Sarah J. Parsons Professor of Microbiology Phone: (434) 924-2352 Fax: (434) 982-0689 Office: Jordan 2-11 Email: sap@virginia.edu Homepage: Click Here

Research Interest

Our interests focus on neuroendocrine (NE) cells of the prostate and the role they play in promoting androgen-independent growth of prostate tumors. NE cells are secretory cells that populate both normal and malignant prostate tissue, but they arise by two different mechanisms in these different types of prostate tissue. NE cells of the normal gland appear to originate from the neural crest during embryogenesis, but NE cells of cancerous prostates are thought to derive from tumor cells themselves, which have undergone a process of de-differentiation and subsequent trans-differentiation in response to extracellular stimuli found in the local environment. In fact, in late stage tumors that have become androgen-independent for growth, the number of NE cells increases with increased severity in stage and grade. Furthermore, the proliferative index of neoplastic cells surrounding the NE cells is frequently elevated, suggesting that the NE cells act as a source of paracrine factors that promote the growth of tumor cells. In a direct test of this hypothesis, we have shown that NE cells secrete several factors that carry out this function and can significantly promote androgen-independent growth of human prostate cancer cell lines in tissue culture assays and in tumor growth in nude mice. We are currently studying the mechanism of this enhanced growth, i.e., whether it is due to the secretion of anti-apoptotic factors, proliferative factors, or whether NE cells facilitate selection of a pre-existing, cancer cell variant that can withstand the stressed environment of androgen depletion, which is the current most common form of therapy for prostate cancer. The ability of NE cells to enhance motility and metastases in vitro and in vivo is also being studied. Finally, as an initial step to generating therapies that may ultimately counteract the effects of increased numbers of NE cells in prostate cancer, we are focusing on signaling mechanisms that regulate the process of NE cell differentiation as well as responses of tumor cells to secreted products of NE cells. The latter focuses on the roles of the EGF receptor and c-Src tyrosine kinases in mediating the intracellular responses of many of these factors. These two proteins have already been exploited as targets of therapeutic intervention in breast cancer and are just beginning to be examined as such targets in prostate cancer.

Representative Recent Publications

1. Cox, M.E., P.D. Deeble, S. Lakhani, and S.J. Parsons. 1999. Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: Implications for prostate cancer progression. Cancer Research 59: 3821-3830.

2. Cox, M.E., P.D. Deeble, and S.J. Parsons. 2000. Activated 3',5'-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line. J. Biol. Chem. 275: 13812-13818.

3. Deeble, P.D., D.J. Murphy, S.J. Parsons, and M.E. Cox. 2001. IL-6 and cAMP-mediated signaling potentiate neuroendocrine differentiation of LNCaP prostate tumor cells. Mol. Cell. Biol. 21: 8471-8482. Cover illustration.

4. Deeble, P.D., M.E. Cox, M. Wu, and S.J. Parsons. 2001. Neuroendocrine cells and paracrine signaling in prostate cancer progression. Recent Res. Devel. Endocrinol. 2: 357-374.

5. Deeble, P.D., M.E. Cox, H.F. Frierson, Jr., R. Sikes, M. Wu, E.A. Bissonette, R. Davidson, and S.J. Parsons. 2002. PKA-mediated NE-like differentiation enhances androgen-independent growth and tumor forming capacity of LNCaP prostate carcinoma cells. Manuscript in preparation.

For more information email sap@virginia.edu.