In the journal Cell, researchers report new evidence to explain why prostate cancer and other hormone-dependent cancers may become resistant to hormone therapies. Their findings further suggest that a similar mechanism may play an essential role in reproductive physiology, including critical events of pregnancy.
Led by Michael Rosenfeld and David Rose at the University of California, San Diego, the group found in studies of cell cultures that so-called macrophages--components of the innate immune system that drive inflammatory reactions--physically interact with prostate cancer cells. That interaction, in turn, reverses the activity of hormone receptors in cancer cells that respond to androgens, such as testosterone, leading to shifts in the expression of other genes. The study's co-first authors were Ping Zhu and Sung Hee Baek, also of UCSD.
"While hormone resistance can likely be acquired in multiple ways, it appears we may have uncovered a general contributor to hormone resistance in prostate cancer," Rosenfeld said.
"Hormone resistance is a particular problem in prostate cancer, where it occurs in a very high percentage of cases," Rose added. "We think we've now made a connection between inflammation and resistance to particular cancer drugs."
Androgens, acting via androgen receptors, are essential for normal growth and function of the prostate gland and have been implicated in the progression of prostate cancer. Selective androgen receptor modulators (SARMs) --drugs intended to inhibit the activity of androgen receptors--are therefore standard treatment for prostate cancer. However, prostate cancers often become resistant to such treatment. A similar, though less common, phenomenon can also occur in breast cancers treated with drugs that target the hormone receptor for estrogen.
The new study reports that an inflammatory chemical produced by macrophages can lead to resistance by setting in motion other changes that reverse the function of SARMs. Those alterations, in effect, turn the androgen receptor-inhibiting drugs into activators.
"This is the last thing you want because that makes the prostate and cancer grow," Rosenfeld said.
Macrophage cells of the immune system infiltrate virtually all prostate tumor samples, the researchers found. They further showed that blocking one of the major chemicals secreted by macrophages prevented SARMs from stimulating androgen receptors, evidence that the inflammatory chemical plays a critical role in the development of drug resistance.
That chemical interaction depends on a portion of the androgen receptor that is specific to all sex steroid receptors, including the estrogen and progesterone receptors, they reported. That region of the receptor is responsible for enlisting a protein that senses inflammatory signals, enabling SARMs to activate genes normally stimulated by active hormone receptors, according to the researchers.
The findings suggest "some very inviting potential" targets for drugs that might prevent the development of hormone resistance in cancers, Rosenfeld said. However, the researchers urge caution as any such advances would take considerably more study.