Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.
BACKGROUND
Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310.


METHODS
Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation.


RESULTS
Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively.


CONCLUSIONS
Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer.
Jongsma
Johan
J
Department of Experimental Urology, Josephine Nefkens Institute, Erasmus University, Rotterdam, Netherlands. jongsma@nki.nl
Oomen
Monique H
MH
Noordzij
Marinus A
MA
Van Weerden
Wytske M
WM
Martens
Gerard J M
GJ
van der Kwast
Theodorus H
TH
Schröder
Fritz H
FH
van Steenbrugge
Gert J
GJ
D000728:Androgens / Q000502:physiology*; D000818:Animals; D034961:Antigens, Nuclear; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D053379:Chromogranin A; D002864:Chromogranins / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000096:biosynthesis; D009490:Neurosecretory Systems / Q000378:metabolism*; D009687:Nuclear Proteins; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins; D011944:Receptors, Androgen / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
D000728:Androgens; D034961:Antigens, Nuclear; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D053379:Chromogranin A; D002864:Chromogranins; D006133:Growth Substances; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011506:Proteins; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D017430:Prostate-Specific Antigen