Photo by Dr. Norm Greenberg
Though most men with advanced prostate cancer dramatically improve after hormone-deprivation therapy, their tumors nearly always come back in a drug-resistant and lethal form. A new study involving Clinical Research Division scientists provides an explanation for the origin of these deadly recurrences, which researchers say opens the door to development of new drugs that will improve survival rates for men with therapy resistant tumors.
The research focused on what scientists have dubbed cancer stem cells. Like adult tissue-forming stem cells, cancer stem cells are believed to be long-lived unspecialized cells that divide infrequently and whose progeny give rise to large numbers of cells committed to a specific function. In recent years, scientists have hypothesized the existence of cancer stem cells as a way to explain why many patients relapse after chemotherapy, which typically kills rapidly dividing tumor cells. Although the cancer stem cells are likely to be few in number, such "sleeper cells" constitute a stubborn, renewable stronghold of drug-resistant cells.
In the new study, the scientists have found strong evidence for the existence of prostate-cancer stem cells in recurrent prostate tumors in mice and in tumor tissue from men undergoing hormone-deprivation therapy. The study also identifies a protein that may be responsible for the suspected prostate-cancer progenitor cells' insensitivity to hormone withdrawal, which researchers say represents a promising target for new drugs that attack therapy-resistant disease.
The study appears in the Aug. 1 issue of Cancer Research and was led by researchers in the laboratories of Drs. Gary Smith and James Mohler at the University of North Carolina. All of the mouse investigations were performed in Dr. Norm Greenberg's laboratory. Dr. Wendy Huss, a former graduate student in Greenberg's lab who is now at North Carolina, was the lead author of the paper.
Discovery of a protein pump
"What this work focuses on is the prostate cancer that kills you — that is, the cancer that comes back after hormone-withdrawal therapy," Greenberg said. "Therapy-resistant tumors probably represent cancers that are more 'stemish' in origin. You sometimes hear people refer to these resistant cells as 'lurker' or 'sleeper' cells." Greenberg said that usually, prostate cancer originates in specialized cells, called epithelial cells, which line the prostate gland.
"These tumor cells produce proteins, called androgen receptors, that cause them to divide in response to hormone, so hormone-withdrawal therapy has a profound effect on these cancers," he said. "Men who have hormone-sensitive cancers who are given hormone-withdrawal therapy at the right time can do very well."
But for most men, he said, the therapy is not curative because it is probably administered after prostate-cancer stem cells have had a chance to emerge in nearby tissue. Researchers suspect that cancer stem cells may develop from normal prostate tissue-forming stem cells, which possibly acquire mutations during a man's lifetime. Another theory, one favored by Greenberg and colleagues, is that normal prostate stem cells are triggered to forge down an atypical path because they receive abnormal stimuli from their cancerous environment and perhaps, from the changes that occur in the prostate as a result of the hormone-withdrawal therapy itself.
Earlier work from the research team had identified small populations of cells that lacked androgen receptor in both normal and cancerous prostate tissue, which they suspected to be stem cells. In the new study, the researchers more thoroughly analyzed these cells and discovered that a protein found on the surface of the cells acts as a pump that removes hormone from the cell. Preventing the normal stem cells from responding to male hormones explains why the cells remain unspecialized, since hormone trigger cells to mature into specialized tissue. It also explains why the prostate-cancer stem cells are insensitive to hormone-withdrawal therapy, Greenberg said.
Implications for other solid cancers
"We now feel that the origin of the emerging disease is that stem-cell population in the prostate," he said. "This protein pump is what allows the cells to maintain their 'stem-ness' — and it's also likely to be very important for this emergent disease."
The discovery opens up many possibilities, Greenberg said.
"Clearly, we have to treat these 'lurker' cells by designing therapies specifically against them," he said. "There are already existing drugs that poison this class of protein pumps, which we plan to begin testing in mice. We expect that what we've found for prostate cancer probably has implications for many other solid cancers."