin, p63, MGMT, and E-cadherin) were studied in both lobes. Results. Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency. However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups. Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration. Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining. Moreover...

‣ T-box transcription factor Brachyury is associated with prostate cancer progression and aggressiveness

Pinto, Filipe; Gomes, Nelma; Pereira, Márcia; Vizcaíno, José R.; Monteiro, Pedro; Henrique, Rui M.; Baltazar, Fátima; Andrade, Raquel P.; Reis, R. M.
Fonte: American Association for Cancer Research Publicador: American Association for Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Purpose: Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury’s expression in prostate cancer. Experimental Design: In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression. Results: We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways...

‣ Curcumin inhibits COPD-like airway inflammation and lung cancer progression in mice

Moghaddam, S.J.; Barta, P.; Mirabolfathinejad, S.G.; Ammar-Aouchiche, Z.; Garza, N. Torres; Vo, T.T.; Newman, Robert A.; Aggarwal, Bharat B.; Evans, Christopher M.; Tuvim, Michael J.; Lotan, Reuben; Dickey, Burton F.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Recent studies have demonstrated that K-ras mutations in lung epithelial cells elicit inflammation that promotes carcinogenesis in mice (intrinsic inflammation). The finding that patients with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer after controlling for smoking suggests a further link between lung cancer and extrinsic inflammation. Besides exposure to cigarette smoke, it is thought that airway inflammation in COPD is caused by bacterial colonization, particularly with non-typeable Hemophilus influenzae (NTHi). Previously, we have shown that NTHi-induced COPD-like airway inflammation promotes lung cancer in an airway conditional K-ras-induced mouse model. To further test the role of inflammation in cancer promotion, we administered the natural anti-inflammatory agent, curcumin, 1% in diet before and during weekly NTHi exposure. This significantly reduced the number of visible lung tumors in the absence of NTHi exposure by 85% and in the presence of NTHi exposures by 53%. Mechanistically, curcumin markedly suppressed NTHi-induced increased levels of the neutrophil chemoattractant keratinocyte-derived chemokine by 80% and neutrophils by 87% in bronchoalveolar lavage fluid. In vitro studies of murine K-ras-induced lung adenocarcinoma cell lines (LKR-10 and LKR-13) indicated direct anti-tumoral effects of curcumin by reducing cell viability...

‣ The type III TGF-β receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-β signaling

Lee, Jason D.; Hempel, Nadine; Lee, Nam Y.; Blobe, Gerard C.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Loss of expression of the type III transforming growth factor-β receptor (TβRIII or betaglycan), a transforming growth factor-β (TGF-β) superfamily co-receptor, is common in human breast cancers. TβRIII suppresses cancer progression in vivo by reducing cancer cell migration and invasion by largely unknown mechanisms. Here, we demonstrate that the cytoplasmic domain of TβRIII is essential for TβRIII-mediated downregulation of migration and invasion in vitro and TβRIII-mediated inhibition of breast cancer progression in vivo. Functionally, the cytoplasmic domain of TβRIII is required to attenuate TGF-β signaling, whereas TβRIII-mediated attenuation of TGF-β signaling is required for TβRIII-mediated inhibition of migration and invasion. Mechanistically, both TβRIII-mediated inhibition of TGF-β signaling and TβRIII-mediated inhibition of invasion occur through the interaction of the cytoplasmic domain of TβRIII with the scaffolding protein GAIP-interacting protein C-terminus (GIPC). Taken together, these studies support a functional role for the TβRIII cytoplasmic domain interacting with GIPC to suppress breast cancer progression.

‣ Label-free monitoring of colonic cancer progression using multiphoton microscopy

Zhuo, Shuangmu; Yan, Jun; Chen, Gang; Chen, Jianxin; Liu, Yuchun; Lu, Jianping; Zhu, Xiaoqin; Jiang, Xingshan; Xie, Shusen
Fonte: Optical Society of America Publicador: Optical Society of America
Tipo: Artigo de Revista Científica
Publicado em 16/02/2011 Português
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Abstract: Real-time histology or virtual biopsy for the diagnosis of colonic cancer is of great medical significance. In this work, we show that label-free multiphoton imaging is feasible and effective in monitoring colonic cancer progression by providing cellular and subcellular details in fresh, unfixed, unstained colonic specimens. Our results also demonstrate the capability of using tissue quantitative analysis of the redox ratio for quantifying colonic cancer progression. These results suggest that multiphoton microscopy has potential to become an in situ histological tool, which is free from the labeling requirement of conventional methods, for the early diagnosis and detection of malignant lesions in the colon.

