Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model

It was previously shown in the PC-295 xenograft that the number of chromogr anin A (CgA)-positive neuroendocrine (NE) cells increased after androgen wi thdrawal. NE cells did not proliferate and differentiated from G(o)-phase-a rrested cells. Here we further characterized ME differentiation, androgen r eceptor status, and apoptosis-associated Bcl-2 expression in the PC-295 mod el after androgen withdrawal to assess the origin of NE cells. PC-295 tumor volumes decreased by 50% in 4 days. Intraperitoneal bromodeoxyuridine (Brd U) incorporation and MIB-1 labeling decreased to 0%, and the apoptosis was maximal at day 4. Androgen receptor expression and prostate-specific antige n (PSA) serum levels decreased rapidly within 2 days. The number of NE cell s increased 6-fold at day 4 and 30-fold at day 7. Five and ten percent of t he CgA-positive cells were BrdU positive after continuous BrdU labeling for 2 and 4 days, respectively. However, no MIB-1 expression was observed in C gA-positive cells. NE cells expressed the regulated secretory pathway marke r secretogranin Pi but were negative for androgen receptor and Bcl-2. Bcl-2 expression did increase in the non-NE tumor cells. In conclusion, androgen withdrawal leads to a rapid PC-295 tumor regression and a proliferation-in dependent induction of NE differentiation. The strictly androgen-independen t NE cells that were still present after 21 days differentiated mainly from G(o)-phase-arrested cells.