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 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.
|Keywords||Androgens/deficiency/*physiology, Animals, Apoptosis, Cell Differentiation, Cell Division, Chromogranins/metabolism, Disease Models, Animal, Humans, Immunoenzyme Techniques, Male, Mice, Mice, Nude, Neoplasm Transplantation, Neurosecretory Systems/metabolism/*pathology, Orchiectomy, Prostatic Neoplasms/metabolism/*pathology, Proteins/metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, Receptors, Androgen/metabolism, Research Support, Non-U.S. Gov't|
Jongsma, J., Oomen, M.H., Noordzij, M.A., van Weerden, W.M., Martens, G.J., van der Kwast, Th.H., … van Steenbrugge, G.J.. (1999). Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model. American Journal of Pathology. Retrieved from http://hdl.handle.net/1765/9049