Neuroendocrine Differentiation in Prostate Cancer
An Unrecognized and Therapy Resistant Phenotype

Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies and has attracted increasing attention in contemporary prostate cancer research .This particular phenotype, however, usually escapes pathological and clinical detection in routine practice. The present review focuses on biological properties of NE tumor cells making them resistant to androgen deprivation and radiation therapy.

Along with secretory luminal cells and basal cells, NE cells constitute the third phenotype of the prostatic epithelium. NE cells produce a number of hormonal growth factors (e.g. serotonine) that may act through endocrine, paracrine and autocrine mechanisms. Their biological functions do not depend on circulating androgens because NE cells consistently lack the nuclear androgen receptor. NE cells have no proliferative capacities and represent a highly specialized, terminal differentiated cell population resistant to the programmed cell death. Morphogenetic studies have identified intermediate phenotypes between the three basic cell types of the prostatic epithelium indicating their common origin from stem cells located in the basal cell layer.

Virtually all prostatic adenocarcinoma show NE differentiation as defined by the most commonly used endocrine marker Chromogranin A. Clinical studies suggest that the extend of NE differentiation increases with tumor progression and the development of androgen-insensitivity. At least 10% of all prostatic malignancies show extensive and multifocal NE features upon immunohistochemical analysis. NE differentiation exclusively occurs in the G0- phase of the cell cycle in which tumor cells are usually resistant to radiation therapy and cytotoxic drugs. In addition, NE tumor cells also escape the programmed cell death. Even under androgen deprivation, only 0, 16 % of NE tumor cells show apoptotic activity. This indicates that the vast majority of NE tumor cells present an immortal cell population in prostate cancer. Although NE tumor cells do not proliferate, they produce a number of NE growth factors with mitogenic properties that maintain cell proliferation in adjacent (exocrine) tumor cells through a paracrine mechanism. NE tumor cells consistently lack the androgen receptor and are androgen-insensitive in all stages of the disease. They derive through a process of intermediate differentiation from exocrine tumor cells, the most prevalent phenotype in common prostatic adenocarcinoma. Elevated serum levels of Chromogranin A in prostate cancer patients correlate with poor prognosis and are scarcely influenced by either androgen-deprivation or chemotherapy. This further highlight the drug resistance of prostate cancer cells with NE features

CONCLUSIONS:
NE differentiation characterizes the second most prevalent phenotype in prostatic adenocarcinoma but remains unrecognized in pathological and clinical practice. NE tumor cells are androgen-insensitive and exert mitogenic effects on adjacent (exocrine) tumor cells. Their cell kinetic features make them particularly resistant to radiation therapy and cytotoxic drugs. Looking for NE differentiation is therefore recommended in the pathological and clinical evaluation of prostate cancer patients for whom radiation and androgen deprivation are therapeutic options.

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