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.
They point out that the results extend the potential role of macrophages in diseases. For example, earlier studies by the researchers suggested a similar mechanism whereby macrophages in fat cells may lead to insulin resistance, Rose said. Macrophages also have clear roles in atherosclerosis, they added.
The unexpected findings also led the group to a perplexing question. "What is the evolutionary reason for this physiological mechanism?" Rose asked. "It certainly didn't arise in the context of hormone-resistant cancers."
The researchers uncovered preliminary evidence to suggest that macrophages may induce important reversals in the gene activity regulated by an estrogen hormone in a similar fashion. The mechanism may therefore play a role in gene expression changes associated with the implantation of a fertilized egg in the uterus, they suggest, a process which constitutes an 'inflammatory event,' they said.
"Local inflammation in response to tissue accumulation of macrophages and other immune cells precedes every major reproductive event in the ovaries and uterus, from ovulation to implantation [of a fertilized egg] and menstruation," wrote Malcolm Parker of Imperial College London in a preview. The current study suggests that infiltrating macrophage cells may provide signals for "local expression of genes otherwise repressed by sex hormone receptors."
Such mechanisms may play an important role in various reproductive processes, such as the induction of muscle contractions characteristic of labor, Parker added. The process may therefore have important implications for understanding reproductive disorders, such as preterm labor, he suggested.
"Preterm labor is now widely considered to be an inflammatory disease that accounts for the majority of neonatal deaths," Parker noted. "Hence, by lifting the veil covering a hitherto unrecognized molecular mechanism, [the current study] has set new challenges. None of these challenges is more important than translating this new molecular information into more effective therapies for hormone-dependent cancers and common reproductive disorders."
The researchers include Ping Zhu, Kenneth A. Ohgi, Ivan Garcia-Bassets, Eliot M. Bourk, and Michael G. Rosenfeld of the Howard Hughes Medical Institute and the University of California, San Diego in La Jolla, CA; Sung Hee Baek of the Howard Hughes Medical Institute and the University of California, San Diego in La Jolla, CA and Seoul National University, Seoul, Korea; Hideki Sanjo, Shizuo Akira, and Paul F. Kotol of Osaka University, Osaka, Japan; Christopher K. Glass and David W. Rose of the University of California, San Diego in La Jolla, CA. This work was supported by grants from NCI to M.G.R., NIH to D.W.R., C.K.G., and M.G.R., and the PCRP to M.G.R.
Zhu et al.: "Macrophage/Cancer Cell Interactions Mediate Hormone Resistance Through A Conserved Nuclear Receptor Derepression Pathway." Publishing in Cell 124, 615–629, February 10, 2006. DOI 10.1016/j.cell.2005.12.032 www.cell.com
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Cell