Regulation of vascular endothelial growth factor in prostate cancer.

Simone De Brot,David O Bates,Atara Ntekim,Cinzia Allegrucci,Nigel P Mongan,Ryan Cardenas,Victoria James,David M Heery,Jenny L Persson,Niels Ødum

doi:10.1530/erc-15-0123

Abstract

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 ~30% 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.

Highlights

Prostate cancer (PCa) is the most common malignancy affecting men in the western world
It became apparent that androgen signaling plays an essential role in localized and metastatic PCa (Wang et al 2009)
Consistent with the essential role played by androgens and the androgen receptor (AR) in hormone-dependent (Yu et al 2010) and refractory PCa (Wang et al 2009), nuclear receptor coregulators have been implicated in prostate carcinogenesis and progression (Debes et al 2003, Rahman et al 2003, Heemers et al 2007)

Summary

DHT DHT

AAA miR-29b (A) The VEGF promoter is regulated by a diverse array of transcription factors, hypoxia-inducible factors (HIFs), specificity protein-1 (Sp1), and most notably in the context of the present review, multiple nuclear receptors, including androgen (Eisermann et al 2013) and estrogen (Buteau-Lozano et al 2002, Dadiani et al 2009), which are indicated in red and yellow respectively. In addition to miR-29b, the VEGF transcript is predicted to contain binding sites for multiple miRNA types (as highlighted in Fig. 2C), such as miR-145 and miR-205, the expressions of which are reduced in PCa and have been shown to regulate VEGF in other cancer types (Szczyrba et al 2010, Fan et al 2012, Yue et al 2012, Boll et al 2013) It remains to be determined how effectively these miRNAs repress VEGF translation in PCa. it is possible that such repression may only occur in specific cellular contexts.

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Conclusion