Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model
January 1999
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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.
- Male
- Animals
- Humans
- Research Support, Non-U.S. Gov't
- Mice
- Mice, Nude
- Cell Differentiation
- Androgens/deficiency/*physiology
- Apoptosis
- Cell Division
- Chromogranins/metabolism
- Disease Models, Animal
- Immunoenzyme Techniques
- Neoplasm Transplantation
- Neurosecretory Systems/metabolism/*pathology
- Orchiectomy
- Prostatic Neoplasms/metabolism/*pathology
- Proteins/metabolism
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Receptors, Androgen/metabolism
- prostate
- -295
- androgen
- expression
- tumor
- castration
- cancer
- androgen withdrawal
- model
- pc -295 model
- differentiation
- receptor
- neuroendocrine differentiation
- androgen receptor
- withdrawal
- neuroendocrine
- minute
- xenograft
- prostatic
- prostate cancer
