Neuroendocrine differentiation in human prostatic tumor models.

Neuroendocrine (NE) cells can be identified in benign and malignant prostatic epithelia. Factors regulating their presence and their functions are poorly understood, mainly due to a lack of suitable experimental models. Fifteen in vitro and in vivo prostatic cancer tumor models, including a number of newly established in vivo models, were studied immunohistochemically for the presence of NE cells under different hormonal conditions. None of the in vitro models (PC-3, DU 145, LNCaP, and TSU) contained NE cells. Five of the seven xenograft models established at this laboratory contained NE cells. In three of these, NE cells were found only in the initial mouse passages. In the other two (PC-295 and PC-310), the NE phenotype was stable. NE features were confirmed by transmission electron microscopy and by Western analysis of chromogranin A expression. Immunohistochemical double-labeling experiments confirmed that NE cells in prostate cancer are post-mitotic (no Ki-67 expression) and do not express the androgen receptor. In the PC-295 and PC-310 models, short-term androgen withdrawal resulted in a rapidly increased number of NE cells. A time course experiment with PC-295-bearing mice strongly suggests that this increase occurred by induction of NE differentiation rather than by rapid proliferation and subsequent differentiation or selective persistence. In conclusion, these models are suitable to resolve fundamental questions with regard to the presence and functions of NE cells in human prostate cancer.