In prostate tumors, both the epithelial and stromal mesenchyme compartments show gene expression changes from their respective normal counterpart. In fact, there are more such changes in the stroma than the epithelium. These include down-regulated expression of genes involved in smooth muscle cell differentiation and those differentially expressed between prostate and bladder, i.e., organ-restricted. In development, the stromal cell type mediates tissue formation from differentiation of stem or progenitor cells. Diseases like cancer may arise as a result of defective stromal signaling. Stromal signaling can be demonstrated by co-culture of stromal cells and embryonal carcinoma NCCIT cells used as a stem cell substitute. In co-culture, stromal cells induce NCCIT cells through diffusible molecules to lose stem cell gene expression, gain expression of prostate genes, alter cytomorphology, and lower proliferation. This NCCIT response is varied as co-cultured bladder stromal cells induce a different gene expression. At the same time, NCCIT factors also affect gene expression of co-cultured stromal cells. NCCIT induces normal prostate tissue (NP) stromal cells to become more like cancer-associated (CP) stromal cells in both mRNA and microRNA expression. In contrast, NCCIT shows minimal effect on CP stromal cells. CP stromal cells may represent a less differentiated state in the prostate stromal cell lineage.