The normal prostate shows a high degree of cellular organization. The basal layer is populated by prostate epithelial stem cells and a population of transiently proliferating/amplifying (TP/A) cells intermediate to the stem cells and fully differentiated cells. The luminal layer is composed of fully differentiated prostate epithelial cells. Neuroendocrine cells are scattered throughout the gland. This organization is also seen in prostate cancer, where the tumor cell origin (cancer stem cells) can be traced to a normal cell type by characteristic keratin expression patterns. Basal cells showed strong expression of K-[keratin]5, but they were only weakly positive for K18. Luminal cells strongly expressed K18. A subpopulation of basal cells coexpressed K5 and K14. These keratin expression patterns changed with the degree of cell differentiation as well as location. The least differentiated stem cells in the basal layer were positive for K5 and K14, with weak expression for K18. Intermediate stages of differentiation were identified by expression of K5 and K18. Neuroendocrine cells also expressed K5 as well as typical neuroendocrine cell markers (eg, chromogranin A). Evidence supporting the hypothesis that prostate cancer arises from malignant transformation of intermediate stem cells included the presence in prostate cancers of keratin patterns associated with the intermediate stages of differentiation, androgen independence of both prostate cancers and intermediate stem cells, and expression of c-met by both the TP/A intermediate stem cells and tumor cells.