Mechanisms Of Prostate Carcinogenesis Research Articles

Renin-angiotensin system: role in the development and progression of prostate cancer

Being the most common malignancy in men, prostate cancer (PCa) is a significant social and medical problem. The development of new approaches to the diagnosis, prognosis, and treatment of PCa is one of the most important tasks of current urological oncology.The renin-angiotensin cascade plays a crucial role in the regulation of most physiological and pathophysiological conditions in the human organism, including vascular tone, blood pressure, development and progression of atherosclerosis, and key metabolic processes. The classical regulation axis of the renin-angiotensin system (RAS) is well known and includes angiotensin converting enzyme (ACE)/angiotensin II/ angiotensin II receptors. Recently, new RAS elements have been found and described, such as ACE2 (homologue of ACE), angiotensin isoforms 1—7, alamandin, etc. This resulted in the discovery of many new alternative axes of RAS regulation, including ACE2/angiotensin-(1—7)/ MAS receptor, prorenin/(pro)renin receptor/MAP kinase, and angiotensin A/almandin/receptor D (MrgD). The prostate gland has a local RAS; all main components of RAS are expressed in prostate tissues.This review analyzes molecular mechanisms underlying carcinogenic effects of RAS, as well as classical and alternative pathways of RAS regulation in PCa. We have described the results of studies evaluating individual RAS parameters in PCa, which confirm the existence of a complex network between various elements of local RAS and molecular and cellular mechanisms of prostate carcinogenesis. RAS has been proved to play an important role in PCa development and progression.We have also covered new therapeutic targets for PCa treatment, presumable mechanisms of action, and prospects of using RAS inhibitors for PCa.

Mechanisms of prostate carcinogenesis and its prevention by a γ-tocopherol-rich mixture of tocopherols in TRAMP mice

Tocopherols belong to a subgroup of the vitamin E family. Dietary feeding of a γ-tocopherol-rich mixture of tocopherols(γ-Tm T) inhibits prostate tumorigenesis in TRAMP mice. In this study, we aimed to investigate mechanisms of prostate carcinogenesis in TRAMP mice by identifying differentially expressed pathways and effects of γ-Tm T on these pathways. Eight-week-old TRAMP and age-matched C57BL/6 mice were administered either 600 mg/kg of γ-Tm T or a control vehicle via oral gavage. Twelve hours after dosing, prostate tissues were collected for RNA extraction. Whole genome mouse microarrays were used to examine gene expression profiles. The expression of the selected genes were validated using quantitative PCR. Thousands of genes and various pathways were altered in the prostates of TRAMP mice. Compared to C57BL/6 mice, TRAMP mice exhibited enhanced proliferation, suppressed expression of antioxidant and phase II detoxification enzymes, and metabolic reprogramming in the prostate. γ-Tm T differentially regulated the gene expression profiles of TRAMP and C57BL/6 mice, with only a small percentage of genes overlapping. γ-Tm T inhibited genes involved in proliferation and glucose metabolism and induced several antioxidant/phase II detoxification genes in TRAMP mice. γ-Tm T modulates multiple aberrant pathways in the prostate of TRAMP mice, which might represent important mechanisms for prostate cancer prevention.

Abstract 5028: MicroRNA-212 targets multiple signaling pathways in prostate cancer

Abstract Prostate cancer (PCa) is the most common type of cancer in men in the United States. While metastasis is the most common cause of death among PCa patients, no specific markers have been assigned to the severity of the disease. Identification of molecular factors could improve diagnosis and therapeutic intervention of PCa. MicroRNAs represent a promising new class of circulating biomarkers owing to their inherent stability and resilience. Studies in our lab have demonstrated that miR-212 is a differentially modulated circulatory microRNA in prostate cancer patients. Identification and validation of miRNA targets provides functional insights in mechanisms of prostate carcinogenesis and strategies for therapy. The present study was aimed to investigate and validate the targets for miR-212 to elucidate its role in prostate cancer and identify potential biomarkers and/or therapeutic targets for prostate cancer. Common mRNA targets of miR-212 were extracted from four web-based databases: TargetScan, miRanda, RNAhybrid, and PicTar. Some of the important common targets for miR-212 included DEDD, E2F5, GRM3, G2L1, SPRED1, SIRT1, SOS1, RASA1, PEA15, MYC, MAPK3, MAPK1 and HMGA2. Out of these SIRT1, SOS1, SPRED1, RASA1 were picked for further validation based on their documented role in carcinogenesis and tumor progression. Transfection studies with miR-212 mimics were performed in PC3 and LnCap prostate cancer cell lines. Western blotting was used to see the initial expression of various targets. 3′UTR-Luciferase reporter assay was performed for validating the target inhibition by miR-212. In addition, Cell proliferation assay and wound-healing assay were performed to evaluate the effects of miR-212 on PCa cell proliferation and migration. In summary the present study identifies and validates miR-212 targets and examines the functional significance of miR-212 in prostate cancer (PCa) cells lines. *Contributed equally. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5028. doi:1538-7445.AM2012-5028

