Androgen deprivation therapy, heavily-prescribed for men with prostate cancer, may have an unforeseen downside. According to a new study, lack of androgen may make any surviving cancer cells more invasive.

Generally, when prostate tumors are deprived of androgens (male sex hormones, notably testosterone and its precursors), they shrink for extended periods of time. But androgen deprivation therapy, Johns Hopkins researchers have found, may produce a protein called nestin, which makes prostate cancer cells more likely to spread throughout the body.

The Johns Hopkins researchers caution that their discovery is far too preliminary for prostate cancer patients or physicians to stop using it, but they believe that the finding could eventually lead to changes in this standard treatment for a sometimes deadly disease. The therapy is effective at slowing tumor growth, they emphasize

A team led by David Berman, an assistant professor of pathology, urology and oncology at The Johns Hopkins University School of Medicine identified this unsuspected potential problem with treatments that suppress testosterone after discovering that the gene that codes for the protein, called nestin, was active in lab-grown human prostate cancer cells.

Curious about whether prostate cancer cells in humans also produce nestin, the team looked for nestin in cells taken from men who had surgery to remove locally confined cancers of their prostates and found none.

But when they looked for nestin in prostate cancer cells isolated from patients who had died of metastatic prostate cancer – in which cancer cells spread out from the prostate tumor – they found substantial evidence that the nestin gene was active.

What was different, Berman speculated, is that androgen deprivation therapy, a treatment that reduces testosterone in the body, is generally given only when prostate cancers become aggressive and likely to metastasize.

Because prostate cancer growth is typically stimulated by testosterone, the treatment is thought to slow tumor growth and weaken the disease. Patients who eventually die because their disease metastasizes are almost certain to have received this type of therapy, he says.

Speculating that depriving cells of androgens might also affect nestin expression, the researchers experimented on a prostate cancer cell line that depends on androgens to grow. When they removed androgens from the chemical mixture that the cells live in, their production of nestin increased.

Aware that the nestin gene has long been suggested to play some role in cell growth and development, Berman and his colleagues used what they describe as a bit of “laboratory sabotage” called RNA interference to decrease the genetic expression of nestin.

They found that these nestin-void cells weren’t able to move around and through other cells nearly as efficiently as could cells with normal nestin levels.

Prostate cancer cells with hampered nestin expression were also less likely than normal prostate cancer cells to migrate to other parts of the body when transplanted into mice. However, while nestin expression seemed pivotal for metastasis in these experiments, it didn’t seem to make a difference in tumor growth.

“What all this suggests is that nestin levels increased when prostate cancer cells are deprived of androgens and may encourage the cells to metastasize,” says Berman.

In men, androgen deprivation may occur either naturally, through aging or by means of anti-prostate cancer drugs, Berman notes:

“These results specify a function for nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread.”

Besides Berman, other Johns Hopkins researchers involved in this study were Wolfram Kleeberger, M.D., G. Steven Bova, M.D., Matthew E. Nielsen, M.D., Mehsati Herawi, M.D., Ph.D., Ai-Ying Chuang, M.D., and Jonathan I. Epstein, M.D.

Published in the Oct. 1, 2007 issue of Cancer Research, this research was funded by grants from the National Institutes of Health, National Cancer Institute, Evensen Family Foundation, and German Cancer Aid Foundation.

androgen blockade