Androgen has the dual ability of agonistically stimulating the rate of prostatic cell proliferation while antagonistically inhibiting the rate of prostatic cell death and thus the total prostatic cell content is continuously dependent upon adequate levels of androgen. Excessive androgen can increase both the rate at which the normal prostate grows to its maximum adult size and the rate at which BPH tissue grows to its maximal neoplastic size. Excessive androgen alone, however, cannot produce BPH in human. Thus, additional factors are involved in the etiology of BPH> A stem cell unit model for the organization of the prostatic epithelium has been developed by the co-investigator which can explain what limits the growth of the normal and neoplastic prostate. In this model, a self renewing androgen independent prostatic stem cell gives rise to a hierarchically expanding population of androgen independent amplifying cells which in turn subserve a hierarchically expanding population of androgen dependent transit cells (i.e. functionally active secretory cells). Based upon this stem cell model, there are at least two ways in which BPH could develop from the normal gland; 1) the total number of stem cell units could increase, and/or 2) an increase in the clonal expansion of transit cells could occur. To determine whether either or both of these changes are characteristic of human BPH tissue, in vivo assays will be developed and used to quantitate both the number of stem cell units and the clonal expansion of transit cells in BPH vs normal prostatic tissue (Specific Aim #1). Besides these in vivo xenograft assays, quantitative immunocytochemical assays using formalin fixed paraffin embedded histological section will be used to determine the daily rate of proliferation (i.e.kp) and daily rate of death (i.e. kd) of epithelial and stromal cells in both growing and maintenance phases of BPH vs age matched normal prostatic tissue (Specific aim 2). Based upon the results of these studies, it will be possible to resolve whether there are changes in either stem cell number and/or enhanced expansion of transit cells. To determine whether such changes are the results of differential inductive abilities of stromal cells in normal vs BPH tissue, in vivo assays will be developed and used to quantitate the inductive ability of stromal cells from BPH vs normal prostatic tissue on prostatic epithelial cell growth (Specific Aim #3).
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