Abstract 3878: The different genetic alterations between Western and Chinese samples indicate alternate pathways of prostate cancer development

Abstract Prostate cancer is the most common male cancer in Western countries, but much less frequent in Asian countries. We systematically investigated genomic changes in prostate cancers from UK and China to determine genetic similarity and difference and potential alternative mechanisms of prostate carcinogenesis in these high and low cancer incidence populations. Using Affymetrix array 6.0 microarrays, we analyzed genome-wide genomic alterations in 32 UK and 39 Chinese prostate cancer samples. Distinct difference in genomic alterations between Western and Chinese prostate cancers were found, including loss of 21q22 and PTEN deletion, which are the most common genomic changes in Western prostate cancer but rarely detected in the Chinese samples. To further evaluate the difference between Western and Chinese samples, FISH analysis for PTEN deletion and ERG rearrangements and immunohistochemistry analysis for PTEN and ERG expressions were applied to UK (n=160) and Chinese (n=143) prostate cancer tissue microarrays (TMAs). PTEN deletion and ERG rearrangements were found at a significantly higher frequency in samples from UK (42.3% and 37.4%) than China (14.3% and 7.5% respectively) (P<0.001 for both). Both PTEN (76.1% vs 36.3%, p<0.01) and ERG protein were also differentially expressed. Interestingly, the nuclear locations of ERG are also significantly different from UK and China samples. Cytoplasmic expression was significantly higher in UK (46.4%) than Chinese ones (25.0%) (p=0.001) and nuclear expression was significantly lower in UK (15.0%) than Chinese ones (34.4%) (p<0.001). The ERG cytoplasmic expression is much tighter correlated to ERG rearrangements than nuclear expression in UK cancer. We further detected that PTEN deletion and ERG rearrangements were at a higher frequency in High-grade prostatic intraepithelial neoplasia (HGPIN) lesions from UK (21.4% and 21.1% respectively) than China (both 0%). Cytoplasmic expression in UK HGPINs (50.0%) was also significantly higher than that in Chinese ones (10.0%) (p=0.002), while the nuclear expression of ERG in UK (27.8%) and Chinese (23.3%) HGPINs were similar (p=0.738). Subsequently, we found that AR CAG repeat lengths, which is associated with AR activity, is significantly shorter in the UK than Chinese patients (P<0.05). In conclusion, we compared genetic alterations in prostate cancer samples from UK and China and found there are significant differences between the two groups, commencing at pre-invasive, HGPIN, stage. Our findings suggest that tumours arise in Western and Chinese populations by alternative pathogenetic mechanisms. These alterations, differentially presented in these two populations may be key genetic changes underlying the regional/ethnic difference in clinical incidence and may be induced by specific environmental and/or genetic risk factors that Western men are exposed to. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3878. doi:10.1158/1538-7445.AM2011-3878

Abstract 123: miR-145 function as a tumor suppressor targeting multiple oncogenes in prostate cancer

Abstract Prostate cancer remains one of the most prevalent cancers and a major cause of morbidity and mortality in the western world. Disease progression and the development of hormone refractory disease remain major causes of cancer-related death. The understanding of the new molecular pathways of hormone refractory would be helpful in improving diagnosis and therapy of the disease. microRNAs (miRNAs) are small, non-coding RNAs with a length of approximately 22 nucleotides. They regulate gene expression by promoting mRNA cleavage and at the posttranscriptional level by translational suppression. They play important roles in various biological and metabolic processes, including development, differentiation, signal transduction, cell maintenance, and cancer. Bioinformatic predictions indicate that miRNAs regulate more than 30% of the protein coding genes. It is estimated that approximately 1,000 miRNAs exist in the vertebrate genome. An important role for miRNAs in the development of cancer has emerged in recent years. miRNAs are aberrantly expressed in many human cancers, and they may function as oncogenes or tumor suppressors. Up-regulated miRNAs could function as oncogenes by negatively regulating tumor suppressor genes, while down-regulated miRNAs could act as tumor suppressors, inhibiting cancers by regulating oncogenes. Down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer, suggesting that miR-145 function as a tumor suppressor. In this study, we focused on target identification of miR-145 in prostate cancer, based on gene-wide gene expression analysis of miR-145 transfection cells. According to our expression analysis showed that down-regulated genes (FSCN1, UNG and EIF4EBP2) were identified. Loss-of-function assays revealed that FSCN1 inhibited cell proliferation, migration, and invasion in PC3 and DU145 cells, suggesting FSCN1 function as an oncogene. The identification of tumor suppressive miRNA and their target genes could provide new insights into potential mechanisms of prostate carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 123. doi:10.1158/1538-7445.AM2011-123

