The phenotype and proliferative potential of prostatic epithelial cells, from organogenesis to the development of androgen independent growth, is modulated through interactions with the microenvironment: age and androgenic milieu represent two components of the microenvironment clearly related to human prostate cancer. Perturbation of the homeostatic interactions between stroma and epithelium could represent a major early event in the genesis of prostate cancer and result in dramatic phenotypic plasticity of the epithelial cells. Most prostate cancers demonstrate phenotypic characteristics of secretory epithelial cells, including androgen-dependent growth mediated via androgen-regulated production of growth regulatory factors by prostatic stromal cells. Proliferation and survival of benign and neoplastic prostate epithelial cells is determined by the presence in the microenvironment of members of the insulin-like growth factor family, epidermal growth factor family, TGF-beta family, and HGF and of their cognate receptors on the epithelial membrane, including HGF receptor c-met and the mannose-6-phosphate/IGF ll receptor which binds both TGF-beta1 and IGF-ll. The hypothesis of this proposal is that these microenviromentally-available effectors are critical factors that modulate the neoplastic phenotype of prostate cancer cells throughout tumor progression, including expression of androgen-independent growth. Expression and response of these genes will be evaluated in an androgen-responsive prostate tumor epithelial cell line established from the Dunning H tumor; a stromal cell line established from the same tumor; an androgen-responsive prostate epithelial cell line established from a regenerating prostate and a stromal cell line established from the same regenerating prostate.
The Specific Aims are: (1) Characterize the pattern of basal gene expression, androgen-induced gene expression and gene expression in cocultures of an androgen-responsive rat prostate epithelial cell line, an androgen-responsive neoplastic prostate epithelial cell line established from the Dunning H tumor, and normal and tumor-derived stromal cell lines; (2) Establish whether androgen-independent growth is facilitated by ligand-independent activation of the androgen receptor by microenvironmentally available effector molecules; and (3) Characterize the ability of the in vivo tissue microenvironment, including age effects, to modulate the phenotpye of benign, neoplastic and genetically manipulated prostate epithelial cell lines.
