Abstract
Androgens regulate vascular regeneration through the induction of angiogenic factors such as VEGF in both normal prostate epithelial cells as well as hormone-responsive cancer cells. Androgen deprivation induces the apoptotic death of androgen-sensitive luminal epithelial or prostate cancer cells. Androgen deprivation also has an impact on the other cell types in the prostate tissue microenvironment including vascular endothelial cells. In animal models, castration results in not only a rapid involution of the prostate but also a reduction in prostatic endothelial cell proliferation, blood flow, and the induction of a hypoxic environment. Hypoxia is a well-known inducer of angiogenesis and neovascularization. Under hypoxic conditions, VHL protein levels decrease and the transcription factor HIF1α is stabilized and transactivates angiogenic factor VEGF. Previous studies have suggested that the tumor suppressor p53 is also induced by hypoxia. Increased p53 expression usually induces cell cycle arrest or apoptosis. However, p53 can also play a role in limiting angiogenesis through the upregulation of anti-angiogenic TSP-1, inhibition of HIF1α, and the transcriptional repression of VEGF. ELL-associated factor 2 (EAF2) was identified as an androgen-responsive tumor suppressor gene that is decreased in prostate cancer and has been shown to regulate p53 target gene TSP-1, to bind and stabilize VHL and to upregulate HIF1α. Interaction of EAF2 and its binding partners p53 and VHL in the regulation of pro-angiogenic HIF1α and anti-angiogenic TSP-1 in the prostate may be critical for maintaining normal tissue homeostasis. Dysregulation of these interacting pathways could lead to increased vascularization and prostate tumorigenesis.
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Pascal, L.E., Wang, Z. (2013). Regulation of Angiogenesis by Androgen-Responsive Gene EAF2. In: Wang, Z. (eds) Androgen-Responsive Genes in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6182-1_17
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DOI: https://doi.org/10.1007/978-1-4614-6182-1_17
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