Using both animal and human models, the main goal of this project is to investigate cellular and molecular mechanisms of smooth muscle (SM)- epithelial interactions which regulate growth and differentiation of normal and malignant prostatic epithelium (PRE). The hypothesis is that SM differentiates in the prostate as a result of reciprocal SM <-> epithelial interactions that play a homeostatic role in maintaining adult prostatic structure and function. During prostatic carcinogenesis progressive perturbation of SM <-> epithelial signaling leads to development of a tumor stroma from dedifferentiated SM cells which either actively promote or permit prostatic carcinogenesis. To pursue this model of prostatic neoplasia, the following specific aims will be pursued: (l) Analysis of response of PRE to SM cells versus tumor stroma. (2) Analysis of differential effects of normal PRE versus prostatic carcinoma cells on differentiation of SM cells. (3) Identification and characterization of paracrine factors regulating PRE growth and SM differentiation. (4) Analysis of androgenic mechanisms of SM differentiation. (5) Analysis of stromal regulation and reversibility of epithelial B-cadherin. (6) Characterization of the E-cadherin system and epithelial adhesion in PRE cells growing in vitro in association with normal or tumor stromal cells to determination whether effects of stromal cells on the E-cadherin system in PRE is mediated via direct cell contact or paracrine acting molecules. (7) Reversal or inhibition of reduced PRE adhesion by pharmacologic agents.
The specific aims of this study will be examined through analysis of tissue recombinants in vivo, use of transgenic mice, cell culture, immunocytochemistry, and a variety of biochemical and molecular methods (RT-PCR, RNase protection, Western blot, protein purification, and gel electrophoresis). Frog the proposed studies it is anticipated that the work will identify new diagnostic markers useful for discriminating between aggressive versus slow growing prostatic tumors. In addition, it is possible that this study will identify one or more strategies for regulating the growth, differentiation and)'or invasive behavior of prostatic carcinoma cells.
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