Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate

Abstract

Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182-1186, 1971 proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous "antiangiogenic" agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead antiangiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients.androgens; androgen receptor; vitamin D; endothelium; prostate cancer

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

“…Indeed, and in agreement with the results herein, our research group has previously reported that not only VEGF but also AR expression was significantly decreased following nintedanib administration to TRAMP mice during earlier time intervals in relation to those in the present study . Furthermore, it is well known that endogenous AR expression is important for regulating tumor cell differentiation and proliferative status and that the maintenance of this receptor function is a critical factor for prostate cancer development and progression . Finally, considering the aforementioned data, we speculate that negative interferences on VEGF‐mediated pro‐angiogenic signaling in the prostate, such as nintedanib administration, can lead to simultaneous reduction in AR expression, thus indicating one of the mechanisms whereby this anti‐angiogenic agent slows tumor progression in TRAMP mice.…”

Androgens Modulate Endothelial Function and Endothelial Progenitor Cells in Erectile Physiology

“…Specifically, binding of VEGF to its receptors on endothelial cells promotes and enhances vascular permeability and facilitates angiogenesis and revascularization [ 40 ]. More interestingly, Godoy et al [ 57 ] linked androgens to the upregulation of VEGF and mitotic cyclins, which are known to increase EPC proliferation [ 57 ]. In clinical studies it was demonstrated that flow-mediated dilation (FMD) is reduced in patients with TD and is enhanced in response to testosterone therapy [ 23 , 58 - 60 ].…”

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

“…The improved understanding of prostate cancer biology in recent years led to the development of drugs directed against precise tumorigenesis-associated molecular pathways [ 2 ]. Angiogenesis, the development of new blood vessels, is recognized as one of the hallmarks of malignancy and prostate vasculature has been shown to play an important role in regulating the size and function of prostate malignancies [ 3 , 4 ]. Accordingly, several anti-angiogenic drugs have been tested in phase II and III trials in prostate cancer patients [ 5 ], including the oral non-selective tyrosine kinase inhibitors Sunitinib and Sorafenib.…”