Synergy of p53 and Rb Deficiency in a Conditional Mouse Model for Metastatic Prostate Cancer

Zhou, Zhe; Flesken‐Nikitin, Andrea; Corney, David C.; Wang, Wei; Goodrich, David W.; Roy-Burman, Pradip; Nikitin, Alexander Yu.

doi:10.1158/0008-5472.can-06-0486

Cited by 278 publications

(288 citation statements)

References 42 publications

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“…Interestingly, none of the single-gene deletion models shows a significant PCa phenotype, but their synergistic inactivation results in cancer onset. For instance, simultaneous inactivation of p53 and Rb results in the formation of highly metastatic tumors that are resistant to castration and show NE differentiation (Zhou et al 2006). The best of (Wang et al 2003, Grabowska et al 2014.…”

Section: Mouse Models Of Pca and Relevant Aspects Of Angiogenesis/vegmentioning

confidence: 99%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to w30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically %24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling.

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Section: Mouse Models Of Pca and Relevant Aspects Of Angiogenesis/vegmentioning

confidence: 99%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

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“…p53 deletion has been shown to synergize with Pten targeted inactivation (26) or Rb deficiency (27) to induce murine PCa, indicating that loss of p53 may play an important role in initiation and progression of PCa.…”

Section: Combined Erg Overexpression and P53 Deletion In Prostate Epimentioning

confidence: 99%

ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells

Zong

Goldstein³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

187

175

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Chromosomal rearrangements involving erythroblast transformation specific (ETS) family transcription factors were recently defined as the most common genetic alterations in human prostate cancer. Despite their prevalence, it is unclear what quantitative role they play in either initiation or progression of the disease. Using a lentiviral transduction and dissociated cell prostate regeneration approach, we find that acutely increased expression of ETS proteins in adult murine prostate epithelial cells is sufficient to induce the formation of epithelial hyperplasia and focal prostatic intraepithelial neoplasia (PIN) lesions, but not progression to carcinoma. However, combined expression of ERG with additional genetic alternations associated with human prostate cancer can lead to aggressive disease. Although ERG overexpression does not cooperate with loss of the tumor suppressor p53, it does collaborate with alterations in PI3K signaling, such as Pten knockdown or AKT up-regulation, to produce a well-differentiated adenocarcinoma. Most striking is our finding that overexpression of androgen receptor (AR) does not give rise to any hyperplastic lesions, but when combined with high levels of ERG, it promotes the development of a more poorly differentiated, invasive adenocarcinoma. These findings suggest that in human prostate cancer, the most potent function of ETS gene fusions may be to synergize with alternative genetic events and provide different pathways for carcinoma production and invasive behavior. Our results provide direct evidence for selective cooperating events in ERG-induced prostate tumorigenesis and offer a rational basis for combined therapeutic interventions against multiple oncogenic pathways in prostate cancer.AKT ͉ androgen receptor ͉ ERG ͉ prostate cancer ͉ PTEN H uman cancer is a multigene disorder in which several somatic mutations in cancer predisposition genes are required in a stepwise manner (1). The first genetic alteration usually confers a selective growth advantage and subsequently results in clonal expansion to initiate the neoplastic process. But the cells must accumulate several other rate-limiting mutations over a long period to become malignant (2). For prostate cancer (PCa), various oncogenes and tumor suppressor genes, including NKX3.1, PTEN, p27, and p53, and androgen receptor (AR) signaling have been implicated in the disease progression (3). However, the key initiating steps in prostate carcinogenesis remain uncertain, and most genetic alterations that can collaborate to drive tumor progression have yet to be elucidated.Chromosomal translocations play critical roles in hematological malignancies (4). Several lines of evidence in epithelial cancers of distinct tissue origins suggest that acquired chromosomal rearrangements could also be the common genetic events in many, if not all, epithelial cancers (5). Recent studies showed that 50-80% of patients with PCa were found to harbor fusion transcripts between an androgen-regulated gene, TMPRSS2, and members of the erythroblast tr...

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“…1997, Zhou et al 2006). While LNCaP cells express the wild-type p53 (Isaacs et al 1991, Carroll et al 1993, NCI-H660, and PSK-1, two human prostatic small cell carcinoma cell lines, exhibit truncated and mutated p53 proteins respectively (van Bokhoven et al 2003).…”

Section: Conclusion and Prospectivesmentioning

confidence: 99%

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

Yuan¹,

Veeramani²,

Lin³

2007

Endocr Relat Cancer

213

184

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Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as 'NE-like PCa cells'. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.

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Synergy of p53 and Rb Deficiency in a Conditional Mouse Model for Metastatic Prostate Cancer

Cited by 278 publications

References 42 publications

Regulation of vascular endothelial growth factor in prostate cancer

Regulation of vascular endothelial growth factor in prostate cancer

ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

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