Neuroendocrine differentiation in prostate cancer: new insights and clinical implications

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Background

Prostate cancer is the leading incident malignancy in the aging population of industrialized countries, with an increasing incidence. Early stage prostate cancer (PCa) is responsive to androgen ablation therapy, but invariably recurs as castration-resistant and highly aggressive. Neuroendocrine differentiation (NED) in prostatic adenocarcinomas is associated to the onset of hormone-refractory disease in vivo and a hallmark of advanced androgen-independent prostate cancer, for which no succesful therapy exists. A high proportion of PCa display focal NED at diagnosis, usually revealed by immunohistochemichal CgA expression. During antiandrogen or androgen-withdrawal therapy the NED is often increased but its prognostic value is controversial.
Neuroendocrine (NE) cells, widely distributed in the normal prostate, have been identified in every grade and stage of PCa, and are also present in prostatic intraepithelial neoplasia and in metastatic PCa. NED is increased in high grade and high stage tumors and particularly in hormonally treated and castration-resistant tumors. About 5-10% of PCa contain abundant NE tumor cells .
In comparison to secretory prostatic epithelial cells, the NE cells, whether benign or malignant, do not express androgen receptor (AR) and PSA. NE cells are considered terminally differentiated and post-mitotic and their origin in PCa is still controversial, altough it is becoming increasingly clear that NE cells in PCa are different from normal prostate NE cells, i.e, in their differential expression of proteins. Altough it has been proposed that they share the same origin with normal NE cells, and then become differentiated form intermediate stem cells, accumulate evidence suggest that adenocarcinoma cells can undergo a transdifferentiation process to become NE cells.

The propensity of PCa cells to take a transdifferentiation pathway toward a NE phenotype is due to several microenvironmental conditions such as androgen depletion, which is the classic stimulator of NED in human PCa (LNCaP) cells, but NED can also be induced by many other means, such as an increased intracelular level of c AMP, ionizing radiation therapy, adrenergic factors or an increase in the interleukin-6 signaling cascade. It has been suggested that androgen deprivation therapy can play a pivotal role in modulating the prognostic role of NED where NE cells could increase the rate of acquisition of the androgen-insensitive state in hormonally treated patients.
Although the NE tumor cells appear to be nonmitotic, they are involved in the proliferation of the surrounding tumor cells by secreting paracrine peptides, which may activate signaling pathways that stimulate tumor cell growth and may provide a survival advantage under hormone deprived and/or chemotherapeutic conditions. Receptors for some of the neuroendocrine products have been found in the benign prostate and/or PCa including serotonin, bombesin/GRP, neurotensin, somatostatin, cholecystokinin, Neuropeptide Y and calcitonin.

Neuroendocrine cells may also increase the antiapoptotic activity in surrounding cells through an overexpression of BCL-2 and may, thus, confer apoptotic-resistance to neighboring cells. Furthermore, NE cells express the antiapoptotic protein survivin. As we have previously described, neuropeptides bombesin and calcitonin modulate etoposide-induced apoptosis in androgen dependent and independent prostate cancer cell lines, also blocking intracelular ion changes.

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