BACKGROUND.
Information is presented on prostatic neuroendocrine cells and neuroendocrine differentiation in prostatic carcinoma. The prognostic and therapeutic implications of neuroendocrine differentiation in prostatic carcinoma are reviewed. METHODS. Data are presented that support the intriguing link between neuroendocrine differentiation, tumor progression, and androgen-independent prostate cancer. The hormones, and the receptors, expressed by prostatic neuroendocrine cells are investigated in order to elucidate their significance for prognosis and therapy. RESULTS. The prognostic significance of neuroendocrine differentiation in prostatic malignancy has been controversial, but recent studies employing markers such as chromogranin A and neuron-specific enolase suggest that neuroendocrine differentiation, as reflected by increased tissue expression and/or blood levels of these neuroendocrine secretory products, correlates with poor prognosis, tumor progression, and androgen-independence. Since all malignant neuroendocrine cells are devoid of androgen receptors and since neuroendocrine phenotypic expression is not suppressed by androgen ablation, clonal propagation of androgen receptor-negative neuroendocrine cells may play an important role in the pathway towards the androgen-independent state of prostatic carcinoma. This would have significant implications for the treatment of prostate cancer, as several of the hormones known to be expressed by neuroendocrine-differentiated, malignant prostatic cells are potential candidates for drug therapy. A limited number of hormones have been tested in this context, in particular somatostatin, bombesin, and serotonin. CONCLUSIONS. Neuroendocrine differentiation in carcinoma of the prostate appears to be associated with poor prognosis, tumor progression, and the androgen-independent state, for which there is currently no successful therapy. Therefore, new therapeutic protocols and trials need to be developed to test drugs based on neuroendocrine hormones and/or their antagonists. An evaluation of this new therapeutic approach against prostatic carcinoma with neuroendocrine differentiation, including hormone-refractory cancer, is easily justified, since these tumors are unresponsive to current modes of therapy.