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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The impact of bcl-2 proto-oncogene expression on the pathogenesis and progression of prostate cancer was examined in a transgenic mouse model. Probasin-bcl-2 transgenic mice were crossed with TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) mice that express the SV40 early genes (T/t antigens) under probasin control. Prostate size, cell proliferation, apoptosis, and the incidence and latency of tumor formation were evaluated. The double transgenic, probasin-bcl-2 X TRAMP F1 (BxT) mice exhibited an increase in the wet weight of the prostate. This was associated with an increase in proliferation, attributable to T/t antigens, and a decrease in apoptosis attributable to bcl-2. The latency to tumor formation was also decreased in the BxT mice compared to the TRAMP mice. The incidence of metastases was identical in both the TRAMP and BxT mice. Lastly, the incidence of hormone-independent prostate cancer was reduced in the BxT mice compared to the TRAMP mice. Together, these results demonstrate that bcl-2 can facilitate multistep prostate carcinogenesis in vivo.
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PMID:Bcl-2 accelerates multistep prostate carcinogenesis in vivo. 1107 42

Because prostate cancer has a long latency period and is typically diagnosed in elderly men, it represents an ideal candidate disease for chemoprevention. Therefore, even a modest delay achieved through intervention could have a significant impact on the outcome of this disease. Epidemiological and laboratory studies have provided convincing evidence that diet, genetic factors, and lifestyle are major causes of prostate cancer. Although surgery, radiotherapy, and hormone therapy are the most widely accepted curative options for a selected group of patients suffering from prostate cancer, the side effects of these treatments are many. In recent years, many dietary agents have been being described that show a wide range of chemopreventive effects in cell culture and selected animal model systems of prostate carcinogenesis. One such agent is the beverage tea, which, next to water, is the most popularly consumed beverage in the world. The epidemiological studies and recent data, amassed from various laboratories around the world, provide evidence that tea polyphenols such as epigallocatechin-3-gallate, epigallocatechin, and epicatechin-3-gallate may have the potential to lower the risk of prostate cancer in the human population. Recently, it has been shown that green tea polyphenols, when given to TRAMP, a transgenic mouse model that mimics progressive forms of human prostate cancer, exert remarkable preventive effects against prostate cancer development. Chemoprevention of prostate cancer by tea polyphenols appears to occur through the modulation of various molecular targets. This article attempts to address the issue of the possible use of tea, especially green tea, for the chemoprevention of prostate cancer.
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PMID:Tea beverage in chemoprevention of prostate cancer: a mini-review. 1476 33

Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor.
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PMID:Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice. 1580 73

Circulating insulin-like growth factor-I (IGF-I) levels have been shown to be related to risk of prostate cancer in epidemiologic studies. While specific genetic loci responsible for interindividual variation in circulating IGF-I levels in normal men have not been identified, candidate genes include those involved in the growth hormone (GH)-IGF-I axis such as the hypothalamic factors GH releasing hormone (GHRH) and somatostatin and their receptors. To investigate the role of the GH-IGF-I axis on in vivo prostate carcinogenesis and neoplastic progression, we generated mice genetically predisposed to prostate cancer (the TRAMP model) to be homozygous for lit, a mutation that inactivates the GHRH receptor (GHRH-R) and reduces circulating levels of GH and IGF-I. The lit mutation significantly reduced the percentage of the prostate gland showing neoplastic changes at 35 weeks of age (P=0.0005) and was also associated with improved survival (P<0.01). These data provide an example of a germ line mutation that reduces risk in an experimental prostate carcinogenesis model. The results suggest that prostate carcinogenesis and progression may be influenced by germ line variation of genes encoding signalling molecules in the GH-IGF-I axis.
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PMID:A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. 1587 Jul 5

