Neuroendocrine differentiation in prostate carcinoma: focusing on its pathophysiologic mechanisms and pathological features

Alberti, Contardo (2010) Neuroendocrine differentiation in prostate carcinoma: focusing on its pathophysiologic mechanisms and pathological features. Il giornale di chirurgia, 31 (11/12). pp. 575-578. ISSN 1971-145X

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Prostate carcinoma, even at advanced stages, responds in most patients to androgen deprivation therapies, that are able to exploit the androgen-sensitivity of prostate cancer cells. However, more than half of such tumors, within one to three years, escape these treatments, thus progressing to the hormone-refractory condition. Intriguing links between the development of hormone-insensitivity and neuroendocrine (NE) differentiation in prostate carcinoma have been hypothesized. While, some time ago, NE cells have been considered as derived from progenitor neural crest cells, currently are thought to arise, as well as both basal and secretory cells of prostate gland, from common pluripotent stem cells. NE cell are nonproliferative, terminally differentiated, PSA/acid phosphatase and androgen receptor (AR)-negative cells, moreover exhibiting an antiapoptotic phenotype due to survivin expression. They secrete a wide range of peptide hormones and biogenic amine serotonin and express neuronal markers such as chromogranins A, B, C (CgA, B, C) and neuron specific enolase (NSE) together with synaptophysin. The propensity of prostate cancer cells to undergo a transdifferentiation pathway towards NE phenotype is due to several microenvironmental conditions such as androgen depletion (induced by LH-RH analogs or antagonists, antiandrogens, 5-α-reductase inhibitors), ionizing-radiation therapy, adrenergic factors, increase in interleukin-6 signaling cascade. NE differentiation in prostate malignancy arises in three different forms: carcinoid, oat cell carcinoma, focally NE-differentiated conventional tumor. Selective expression of stem cell-associated markers, such as CD44/Oct4A gene, in NE cancerous cells explain their therapy escape together with tumor recurrence and metastasis. Malignant NE cells, although unable to proliferate, increase the proliferation of the neighboring nonneuroendocrine cancer cells, by providing them with hormone peptide-mediated growth paracrine stimuli. Aberrantly activated glutamic acid decarboxylase-independent pathway for production of GABA (γ-amino-butyric acid) appears to be a constant feature of invasive NE tumors. Serum levels of CgA reflect NE differentiation in prostate carcinoma more suitably than those of NSE. Intriguingly, intermittent androgen deprivation therapy, by preventing NE differentiation, significantly reduces the risk of a rise in serum CgA levels meanwhile delaying the time of cancer progression due to hormone-independence. Although valuable insights into the nature of NE differentiation in prostate carcinoma have been achieved in the last decades, additional understanding is needed about its pathogenetic mechanisms in order to devise novel therapy strategies to target them.

Item Type: Article
Uncontrolled Keywords: Carcinoma della prostata - Tumore neuroendrocrino - Radioterapia - Nevirapina - Ablazione di androgeni
Subjects: 600 Tecnologia - Scienze applicate > 610 Medicina e salute (Classificare qui la tecnologia dei servizi medici) > 617 Rami vari della medicina; Chirurgia
Depositing User: Nadia Del Gobbo
Date Deposited: 27 Apr 2016 10:47
Last Modified: 27 Apr 2016 10:47

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