Androgen deprivation of the 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 studi ed NE differentiation after androgen withdrawal in the androgen-dependent p rostate cancer xenograft PC-310, Expression patterns of chromogranin A, sec retogranin III, and prohormone convertase-l were analyzed at both protein a nd mRNA level to mark the kinetics of NE differentiation both in vivo and i n 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-depriva tion experiments were performed similarly, PC-310 tumor volumes decreased b y 50% in 10 days postcastration, Proliferative activity and prostate-specif ic antigen (PSA) serum levels decreased to zero postcastration, whereas PSA levels in PC-310C culture media first decreased and subsequently increased after 5 days. bt vivo, androgen-receptor (AR) expression decreased initial ly but returned to control level:from 5 days postcastration on. CgA, secret ogranin III, and secretogranin V expression increased in vivo from 5 days p ostcastration on. Subsequently, prohormone convertase-l and peptidyl alpha- amidating monooxygenase-as well as the vascular endothelial growth factor w ere expressed from 7 days postcastration on, and, finally, growth factors s uch as gastrin-releasing peptide and serotonin were expressed in a small pa rt of the NE cells 21 days postcastration, The PC-310 tumors did not show c olocalization 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 expressio n relapsed after prolonged androgen suppression in PC-310C. For PC-310C cel ls, this relapse was associated with the secretion of PSA. PC-310C is the f irst culture of human prostatic cancer cells having the NE phenotype. The P C-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 o f both NE- and AR-positive dormant tumor residues, capable of actively prod ucing NE growth factors via a RSP, possibly leading to hormone refractory d isease.