‣ Current perspectives on skeletal health and cancer progression across the disease continuum in breast cancer—the role of bisphosphonates

Aft, R
Fonte: Cancer Intelligence Publicador: Cancer Intelligence
Tipo: Artigo de Revista Científica
Publicado em 23/08/2012 Português
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56.74327%
Pre-clinical and clinical evidence suggest that bisphosphonates inhibit both bone resorption and cancer progression. New and updated analyses from several large, controlled studies in pre- and post-menopausal women with early stage breast cancer (BC) suggest that addition of bisphosphonates improves cancer-related outcomes, particularly in patients with a ‘low-estrogen environment’. Further, preliminary clinical data suggest that bisphosphonate therapy may reduce circulating tumour cell numbers (a negative prognostic indicator of disease-free and overall survival) in patients with advanced/metastatic disease. These new findings warrant reconsideration of the therapeutic role of bisphosphonates in BC.

‣ Epithelial-mesenchymal transition in breast cancer progression and metastasis

Wang, Yifan; Zhou, Binhua P.
Fonte: Sun Yat-sen University Cancer Center Publicador: Sun Yat-sen University Cancer Center
Tipo: Artigo de Revista Científica
Publicado em /09/2011 Português
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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.

‣ Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Chai, Ming G.; Kim-Fuchs, Corina; Angst, Eliane; Sloan, Erica K.
Fonte: MyJove Corporation Publicador: MyJove Corporation
Tipo: Artigo de Revista Científica
Publicado em 28/06/2013 Português
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Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

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

Liao, Wen-Ting; Feng, Yan; Li, Men-Lin; Liu, Guang-Lin; Li, Man-Zhi; Zeng, Mu-Sheng; Song, Li-Bing
Fonte: Sun Yat-sen University Cancer Center Publicador: Sun Yat-sen University Cancer Center
Tipo: Artigo de Revista Científica
Publicado em /09/2011 Português
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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 Western 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.

‣ Using real-time impedance-based assays to monitor the effects of fibroblast-derived media on the adhesion, proliferation, migration and invasion of colon cancer cells

Dowling, Catríona M; Herranz Ors, Carmen; Kiely, Patrick A
Fonte: Portland Press Publicador: Portland Press
Tipo: info:eu-repo/semantics/article; all_ul_research; ul_published_reviewed
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peer-reviewed; Increasing our knowledge of the mechanisms regulating cell proliferation, migration and invasion are central to understanding tumour progression and metastasis. The local tumour microenvironment contributes to the transformed phenotype in cancer by providing specific environmental cues that alter the cells behaviour and promotes metastasis. Fibroblasts have a strong association with cancer and in recent times there has been some emphasis in designing novel therapeutic strategies that alter fibroblast behaviour in the tumour microenvironment. Fibroblasts produce growth factors, chemokines and many of the proteins laid down in the ECM (extracellular matrix) that promote angiogenesis, inflammation and tumour progression. In this study, we use a label-free RTCA (real-time cell analysis) platform (xCELLigence) to investigate how media derived from human fibroblasts alters cancer cell behaviour. We used a series of complimentary and novel experimental approaches to show HCT116 cells adhere, proliferate and migrate significantly faster in the presence of media from human fibroblasts. As well as this, we used the xCELLigence CIMplates system to show that HCT116 cells invade matrigel layers aggressively when migrating towards media derived from human fibroblasts. These data strongly suggest that fibroblasts have the ability to increase the migratory and invasive properties of HCT116 cells. This is the first study that provides real-time data on fibroblast-mediated migration and invasion kinetics of colon cancer cells.

‣ Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein α; Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein alpha

Buchanan, G.; Ricciardelli, C.; Harris, J.; Prescott, J.; Yu, Z.; Jia, L.; Butler, L.; Marshall, V.; Scher, H.; Gerald, W.; Coetzee, G.; Tilley, W.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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56.994385%
Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine-rich tetratricopeptide repeat containing protein alpha (alphaSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that alphaSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of alphaSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of alphaSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/alphaSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression...

