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(American Journal of Pathology. 1999;154:543-551.)
© 1999 American Society for Investigative Pathology

Regular Articles

Kinetics of Neuroendocrine Differentiation in an Androgen-Dependent Human Prostate Xenograft Model

Johan Jongsma* , Monique H. Oomen* , Marinus A. Noordzij* , Wytske M. Van Weerden* , Gerard J. M. Martens , Theodorus H. van der Kwast , Fritz H. Schröder* and Gert J. van Steenbrugge*

From the Departments of Urology* and Pathology, Erasmus University, Rotterdam, and the Department of Animal Physiology, University of Nijmegen, Nijmegen, The Netherlands

It was previously shown in the PC-295 xenograft that the number of chromogranin A (CgA)-positive neuroendocrine (NE) cells increased after androgen withdrawal. NE cells did not proliferate and differentiated from G₀-phase-arrested cells. Here we further characterized NE differentiation, androgen receptor status, and apoptosis-associated Bcl-2 expression in the PC-295 model after androgen withdrawal to assess the origin of NE cells. PC-295 tumor volumes decreased by 50% in 4 days. Intraperitoneal bromodeoxyuridine (BrdU) incorporation and MIB-1 labeling decreased to 0%, and the apoptosis was maximal at day 4. Androgen receptor expression and prostate-specific antigen (PSA) serum levels decreased rapidly within 2 days. The number of NE cells increased 6-fold at day 4 and 30-fold at day 7. Five and ten percent of the CgA-positive cells were BrdU positive after continuous BrdU labeling for 2 and 4 days, respectively. However, no MIB-1 expression was observed in CgA-positive cells. NE cells expressed the regulated secretory pathway marker secretogranin III 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-independent induction of NE differentiation. The strictly androgen-independent NE cells that were still present after 21 days differentiated mainly from G₀-phase-arrested cells.

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