Stimulation of Cell Proliferation and Carcinogenic and Tumor Promoting Effects of Androgens

Androgen receptor-mediated stimulation of prostatic cell proliferation by androgens has been implicated in human prostate carcinogenesis [135, 235]. However, there is no direct evidence that elevation of circulating testosterone leads to increased cell proliferation in the human prostate. Androgen administration to castrated rodents causes elevation of prostatic cell proliferation similar to that observed in cell cycle synchronization experiments with cells in vitro [240]. The increase in prostatic cell proliferation caused by androgen administration to castrated rodents is only transient, and after a few days cell turnover returns to its normal very low level [240]. Thus, continued androgen treatment of rodents does not result in constantly elevated rates of cell proliferation in the male accessory sex glands, but probably only supports differentiation. DHT may even suppress prostatic cell proliferation in intact rats [206]. Thus, continuous stimulation of cell proliferation is unlikely be the major mechanism of the enhancing effects of androgens on prostate carcinogenesis in rodents and possibly humans. There are conceivably also other, non-hormonal, factors that affect prostatic cell proliferation, such as inflammatory insults (prostatitis) [241, 242] and possibly sexual activity. Strong support for a cell proliferation hypothesis is derived from rodent experiments that indicate that increased prostatic cell proliferation at the time of exposure to carcinogens can enhance the sensitivity of the tissue to the carcinogenic effects of these agents [199, 220-223]. Stimulation of cell proliferation during carcinogen exposure increases the likelihood that promutagenic DNA damage, such as carcinogen-DNA adducts, will be fixed as permanent somatic mutations. Increased cell proliferation may thus enhance the carcinogenic effects of low level exposure to environmental and endogenous carcinogens in humans.

Importantly, the rate of cell proliferation at the time of carcinogen exposure may be only one of several androgen-related factors that determine sensitivity of the prostate to cancer induction by carcinogens through androgen-receptor mediated mechanisms. For example, Sukumar et al. [243] have hypothesized that prostate cells that have undergone critical genetic alterations (activating mutations in oncogenes or inactivating alterations in tumor suppressor genes) may be selectively sensitive to stimulation of cell proliferation by androgens. These cells could thus have a selective growth advantage over normal cells, which do not respond to chronic testosterone treatment with sustained proliferation, but with cellular differentiation [200]. However, this hypothesis has not been critically tested. It is also possible that androgens, in addition to other factors, influence the effectiveness of indirect-acting carcinogens that are metabolized in the prostate itself.

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