Fibroblasts are important contributors to both benign and malignant growth of prostate epithelial cells in vivo. In the human prostate cancer model that we have established, we can grow human LNCaP tumors reproducibly in athymic mice by coinoculating the animals with human LNCaP epithelial cells plus fibroblasts derived from either the prostate or bone; human lung, normal rat kidney, and embryonic mouse fibroblasts were inactive. We have delivered conditioned medium isolated from competent fibroblasts directly to sites where the tumor cells were injected and found that the conditioned medium alone confers tumorigenicity. Further studies of the mechanism of fibroblast-epithelial interaction have indicated that close metabolic cooperation between fibroblast and epithelial cells, involving the production of growth factors by the epithelial cells and the production of extracellular matrices and growth factors by the fibroblasts (assayed in vitro), is important in promoting prostate tumor growth in vivo. We have also investigated the possible in vivo interaction between extracellular matrix proteins such as laminin, collagens, heparan sulfate proteoglycans and Matrigel and prostate epithelial cells. Selective extracellular-matrix components were found to confer tumorigenicity to the prostate epithelial cells. Moreover, extracellular-matrix components were observed to induce cancer cell differentiation and alter permanently the morphology, gene expression and tumorigenic potential of the cancer epithelial cells.