Human prostate cancer risk factors

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

Sex hormone-induced prostatic carcinogenesis in the noble rat: the role of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the development of prostate cancer.

Despite extensive effort, the mechanisms of prostate carcinogenesis are still unknown. We report on a modified method which enabled us to induce a high incidence of prostate carcinogenesis in the Noble rat and examined the role of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) and their receptors during sex hormone-induced prostate carcinogenesis. Noble rats were implanted subcutaneously with a combination of testosterone and estradiol capsules for up to 12 months. Animals were sacrificed starting at 2 months after implantation, and the prostate gland was removed for histopathological and immunohistochemical studies. The results showed that hyperplasia/dysplasia was detected as early as 2 months after treatment, while carcinoma in situ was induced in 4 months and adenocarcinoma in 7 months. Our data suggest that IGF-1, produced by stromal cells in hyperplasia, exerted its effects, through a paracrine mode, on epithelial cells which were IGF-1 receptor (IGF-1R)-positive. The production of IGF-1 appeared to switch to epithelial cells in adenocarcinoma, through which it regulated tumor cell growth via autocrine mode by binding to IGF-1R of carcinoma cells. On the other hand, VEGF was overexpressed in hyperplastic/dysplastic and carcinoma cells, while VEGF-R was detected in endothelial cells. The results suggest that overexpression of VEGF in deranged epithelia and arterial muscle cells may exert its influence on stromal angiogenesis and abnormal growth of prostate gland. A modified Noble rat model with a high incidence of prostate carcinogenesis has been developed. Using this model, we have further established that IGF-1 and VEGF may be the critical regulators in mediating epithelial-stromal interactions in sex hormone-induced prostate carcinogenesis.

Sex hormone‐induced prostatic carcinogenesis in the Noble rat: The role of insulin‐like growth factor‐1 (IGF‐1) and vascular endothelial growth factor (VEGF) in the development of prostate cancer

BACKGROUND Despite extensive effort, the mechanisms of prostate carcinogenesis are still unknown. We report on a modified method which enabled us to induce a high incidence of prostate carcinogenesis in the Noble rat and examined the role of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) and their receptors during sex hormone-induced prostate carcinogenesis. METHODS Noble rats were implanted subcutaneously with a combination of testosterone and estradiol capsules for up to 12 months. Animals were sacrificed starting at 2 months after implantation, and the prostate gland was removed for histopathological and immunohistochemical studies. RESULTS The results showed that hyperplasia/dysplasia was detected as early as 2 months after treatment, while carcinoma in situ was induced in 4 months and adenocarcinoma in 7 months. Our data suggest that IGF-1, produced by stromal cells in hyperplasia, exerted its effects, through a paracrine mode, on epithelial cells which were IGF-1 receptor (IGF-1R)-positive. The production of IGF-1 appeared to switch to epithelial cells in adenocarcinoma, through which it regulated tumor cell growth via autocrine mode by binding to IGF-1R of carcinoma cells. On the other hand, VEGF was overexpressed in hyperplastic/dysplastic and carcinoma cells, while VEGF-R was detected in endothelial cells. The results suggest that overexpression of VEGF in deranged epithelia and arterial muscle cells may exert its influence on stromal angiogenesis and abnormal growth of prostate gland. CONCLUSIONS A modified Noble rat model with a high incidence of prostate carcinogenesis has been developed. Using this model, we have further established that IGF-1 and VEGF may be the critical regulators in mediating epithelial-stromal interactions in sex hormone-induced prostate carcinogenesis. Prostate 35:165–177, 1998. © 1998 Wiley-Liss, Inc.