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Review
. 2017 Apr 10;9(4):32.
doi: 10.3390/cancers9040032.

The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer

Kurtis Eisermann  1 , Gail Fraizer  2
Affiliations
Review

The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer

Kurtis Eisermann et al. Cancers (Basel). .

Abstract

Prostate cancer progression is controlled by the androgen receptor and new blood vessel formation, or angiogenesis, which promotes metastatic prostate cancer growth. Angiogenesis is induced by elevated expression of vascular endothelial growth factor (VEGF). VEGF is regulated by many factors in the tumor microenvironment including lowered oxygen levels and elevated androgens. Here we review evidence delineating hormone mediated mechanisms of VEGF regulation, including novel interactions between the androgen receptor (AR), epigenetic and zinc-finger transcription factors, AR variants and the hypoxia factor, HIF-1. The relevance of describing the impact of both hormones and hypoxia on VEGF expression and angiogenesis is revealed in recent reports of clinical therapies targeting both VEGF and AR signaling pathways. A better understanding of the complexities of VEGF expression could lead to improved targeting and increased survival time for a subset of patients with metastatic castration-resistant prostate cancer.

Keywords: AR; CRPC; VEGF; androgen receptor; angiogenesis; hypoxia; prostate cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Androgen mediated regulation of vascular endothelial cell growth factor (VEGF) transcription. (A) Promoter analysis of VEGF. The VEGF promoter (VEGFA accession number AB021221) was downloaded from Ensembl and binding sites were predicted by MatInspector and located on the VEGF promoter sequence [50]. Potential androgen receptor binding sites (ARE), HIF1α binding sites (HIF-1) and zinc finger transcription factor binding sites (Sp1, Egr1, and WT1) thought to play a role in VEGF regulation are color coded according to the legend; (B) Model of androgen regulation of VEGF in prostate cancer showing the AR in a complex with Sp1 and bound to the GC-rich region of the VEGF core promoter. Note that ligand binding replaces HSP binding in the cytoplasm, but within the nucleus Sp1 binding recruits the AR to the core promoter region of the VEGF gene.
Figure 2
Figure 2
Targeting both VEGF induction of angiogenesis and androgen synthesis or AR signaling inhibits two critical signaling pathways in prostate cancer (PC) progression. Note that hypoxia induced VEGF can also be suppressed by targeting HIF1α with HIF1 inhibitors (not shown).
See this image and copyright information in PMC

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