‣ Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression

Wang, Q.; Bailey, C.; Ng, C.; Tiffen, J.; Thoeng, A.; Minhas, V.; Lehman, M.; Hendy, S.; Buchanan, G.; Nelson, C.; Rasko, J.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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L-Type amino acid transporters such as LAT1 and LAT3 mediate the uptake of essential amino acids. Here, we report that prostate cancer cells coordinate the expression of LAT1 and LAT3 to maintain sufficient levels of leucine needed for mTORC1 signaling and cell growth. Inhibiting LAT function was sufficient to decrease cell growth and mTORC1 signaling in prostate cancer cells. These cells maintained levels of amino acid influx through androgen receptor-mediated regulation of LAT3 expression and ATF4 regulation of LAT1 expression after amino acid deprivation. These responses remained intact in primary prostate cancer, as indicated by high levels of LAT3 in primary disease, and by increased levels of LAT1 after hormone ablation and in metastatic lesions. Taken together, our results show how prostate cancer cells respond to demands for increased essential amino acids by coordinately activating amino acid transporter pathways vital for tumor outgrowth.; Qian Wang, Charles G. Bailey, Cynthia Ng, Jessamy Tiffen, Annora Thoeng, Vineet Minhas, Melanie L. Lehman, Stephen C. Hendy, Grant Buchanan, Colleen C. Nelson, John E.J. Rasko and Jeff Holst

‣ The secretome in cancer progression

Paltridge, J.; Belle, L.; Khew-Goodall, Y.
Fonte: Elsevier Science BV Publicador: Elsevier Science BV
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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The secretome is the collection of all macromolecules secreted by a cell, and is a vital aspect of cell-cell communication in eukaryotes. In cancer, tumour cells often display secretomes with altered composition compared to the normal tissue from which they are derived. These changes can contribute to the acquisition and maintenance of the recognised hallmarks of cancer. In addition, evidence is emerging for a more sophisticated role for the tumour secretome in cancer, with significant implications for malignant disease progression. In this review, we highlight recent advances in our understanding of factors contributing to secretome alterations in cancer, including genetic mutations, microRNA-based regulation and the influence of the tumour microenvironment. The contribution of secreted factors in maintenance and function of cancer stem cells, and of tumour-derived factors in specification of a pre-metastatic niche are also discussed. Collectively, evidence from the current literature suggests that the tumour secretome, consisting of factors derived from cancer stem cells, non-stem cells and the surrounding stroma, plays a deterministic role in cancer progression, and may constitute a key therapeutic target in many cancers. This article is part of a Special Issue entitled: An Updated Secretome.; James L. Paltridge...

‣ Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression

Henr??quez-Hern??ndez, Luis Alberto; Valenciano, Almudena; Foro-Arnalot, Palmira; ??lvarez-Cubero, Mar??a Jes??s; C??zar Olmo, Jos?? Manuel; Su??rez-Novo, Jos?? Francisco; Castells-Esteve, Manel; Fern??ndez-Gonzalo, Pablo; De-Paula-Carranza, Bel??n; Ferre
Fonte: Biomed Central Publicador: Biomed Central
Tipo: Artigo de Revista Científica
Português
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Background Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression.; Methods A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Biotrove OpenArray?? NT Cycler. Clinical tumor stage, diagnostic PSA serum levels, and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator.; Results SNPs rs11615 (ERCC1) and rs17503908 (ATM) appeared as risk factors for prostate cancer aggressiveness. Patients wild homozygous for these SNPs (AA and TT, respectively) were at higher risk for developing cT2b ??? cT4 (OR???=???2.21 (confidence interval (CI) 95% 1.47 ??? 3.31), p???

