The opposing action of stromal cell proenkephalin and stem cell transcription factors in prostate cancer differentiation

Background Loss of prostate cancer differentiation or de-differentiation leads to an untreatable disease. Patient survival would benefit if this can be prevented or reversed. Cancer de-differentiation transforms luminal-like (differentiated) adenocarcinoma into less luminal-like and more stem-like (undifferentiated) small cell carcinoma through a sequential activation of stem cell transcription factors (scTF) POU5F1, LIN28A, SOX2 and NANOG. Like stem cells, prostate small cell carcinoma express this quartet of scTF as well as a 10-fold lower level of beta 2-microglobulin (B2M) than that of differentiated cell types. In organ development, prostate stromal mesenchyme cells mediate epithelial differentiation in part by secreted factors. Methods The identified prostate stromal-specific factor proenkephalin (PENK) was cloned, and transfected into scTF(+)B2M(lo) stem-like small cell carcinoma LuCaP 145.1, reprogrammed luminal-like scTF(-)B2M(hi) LNCaP, and luminal-like scTF(-)B2M(hi) adenocarcinoma LuCaP 70CR. The expression of scTF, B2M and anterior gradient 2 (AGR2) was analyzed in the transfected cells. Results PENK caused down-regulation of scTF and up-regulation of B2M to indicate differentiation. When transfected into reprogrammed LNCaP, PENK reversed the reprogramming by down-regulation of scTF with attendant changes in cell appearance and colony morphology. When transfected into LuCaP 70CR, PENK up-regulated the expression of adenocarcinoma antigen AGR2, a marker associated with cancer cell differentiation. Conclusions Prostate cancer cells appear to retain their responsiveness to stromal PENK signaling. PENK can induce differentiation to counter de-differentiation caused by scTF activation. The many mutations and aneuploidy characteristic of cancer cells appear not to hinder these two processes. Loss of prostate cancer differentiation is like reprogramming from luminal-like to stem-like.

Automated summary

The loss of prostate cancer differentiation can lead to an untreatable disease, but the prostate stromal-specific factor PENK has shown potential to induce differentiation and counteract de-differentiation in cancer cells. This suggests that cancer cells may still be responsive to stromal signaling and that differentiation can potentially be induced despite genetic mutations.