1. Kinetics of Neuroendocrine Differentiation in an Androgen-Dependent Human Prostate Xenograft Model
- Author
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Gert J. van Steenbrugge, Marinus A. Noordzij, Wytske M. van Weerden, Theodorus H. van der Kwast, Fritz H. Schröder, Johan Jongsma, Gerard J.M. Martens, and M. H. A. Oomen
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Cellular differentiation ,Mice, Nude ,Apoptosis ,Biology ,Neuroendocrine differentiation ,Pathology and Forensic Medicine ,Immunoenzyme Techniques ,chemistry.chemical_compound ,Mice ,Internal medicine ,medicine ,Chromogranins ,Animals ,Humans ,Neuroendocrine cell ,Secretogranin III ,Chromogranin A ,Prostatic Neoplasms ,Proteins ,Cell Differentiation ,Androgen ,Neurosecretory Systems ,Androgen receptor ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Receptors, Androgen ,biology.protein ,Androgens ,Orchiectomy ,Bromodeoxyuridine ,Cell Division ,Neoplasm Transplantation ,Regular Articles - Abstract
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 G 0 -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 G 0 -phase-arrested cells.
- Published
- 1999