Many men diagnosed with prostate cancer receive hormone-blocking therapy as part of their treatment. Although the drugs slow or shrink the tumor for a while, they almost invariably stop working, sometimes after only a few months. Now an international team of biologists may have found a reason why: a signal generated by the body's immune cells renders the drugs useless.
Androgens, like testosterone, encourage the growth of prostate cancer cells, so scientists designed drugs called selective androgen receptor antagonists/modulators (SARMs) to block androgen receptors. But cancer cells quickly develop resistance to the drugs, and the beneficial effects almost always disappear within a year. No one was certain how this resistance came about, but there were clues. Macrophages—immune cells involved in inflammation—migrate toward the prostate when cancer strikes.
Suspecting that macrophages might be culprits in drug resistance, molecular biologist Michael Rosenfeld of the University of California, San Diego, and colleagues compared normal cells with cancerous cells from prostate cancer patients. Cancer cells were clearly interacting with macrophages in nearly every sample of tumor tissue, while these interactions only appeared occasionally in healthy tissue. When the team blocked one of the major signaling molecules, called cytokines, that macrophages send out, the SARMs worked properly again.
Rosenfeld's group went on to find that these cytokines trigger a relay team of molecules to alter the androgen receptor. That change makes androgen receptors behave as though the SARMs are hormones instead of hormone-blockers, and so the cancer grows as though the drugs weren't there, the team reports 10 February in . Rosenfeld says elucidating this cascade has shed light on a host of possible molecules for drugs to work on. "Everything in that pathway becomes a potential target."
The study "connects the dots in a very detailed way between macrophages and the hormone receptor signaling pathway," says prostate cancer researcher Charles Sawyers of the University of California, Los Angeles. He notes this link seems to be "really key to the progression of this cancer." Cancer researcher Donald Tindall of the Mayo Clinic in Rochester, Minnesota, points out that the mechanism may be just one of several ways that drug resistance emerges.
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