Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma.
The Dunning R-3327-H rat prostatic adenocarcinoma is a well-differentiated, slow-growing, serially transplantable tumor of spontaneous origin. When intact male rats bearing such an exponentially growing H-tumor s.c. are castrated, tumor growth abruptly stops, demonstrating the initial androgen sensitivity of this tumor. Eventually, however, after an extended period, the tumor invariably relapses and once again appears to grow exponentially. At the time of relapse, the tumor is no longer androgen sensitive but has irreversibly progressed to a completely insensitive state. The mechanism responsible for this irreversible progression has been demonstrated by fluctuation analysis not to be due to environmentally induced adaptation of initially androgen-dependent H-tumor cells to a new androgen-independent state. Instead, the progression is due to the basic heterogeneity of the original H-tumor (i.e., it is composed of a mixture of preexisting clones of both androgen-dependent and androgen-independent tumor cells). Following castration, only the preexisting clones of androgen-independent tumor cells are able to continue exponential growth; the androgen-dependent tumor cells stop proliferating and die. Thus, androgen ablation creates a host environment in which the androgen-independent tumor cells have a highly selective growth advantage over the androgen-dependent cells. Eventually, with time, this selective growth advantage results in a tumor which is completely composed of androgen-independent cells. It is the continuous proliferative growth of these androgen-independent tumor cells which leads to the relapse phenomenon.
D000222:Adaptation, Physiological; D000230:Adenocarcinoma / Q000473:pathology / Q000601:surgery*; D000818:Animals; D002369:Castration; D008297:Male; D009374:Neoplasms, Experimental / Q000473:pathology / Q000601:surgery; D011471:Prostatic Neoplasms / Q000473:pathology / Q000601:surgery*; D051381:Rats; D012641:Selection, Genetic