NEUROENDOCRINE DIFFERENTIATION IN HUMAN PROSTATIC TUMOR-MODELS

Neuroendocrine (NE) cells can be identified in benign and malignant pr ostatic epithelia. Factors regulating their presence and their functio ns are poorly understood, mainly due to a lack of suitable experimenta l models. Fifteen in vitro and in vivo prostatic cancer tumor models, including a number of newly established in vivo models, were studied i mmunohistochemically for the presence of NE cells under different horm onal conditions. None of the in vitro models (PC-3, DU 145, LNCaP, and TSU) contained NE cells. Five of the seven xenograft models establish ed 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-29 5 and PC-310), the NE phenotype was stable. NE features were confirmed by transmission electron microscopy and by Western analysis of chromo granin A expression. Immunohistochemical double-labeling experiments c onfirmed that NE cells in prostate cancer are post-mitotic (no Ki-67 e xpression) and do not express the androgen receptor. In the PC-295 and PC-310 models, short-term androgen withdrawal resulted in a rapidly i ncreased number of NE cells. A time course experiment with PC-295-bear ing 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 prese nce and functions of NE cells in human prostate cancer.