Prostate cancer cells from luminal-like (differentiated) adenocarcinoma to less luminal-like and more stem-like (undifferentiated) small cell carcinoma retain responsiveness to signaling by stromal cell factor proenkephalin (PENK). Stem-like cancer cells, like stem cells, express stem cell transcription factor (scTF) LIN28A, NANOG, POU5F1, SOX2 as well as a 10-fold lower level of β2-microglobulin (B2M). Forced expression of this scTF quartet can reprogram adenocarcinoma cells, as represented by LuCaP xenograft lines, to stem-, small cell carcinoma-like derivatives with the phenotypic change from scTF−B2Mhi to scTF+B2Mlo. Prostate stromal mesenchyme cells control organ development through secreted hormone factors and heterotypic cell contact. The highly expressed prostate stromal-specific PENK, when transfected into scTF+B2Mlo small cell carcinoma LuCaP 145.1, caused down-regulation of scTF and up-regulation of B2M to indicate differentiation. When transfected into scTF-reprogrammed adenocarcinoma-like LNCaP cells, PENK reversed the reprogramming through down-regulation of scTF with attendant changes in cell appearance and colony morphology. When transfected into adenocarcinoma LuCaP 70CR, PENK up-regulated the expression of anterior gradient 2 (AGR2), a marker associated with prostate cancer differentiation and better patient survival. Thus, PENK can induce differentiation to counter cancer de-differentiation due to activation of scTF. Loss of cancer differentiation leads to an untreatable disease. Patient survival would benefit if this can be reversed or prevented. Prostate cancer de-differentiation is likened to reprogramming. Cancer cells containing multiple mutations and being aneuploid can, like normal cells, still undergo differentiation.