) Prostatic carcinoma is a unique malignancy in which histologically recognizable but biologically indolent carcinomas significantly outnumber life-threatening clinically aggressive carcinomas. Age is strongly associated with the development of both indolent and aggressive prostatic carcinoma, a cancer characterized by neoplastic epithelial cells intimately associated with, and influenced by, their stromal microenvironment. The development and progression of prostatic carcinoma results from a complex interplay of tumor- specific genetic alterations and stromal-specific microenvironmental influences. We have demonstrated recently that the capacity of the hepatic tissue microenvironment to suppress the neoplastic phenotype of a tumorigenic rat liver epithelial cell line is lost with age. This application will test the hypothesis that the potential for prostatic carcinoma to develop to clinical significance is determined by the capacity of the genomic changes acquired by the developing carcinoma to allow it to escape suppression by the prostatic microenvironment, and that the suppressive effect of the microenvironment progressively diminishes with age. Three lines of experimental studies are proposed to test our hypothesis: (1) the Dunning R- 3327 rat prostatic adenocarcinoma model will be utilized to determine if there is an age-dependent loss of the ability of the prostate microenvironment to suppress growth of prostatic cancer cells transplanted into the prostate of syngeneic animals; (2) age-related changes in paracrine, autocrine, or extracellular matrix factors essential for mediating the suppressive effects of the tissue microenvironment will be investigated by reconstituting cell- cell and cell-matrix interactions in vitro using stromal cells and extracellular matrix components isolated from prostates of animals of various ages; and (3) patterns of gene expression and distribution of critical components of the microenvironment that change with age or show gradients of change locally in the presence of carcinoma will be characterized in human radical prostatectomy specimens. If prostaticstroma undergoes age related changes that diminish the suppressive effect of the microenvironment upon the development, growth, invasivenessor metastatic potential of prostatic carcinomas, means for reversing or preventing these specific changes should be explored.
