Androgen deprivation of the PC-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation.
Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating neuropeptides via a regulated secretory pathway (RSP). We studied NE differentiation after androgen withdrawal in the androgen-dependent prostate cancer xenograft PC-310. Expression patterns of chromogranin A, secretogranin III, and prohormone convertase-1 were analyzed at both protein and mRNA level to mark the kinetics of NE differentiation both in vivo and in vitro. PC-310 tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, and 21 days postcastration. PC-310C cultures initiated from collagenase-treated tumor tissue could be maintained up to four passages, and androgen-deprivation experiments were performed similarly. PC-310 tumor volumes decreased by 50% in 10 days postcastration. Proliferative activity and prostate-specific antigen (PSA) serum levels decreased to zero postcastration, whereas PSA levels in PC-310C culture media first decreased and subsequently increased after 5 days. In vivo, androgen receptor (AR) expression decreased initially but returned to control level from 5 days postcastration on. CgA, secretogranin III, and secretogranin V expression increased in vivo from 5 days postcastration on. Subsequently, prohormone convertase-1 and peptidyl alpha-amidating monooxygenase as well as the vascular endothelial growth factor were expressed from 7 days postcastration on, and, finally, growth factors such as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days postcastration. The PC-310 tumors did not show colocalization of the AR on the NE cells in the tumor residues after 21 days. As in the PC-310 xenograft, NE differentiation was induced and AR expression relapsed after prolonged androgen suppression in PC-310C. For PC-310C cells, this relapse was associated with the secretion of PSA. PC-310C is the first culture of human prostatic cancer cells having the NE phenotype. The PC-310 model system is a potential androgen-dependent model for studying the role of NE cells in the progression of clinical prostate cancer. Androgen deprivation of NE-differentiated prostate cancer may induce the formation of both NE- and AR-positive dormant tumor residues, capable of actively producing NE growth factors via a RSP, possibly leading to hormone refractory disease.
Jongsma
J
J
Department of Experimental Urology, Josephine Nefkens Institute, Erasmus University, Rotterdam, The Netherlands. jongsma@uro.fgg.eur.nl
Oomen
M H
MH
Noordzij
M A
MA
Van Weerden
W M
WM
Martens
G J
GJ
van der Kwast
T H
TH
Schröder
F H
FH
van Steenbrugge
G J
GJ
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D006899:Mixed Function Oxygenases / Q000032:analysis; D009097:Multienzyme Complexes; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D009490:Neurosecretory Systems / Q000166:cytology*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000032:analysis
D000728:Androgens; D053379:Chromogranin A; D002864:Chromogranins; D009097:Multienzyme Complexes; D011944:Receptors, Androgen; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D017430:Prostate-Specific Antigen