Neuroendocrine differentiation of prostate cancer

Benign prostate and prostatic adenocarcinoma contain rare quiescent neuroendocrine cells while small cell neuroendocrine carcinoma (SCNC), a variant form of prostate cancer, contains highly proliferative neuroendocrine tumor cells. We provide evidence that IL-8-CXCR2-P53 pathway keeps the NE cells in a quiescent state normally. P53 mutation inactivates this pathway, resulting in hyper-proliferation and aggressive behavior of the NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are different from those of adenocarcinoma, which explains SCNC′s distinct biology and the clinical observation that it does not respond to hormonal therapy. Prostate cancer is a major health risk for men in Western countries as it is the most common malignancy and the second leading cause of cancer-related deaths. In some countries where prostate cancer is traditionally uncommon such as China, the incidence of prostate cancer has also shown a dramatic increase in recent years. Low grade, organ-confined prostate cancers are curable by surgery or radiation therapy. For patients with recurrent or metastatic prostate cancer, hormonal therapy, by inhibiting androgen production and/or blocking androgen receptor (AR) function, is the treatment of choice. Unfortunately, hormonal therapy is not curative and the cancer nearly always recurs after an initial period of response and inevitably progresses to the castration resistant stage. Newer agents have been developed to inhibit intratumoral androgen production or more effectively block AR function, but resistance occurs quickly. In this article, we will focus our discussion on cellular heterogeneity of human prostate cancer and molecular mechanisms responsible for the development of small cell neuroendocrine carcinoma (SCNC), a lethal form of prostate cancer often seen in patients who have received hormonal therapy.