We previously found that human prostate cancer (CaP) progression is accompanied by differential expression of a panel of 8 informative genes, some of which are metabolically related. Gene profiling focused on this 8-gene pack by northern blot analysis in combination with standard clinical information provided reliable prognostic prediction of human CaP. For a better insight into the potential of this 8-gene signature in tumor detection/classification and therapeutic response, we determined, by qPCR, the expression of these informative genes in the TRAMP mice model of CaP progression. The 8-genes signature resulted effective in discriminating, by linear discriminant analysis (LDA), the prostate of wild type mice from transgenic TRAMP mice developing CaP (P < 0.0002). Since it is known that Green Tea Catechin (GTC) administration to TRAMP mice results in a substantial delay of CaP progression in 80% of the animals, while 20% remain unresponsive, we determined the 8-gene signature in the prostates of GTC-sensitive and GTC-resistant mice. LDA discriminated benign tissue from CaP (i.e. wild-type + chemoprevented, GTC-sensitive TRAMP mice, in which CaP progression was delayed, was discriminated from TRAMP mice + GTC-resistant TRAMP mice, in which CaP developed irrespective of GTC administration; P < 0.01). Moreover, GTC-sensitive TRAMP mice bearing CaP were discriminated from GTCs-resistant ones, (P = 0.0001). These results show that qPCR gene profiling, based on the signature of the 8-genes selected by us, could represent an appropriate means for studying the biological behavior of CaP, which may lead to identifying new tools of potential prognostic value, in that a molecular classification for the presence/absence of cancer and for discriminating GTCs-responsive from GTC-resistant CaP is provided.
Carcinogenesis 2006 May
PMID:Molecular classification of green tea catechin-sensitive and green tea catechin-resistant prostate cancer in the TRAMP mice model by quantitative real-time PCR gene profiling. 1631 98

Understanding prostate stem cells (PSCs) may provide insight for the design of therapeutics for prostate cancer. We have developed a quantitative in vivo colony-forming assay and have demonstrated that the Sca-1 antigen is present on the surface of a prostate cell subpopulation that possesses multiple stem cell properties. Immunofluorescent analysis demonstrates that Sca-1 is expressed by both basal and luminal cells in the proximal region of the adult prostate, but is not expressed by either lineage in more distal regions. The proximal region has been suggested as the PSC niche based on BrdU label-retention studies and the presence of distinct smooth-muscle cells that produce high levels of TGF-beta. Sca-1 is also expressed by nearly all cells within fetal prostate epithelial chords, suggesting Sca-1 may be conserved on PSCs throughout development. Malignant epithelial cells from TRAMP mice, as well as normal prostate cells with lentiviral-mediated alteration of the PTEN/AKT signaling pathway, give rise to PIN lesions and prostate cancer in vivo. Alteration of PTEN/AKT signaling in Sca-1-enriched PSCs also results in PIN lesions, suggesting that PSCs can serve as one target for prostate carcinogenesis.
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PMID:Prostate stem cells and prostate cancer. 1686 53

Vascular endothelial growth factor (VEGF) is a proangiogenic factor upregulated in many tumors. The alternative splicing of VEGF mRNA renders 3 major isoforms of 121, 165 and 189 amino-acids in humans (1 less amino-acid for each mouse VEGF isoform). We have designed isoform specific real time QRT-PCR assays to quantitate VEGF transcripts in mouse and human normal and malignant prostates. In the human normal prostate, VEGF(165) was the predominant isoform (62.8% +/- 5.2%), followed by VEGF(121) (22.5% +/- 6.3%) and VEGF(189) (p < 0.001) (14.6% +/- 2.1%). Prostate tumors showed a significant increase in the percentage of VEGF(121) and decreases in VEGF(165) (p < 0.01) and VEGF(189) (p < 0.05). However, the amount of total VEGF mRNA was similar between normal and malignant prostates. VEGF(164) was the transcript with the highest expression in the mouse normal prostate. Unlike human prostate cancer, tumors from TRAMP mice demonstrated a significant increase in total VEGF mRNA levels and in each of the VEGF isoforms, without changes in the relative isoform ratios. Morpholino phosphorodiamide antisense oligonucleotide technology was used to increase the relative amount of VEGF(121) while proportionally decreasing VEGF(165) and VEGF(189) levels in human prostate cell lines, through the modification of alternative splicing, without changing transcription levels and total amount of VEGF. The increase in the VEGF(121)/VEGF(165-189) ratio in PC3 cells resulted in a dramatic increase in prostate tumor angiogenesis in vivo. Our results underscore the importance of VEGF(121) in human prostate carcinoma and demonstrate that the relative expression of the different VEGF isoforms has an impact on prostate carcinogenesis.
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PMID:Increased expression of VEGF121/VEGF165-189 ratio results in a significant enhancement of human prostate tumor angiogenesis. 1727 99

