[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 the biological properties of NE tumor cells that make them resistant to androgen deprivation and radiation therapy. NE cells produce a number of hormonal growth factors (e.g., serotonin) that may act through endocrine, paracrine, and autocrine mechanisms. 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 adenocarcinomas show NE differentiation as defined by the most commonly used endocrine marker chromogranin A. Clinical studies suggest that the extent of NE differentiation increases with tumor progression and the development of androgen insensitivity. 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 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 represent 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. Looking for NE differentiation is recommended in the pathological and clinical evaluation of prostate cancer patients for whom radiation and androgen deprivation are therapeutic options.