Some of the drugs given to many men during their fight against prostate cancer can actually spur some cancer cells to grow, researchers have found. The findings were published online this week in a pair of papers in the Proceedings of the National Academy of Sciences.

"When a man receives hormone therapy, initially the treatment works well, and his PSA (prostate specific antigen) level goes down," said Edward Messing, M.D., a urologist and an author of the paper. "But inevitably, the PSA will start climbing again, and that is usually the first sign that the treatment is beginning to fail. It's a sign that the cancer in the prostate is making a comeback."

In work funded by the National Cancer Institute, Chang's team found that blocking the receptor indeed prevents some cells in the prostate from growing, just as scientists expected. But Chang's team unexpectedly found that blocking the receptor actually spurs other prostate cells to grow.

"The androgen receptor acts differently in different cells in prostate tissue," said Chang. "It's always been assumed that blocking the androgen receptor will stop all prostate cells from growing, but we have found that that's not the case. Since current treatment acts non-specifically on all the cells having androgen receptors in the prostate, blocking the androgen receptor will give mixed results."

The team found that, as expected, the androgen receptor in prostate support cells known as stromal cells stimulates growth of cells, including cancer cells, in the prostate. He also found, surprisingly, that the receptor actually acts as a tumor suppressor in epithelial cells known as basal cells in the prostate.

Then Chang's team knocked out the androgen receptor in specific sets of prostate cells and studied the results. As expected, when the molecule is turned off in stromal cells, growth of cancer cells in the prostate slows. But when the molecule is turned off in the epithelial cells, it removes one of the body's natural inhibitors that prevents prostate cancer cells from spreading, making cells more likely to invade other tissues.

"While the androgen receptor is really driving prostate cancer, in another sense it appears that the receptor also normally inhibits the spread of cancer cells. It seems to have a dual role. Manipulating the androgen receptor can increase or decrease either of these actions depending on precisely how it's done," said Messing.

Chang says the molecule's versatility in the prostate should not come as a surprise, since the molecule's function elsewhere depends on its location.

"The effects of the androgen receptor on hair growth in men vary dramatically depending on where in the body the receptor is working," said Chang. "When the receptor is very active in the mustache area, more hair grows. When it's very active on the top of the skull, toward the front, hair falls out and men become bald. And the hair on the back of the head is insensitive to the receptor. The effects of hormones depend on the location.

"We found that the same is true within the cells of the prostate itself," said Chang, who is a faculty member in the departments of Urology and Pathology and the James P. Wilmot Cancer Center.

Chang says it's likely that the androgen receptor works differently in different cells partly because the assortment of molecular colleagues it works with within the body changes from situation to situation. Like a foreman turning to a pool of employees to get certain jobs done, the androgen receptor taps different molecules in different situations, forming intricate complexes or groupings that then accomplish various tasks. The receptor works very quickly, assembling a team within seconds, accomplishing a task, then disbanding and making its helpers available to form a brand new team for another task.

Chang's team is working on ways to focus on these molecular "co-factors" as a way to target the androgen receptor differently in different cells, for instance, turning off the receptor in some cells while keeping it on in others, to fight prostate cancer. That type of cell-specific targeting is currently not possible.

The research in the laboratory involved tracking the disease in mice and also analyzing human prostate cancer cells in culture. Nevertheless, the work might include some hints for improving patient care. Possibilities include studying whether androgen suppression therapy might be used to target only specific cells within the prostate, as well as checking whether drugs designed to prevent cancer from spreading should be used in concert with hormone therapy.