Aug. 28, 2008 -- Hormone therapy, the most common treatment for advanced prostate cancer, can boomerang to make the cancer more deadly, mouse studies suggest.
The finding "may revolutionize the way we combat prostate cancer," suggest University of Rochester researchers Chawnshang Chang, PhD, Edward M. Messing, MD, and colleagues.
It's well known that male sex hormones promote the growth of prostate cancer. That's why doctors use hormone therapy -- chemical or physical castration -- to shut off these tumor-promoting androgens.
But Chang's team finds that in different types of prostate cancer cells, androgens actually inhibit prostate cancer. When these tumor cells don't get androgens, they become more aggressive and more invasive.
The lining of the prostate is made up of epithelial cells. The fibrous body of the prostate is made up of stromal cells. On their surfaces, both cell types have triggers -- androgen receptors -- that fire when they encounter sex hormones. Triggering androgen receptors has different effects in each cell type.
"The androgen receptor in the stromal cells always turns the cancer on," Messing tells WebMD. "The androgen receptor in the epithelial cells, at least in the animal models we studied, tends to inhibit cancer."
This, Messing says, helps explain why hormone therapy always works at first but then tends to lose its cancer-inhibiting effect over time.
Since the cancer-promoting effect of androgens is strongest in the earlier stages of cancer, hormone therapy does more good than harm. But as the cancer spreads to distant sites, Messing says, the cancer-inhibiting effect of androgens may become more important. At this point, hormone therapy may do more harm than good.
How can the same hormones have two opposite effects?
"Anyone who has been around teen boys and older men knows that androgen receptors in different parts of the body cause different effects," Messing says. "Androgen receptors on the scalp make older men lose their hair, while androgen receptors on the face make teenagers grow beards. So androgen receptors can do different things in different places."
Doctors have long known that hormone therapy has different effects at different times in different parts of the body, says Peter Nieh, MD, director of the Uro-Oncology Center at Emory University, Atlanta.
"We'd all like to find a silver bullet that attacks one thing but does not hurt anything else. The problem is there is always collateral damage," Nieh tells WebMD.
Chang's team demonstrated the opposite effects of androgen receptors in cell-culture studies and in studies of prostate-cancer-prone mice that lacked androgen receptors only in their prostate epithelial cells. These mice had much more aggressive cancer, apparently because they lost the ability to respond to the cancer-inhibiting effects of androgens.
The researchers also point to studies of prostate glands removed from men with prostate cancer. There were significantly fewer androgen receptors in metastatic prostate cancers than in early prostate cancers or in normal prostate cells.
Nieh notes that human studies will be needed to confirm the suggestion that the cancer-stimulating effect of hormone therapy explains why the treatment often fails after succeeding at first. And he says that even if hormone therapy does stimulate cancer, its inhibitory effect is more important for some patients.
"The idea of continuous hormone therapy for very advanced prostate cancer has been with us for 60 years," Nieh says. "Patients with bone metastases and extensive disease probably have much more of the stromal part of the prostate, the part that is stimulated by androgen. So they well respond better to the cancer-inhibiting aspect of hormone treatment than to any cancer-stimulating aspect."
But the Chang team's mouse studies suggest that hormone therapy may exert a stronger effect on stromal cells early in the course of disease.
Nieh points to clinical trials of intermittent hormone therapy, in which patients go off treatment from time to time. The idea is to lessen the side effects of the treatment and to extend its anticancer effect.
"With intermittent hormone therapy, animal studies suggest you may be getting a balance between the inhibitory and stimulatory effects on the cancer, whereas continuous hormone therapy drives out the inhibitory effect and you are left with the stimulatory effect," he says. "We really won't know in humans for at least four or five years because the trial is just now being done."
Messing hopes that researchers will find a way to make future hormone therapy more specific so that it blocks the cancer-promoting functions of androgen receptors and enhances their cancer-inhibiting effects.
Chang, Messing, and colleagues report their findings in the Aug. 18 early online edition of the Proceedings of the National Academy of Sciences.