Androgen Receptor Mediated Growth of Prostate (Cancer)

Abstract

The understanding of the mode of action of androgens requires insight in the cell biological architecture of the prostate. In the prostate secretory acini, morphologically two cell layers can be discriminated; i.e. the basal and the luminal compartment. The stem cells are thought to be located in the basal compartment. The stem cells have the unique capacity of self-renewal, providing the full repertoire to develop the differentiated ductal system via transient proliferating/amplifying (TP/A) intermediate stem cells. These are in fact early and late progenitors for the exocrine/secretory and neuro-endocrine cells. Exocrine differentiation occurs in the majority of the luminal compartment and is identified by the expression of the androgen receptor (AR), keratin 18 (K18) and prostate specific antigen (PSA). Neuro-endocrine cells are dispersed in the prostate epithelium and express K5 and typical neuro-endocrine markers such as chromogranin A and/or bombesin. The exocrine lineage of differentiation is critically dependent on androgens and thus androgen deprivation therapy will result in declining numbers of secretory/exocrine cells, while the number of stem cells and TP/A intermediate stem cells remains stable. This implies that stem cells and TP/A intermediate stem cells are for their renewal androgen independent, although the TP/A intermediate stem cells are androgen sensitive for expanding the epithelial compartment. Recently, these TP/A intermediate stem cells gained attention because they are thought to play an important role in normal prostate growth as well as in neoplastic transformation. Current hypotheses suggest that from the TP/A cell population, the cancer stem cell develops. Hypothetically, the more committed the cancer stem cell is, the more sensitive the tumour might be for androgen ablation, which could explain why some patients are long-term hormone therapy responders, while others are intrinsically androgen independent. In conclusion, typing of the transformed TP/A intermediate stem cells could enable to discriminate long-term hormone responders from non-responders and could help individualisation of prostate cancer therapy in the future.