‣ New advances on critical implications of tumorand metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence

Mimeault, M.; Batra, Surinder K.
Fonte: Murcia: F. Hernández Publicador: Murcia: F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
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Accumulating lines of experimental evidence have revealed that the malignant transformation of multipotent tissue-resident adult stem/progenitor cells into cancer stem/progenitor cells endowed with a high self-renewal capacity and aberrant multilineage differentiation potential may be at origin of the most types of human aggressive and recurrent cancers. Based on new cancer stem/progenitor cell concepts of carcinogenesis, it is suggested that a small subpopulation of highly tumorigenic and migrating cancer stem/progenitor cells, also designated as cancer- and metastasis-initiating cells, can provide critical roles for primary tumor growth, metastases at distant tissues and organs, treatment resistance and disease relapse. Particularly, cancer initiation and progression to locally invasive and metastatic stages is often associated with a persistent activation of distinct developmental signaling pathways in these immature cells during epithelialmesenchymal transition program. The signaling cascades that are often deregulated in cancer stem/progenitor cells include hedgehog, epidermal growth factor receptor (EGFR), Wnt/ß-catenin, NOTCH, polycomb gene product BMI-1 and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). Importantly...

‣ Hierarchy in gene expression is predictive of risk, progression, and outcome in adult acute myeloid leukemia

Tripathi, Shubham; Deem, Michael W.
Fonte: Universidade Rice Publicador: Universidade Rice
Tipo: Journal article; Text; post-print
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Cancer progresses with a change in the structure of the gene network in normal cells. We define a measure of organizational hierarchy in gene networks of affected cells in adult acute myeloid leukemia (AML) patients. With a retrospective cohort analysis based on the gene expression profiles of 116 AML patients, we find that the likelihood of future cancer relapse and the level of clinical risk are directly correlated with the level of organization in the cancer related gene network. We also explore the variation of the level of organization in the gene network with cancer progression. We find that this variation is non-monotonic, which implies the fitness landscape in the evolution of AML cancer cells is non-trivial. We further find that the hierarchy in gene expression at the time of diagnosis may be a useful biomarker in AML prognosis.

‣ Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development

Bianco-Miotto, T.; Chiam, K.; Buchanan, G.; Jindal, S.; Day, T.; Thomas, M.; Pickering, M.; O'Loughlin, M.; Ryan, N.; Raymond, W.; Horvath, L.; Kench, J.; Stricker, P.; Marshall, V.; Sutherland, R.; Henshall, S.; Gerald, W.; Scher, H.; Risbridger, G.; Cle
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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56.76255%
BACKGROUND: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. METHODS: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. RESULTS: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. CONCLUSIONS: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. IMPACT: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover...

‣ The role of deleterious passengers in cancer

McFarland, Christopher Dennis
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
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The development of cancer from a population of precancerous cells is a rapid evolutionary process. During progression, cells evolve several new traits for survive and proliferation via a few key `driver' mutations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional `passenger' mutations. Passengers are widely believed to have no role in cancer, yet many passengers fall within functional genomic elements that may have potentially deleterious effects on the cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter neoplastic progression. Evolutionary simulations suggest that moderately-deleterious passengers accumulate during progression and largely evade natural selection. Accumulation is possible because of cancer's unique evolutionary constraints: an initially small population size, an elevated mutation rate, and a need to acquire several driver mutations within a short evolutionary timeframe. Cancer dynamics can be theoretically understood as a tug-of-war between rare, strongly-beneficial drives and frequent mildly-deleterious passengers. In this formalism, passengers present a barrier to cancer progression describable by a critical population size...

‣ Role of the Type III TGF-beta Receptor Cytoplasmic Domain in Breast Cancer Progression

Lee, Jason Dole
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 5142718 bytes; application/pdf
Publicado em //2009 Português
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Breast cancer remains among the most common cancers of the developed world. Despite advances in treatment modalities, deaths due to breast cancer are the second leading cause of cancer death among women. The transforming growth factor-beta (TGF-β) pathway is an important modulator of breast cancer progression, acting in a tumor suppressing fashion in early carcinogenesis but switching in a poorly understood fashion to a promoter of cancer progression in later stages. Mutations and loss of function of TGF-β components are common across a variety of cancers. In particular, the expression of the type III TGF-β receptor (TβRIII) is decreased with cancer grade and clinical progression in prostate, lung, ovarian, and pancreatic cancers. In an effort to enhance our understanding of the biology of TGF-β on carcinogenesis, this dissertation looks at the role of TβRIII in breast cancer progression.

Through an examination of clinical specimens, loss of TβRIII was seen at both the message and protein levels with increasing tumor grade. Analysis of correlated patient outcomes showed that low TβRIII expression was predictive of a shorter time to recurrence, demonstrating clinical relevance for TβRIII expression. The contribution of TβRIII to tumor progression was further examined by examining known TGF-β functions...