Our continuous research activities over more than 15 yeras have led to a stem cell model to explain the cellular biology of development and progression of prostate cancer.

The normal prostatic epithelium is composed by three basic cell types (secretory luminal cells, basal cells, and neuroendocrine cells).They arise from a common pluripotent stem cell in the basal layer through transit-amplifying cells that display intermediate phenotypes. The cellular diversity of the prostatic epithelium is maintained through a network of hormonal control, growth factors, and interactions with the basement membrane. Severe differentiation and proliferation disorders occur during the malignant transformation of the prostatic epithelium. In high-grade prostatic intraepithelial neoplasia (HGPIN), basal cells lose their proliferative capacity while luminal cells acquire increased proliferative activity. This process is associated with an abnormal expression of oncogenes (p53, erbB-1, erbB-2, erbB-3, and c-met), the apoptosis-suppressing Bcl-2, and the classic estrogen receptor alpha (ERα). Conversely, the ERβ which mediates chemopreventive effects of phytoestrogens is partially lost in HGPIN. Neoplastic progression to invasion is associated with loss of cell adhesion proteins and formation of new tumor-associated basement membranes, which provide a matrix for invasion. Common prostatic adenocarcinoma is composed of exocrine cell types expressing prostate-specific antigen and cytokeratins 8 and 18, as well as androgen receptors (ARs), making exocrine tumor cells androgen responsive even in androgen-insensitive stages of the disease. The only phenotype of common prostatic adenocarcinoma lacking the nuclear AR shows neuroendocrine differentiation. These endocrine tumor cells do not proliferate or undergo apoptosis, indicating that such tumor cells are androgen-insensitive and escape radiation therapy and other cytotoxic drugs. In addition, endocrine tumor cells secrete a number of endocrine growth factors that can maintain proliferative activity in exocrine tumor cells through a paracrine mechanism.

Androgen- insensitive prostate cancer shares some basic biological properties with prostatic basal cells/ stem cells.
This includes:

• differentiation potency
• androgen- independency
• proliferation capacity
• resistance to the programmed cell death
• re-expression of oncogens restricted to basal cells (p53, erbB-1, erbB-2, erbB-3, Bcl-2)
• re-expression of steroid receptors restricted to basal cells (ERα, PR)

Thus, androgen- insensitive prostate cancer recapitulates the cellular biology of basal cells/ stem cells.

The reappearance of the ERα and PR during tumor progression indicates that these tumors may use the pertinent steroids to survive in an androgen-deprived milieu. This warrants clinical trials to test the efficacy of antiestrogens in the medical treatment of advanced prostate cancer.

References

1. Bonkhoff H (2003)
   Morphogenesis of prostate cancer.
   article in Stem Cell Handbook edited by Stewart Sell (Humana Press)