The aim of this study is to investigate whether an active immunoprophylactic approach combining specific antigens and adjuvant stimuli would be able to inhibit prostate carcinogenesis in transgenic TRAMP mice. A vaccine consisting of allogeneic large T antigen (TAg)-positive SV40-transformed cells combined with systemic recombinant IL-12 was administered to TRAMP mice, starting from when they were still tumor-free at 5-6 weeks of age. The combined vaccine significantly inhibited prostate carcinogenesis, giving a more than doubled median latency time of prostatic tumors (53 weeks in comparison to 26 weeks in control mice). Vaccination with cells alone or IL-12 treatment alone was poorly effective (median latency of 30 and 39 weeks, respectively). The combined vaccine induced a very high CD4 response biased toward the Th1 pathway, with the induction of a humoral response that included TAg-specific antibodies. Therefore, such active immunoprophylactic approach based on the combination of allogeneic SV40 TAg-positive cells and systemic administration of recombinant IL-12 significantly delayed autochthonous urogenital carcinogenesis driven by SV40 TAg in TRAMP mice.
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PMID:Inhibition of prostate carcinogenesis by combined active immunoprophylaxis. 1729 Mar 95

Anti-proliferative properties of genistein in prostate and other cancers have been studied extensively. However, the identification of genistein targets that may mediate its chemopreventive effects in vivo requires further elucidation. In this study, we have demonstrated that the incorporation of genistein in the diet of transgenic adenocarcinoma mouse prostate model (TRAMP/FVB) mice resulted in a reduction in prostate size and the incidence of poorly differentiated (PD) cancer ensuing in an accumulation of prostates at the prostatic intra-epithelial neoplasia (PIN) stage. TRAMP/FVB prostate cancer progression and the onset of PD cancer were characterized by the activation of acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt), phosphorylation of glycogen synthase kinase 3-beta (GSK-3beta), post-transcriptional up-regulation of cyclin D1 and repression of cadherin-1 via snail-1 up-regulation. Incorporation of genistein in the diet significantly inhibited the activation of Akt, restored the activation of GSK-3beta, reduced cyclin D1 levels post-transcriptionally and maintained the expression of the cadherin-1 complex via down-regulation of snail-1. By identifying the Akt-GSK-3 pathway and subsequently its downstream effectors, as targets for genistein chemopreventive action, we have elucidated one possible mechanism by which genistein decreases the proliferative potential, retards cancer progression and maintains the integrity of the prostatic epithelial cells in vivo.
Carcinogenesis 2007 Aug
PMID:Akt GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype. 1746 12

Evidence suggests that the histone deacetylase, SIRT1, is a mediator of life span extension by calorie restriction; however, SIRT1 may paradoxically increase the risk of cancer. To better understand the relationship among SIRT1, energy balance, and cancer, two experiments were done. First, a transgenic mouse model of prostate cancer (transgenic adenocarcinoma of mouse prostate; TRAMP) was used to determine the role of energy balance on SIRT1 expression and the effect of cancer stage on SIRT1 and hypermethylated in cancer-1 (HIC-1). Second, immunohistochemistry was done on human prostate tumors to determine if SIRT1 was differentially expressed in tumor cells versus uninvolved cells. Results show that SIRT1 is not increased in the dorsolateral prostate (DLP) of calorie-restricted mice during carcinogenesis. In contrast, when examined in the DLP as a function of pathologic score, SIRT1 was significantly elevated in mice with poorly differentiated adenocarcinomas compared with those with less-advanced disease. HIC-1, which has been shown to regulate SIRT1 levels, was markedly reduced in the same tumors, suggesting that a reduction in HIC-1 may be in part responsible for the increased expression of SIRT1 in prostatic adenocarcinomas. Furthermore, immunostaining of human prostate tumors showed that cancer cells had greater SIRT1 expression than uninvolved cells. In conclusion, DLP SIRT1 expression from calorie-restricted mice was not altered during carcinogenesis. However, SIRT1 expression was increased in mice with poorly differentiated adenocarcinomas and in human prostate cancer cells. Because SIRT1 may function as a tumor promoter, these results suggest that SIRT1 should be considered as a potential therapeutic target for prostate cancer.
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PMID:SIRT1 is significantly elevated in mouse and human prostate cancer. 1763 71


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