The prostate gland is a simple male sexual accessory tissue that requires androgenic steroids for its embryonic and postnatal development and for maintenance in the adult state. Enigmatically, this tissue is the source of several major debilitating diseases associated with human aging and these diseases are also influenced by the androgenic environment of males. In the past, it was assumed that androgen action on prostate cells was based on a direct role for these steroids in stimulating the proliferation, gene expression and survival of androgen receptor-expressing prostate cells. Significant new evidence obtained from studies of the rat model of prostate growth indicates that, at least part of androgenic control of this tissue may lie at the level of blood flow regulation and the indirect effects of androgenic steroids on the ability of the prostatic vasculature to support sufficient blood flow to the tissue. Experiments in this project will mechanistically conform the relevance of androgen's effects on prostate blood flow and vascular function in the rat model of prostate growth regulation. A variety of drugs that suppress vascular constriction will be tested to determine whether they can also suppress prostate cell apoptosis and prostatic regression following castration. As well, we will identify the vascular-regulating polypeptides factors (positive and negative) produced by the adult rat prostate gland and characterize how these factors respond to androgen stimulation or withdrawal. Our characterization of this molecular response to androgen manipulation will be used to identify appropriate targets so that we can mechanistically determine whether manipulation of the functional activity of these individual molecules, in vivo, will alter the rat prostate's response to androgenic therapies. Coordinate studies of human prostate tissues obtained at acute intervals following androgen-deprivation therapy will enable us to confirm that androgenic steroids similarly affect prostate blood flow in humans. Studies of human prostate cancer xenografts (maintained in male immunodeficient mice) will enable us to determine whether androgen control of tumor blood flow is involved in prostate cancer growth/regression processes. Finally, by characterizing unique genetic differences between human endothelial cells cultured in the presence/absence of androgen-sensitive human prostate cancer cells, we will identify genetic markers of prostate/prostate cancer endothelium that might be useful for the diagnosis or development of novel therapeutics for human prostate diseases. Our work in this project will allow us to address the controversial and critical hypothesis that androgenic steroids control prostate size by regulating the flow of blood to the tissue.
| Ghafar, Mohamed A; Anastasiadis, Aristotelis G; Chen, Min-Wei et al. (2003) Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells. Prostate 54:58-67 |
| Anastasiadis, Aristotelis G; Ghafar, Mohamed A; Salomon, Laurent et al. (2002) Human hormone-refractory prostate cancers can harbor mutations in the O(2)-dependent degradation domain of hypoxia inducible factor-1alpha (HIF-1alpha). J Cancer Res Clin Oncol 128:358-62 |
| Shabsigh, A; Ghafar, M A; de la Taille, A et al. (2001) Biomarker analysis demonstrates a hypoxic environment in the castrated rat ventral prostate gland. J Cell Biochem 81:437-44 |
