Scientists have uncovered a key driver behind the progression of prostate cancer

Scientists at Fred Hutchinson Cancer Research Center have uncovered a key driver behind the progression of prostate cancer, a discovery that the researchers believe could spawn new treatments to prevent the cancer's spread and extend survival.

The study, conducted by Valeri Vasioukhin, Ph.D., and colleagues in Fred Hutchinson's Human Biology Division, in collaboration with researchers at Vanderbilt University, appears as the cover story of the Aug. 24 issue of Cancer Cell.

The work focused on a protein called hepsin, which has been found in high levels in human prostate and ovarian tumors. In the current study, Vasioukhin and colleagues asked what would happen if hepsin was overproduced in mice that had non-progressing forms of prostate cancer. They found that hepsin caused prostate-tumor cells to lose their grip from the surrounding tissue and to spread from the prostate to bone, lung and liver.

Hepsin's specific role in cancer progression, as well as the fact that it is a type of enzyme known as a protease, makes it a highly promising drug target, said Vasioukhin, an assistant member of Fred Hutchinson's Human Biology Division.

"Because hepsin is a protease — and proteases are relatively easy to inhibit — we think it will be possible to develop an inhibitor of hepsin that prevents metastasis," he said. "Previous research has demonstrated that hepsin is not critical for normal cells within the body and, therefore, hepsin inhibitors that are very specific would be unlikely to have significant side effects."

In collaboration with the laboratory of Julian Simon, Ph.D., of Fred Hutchinson's Human Biology and Clinical Research divisions, Vasioukhin's lab plans to search for small molecules that can inhibit hepsin.

"We are hoping that highly specific hepsin inhibitors can be used in the future to block or slow down the progression of prostate cancer from relatively harmless benign tumor to highly advanced metastatic disease."

The spread of cancer from its site of origin to another location in the body is called metastasis, a condition that can dramatically reduce a patient's chances for survival. The majority of prostate cancers are diagnosed while the disease is still confined to the prostate, a stage at which five-year survival rates are nearly 100 percent. In contrast, when the disease has spread to distant parts of the body — commonly to the bone — only about a third of patients survive five years.

While doctors have dramatically improved survival rates for prostate cancer through earlier diagnosis, there remains a need for effective therapies for men whose disease is advanced, said Pete Nelson, M.D., a Human Biology Division investigator and a physician who treats prostate-cancer patients at the Seattle Cancer Care Alliance.

"If hepsin indeed drives metastasis in human prostate cancer and if inhibitors of hepsin can be identified, it could offer new options for patients whose disease has spread," he said. "Alternatively, hepsin activity could be exploited to activate pro-drugs (precursors of chemotherapeutic drugs that are toxic to cells) locally in the tumor environment where the protease is produced at high levels. This approach could spare normal tissues that produce the enzyme at low levels."

Hepsin is a member of a large family of enzymes called proteases, which are found in all animals. Some proteases play an important role in ensuring that cells are organized correctly within a tissue or organ. For example, cells that can give rise to prostate cancer must adhere to a scaffold-like structures, called basement membranes, that keep distinct layers of cells separated from one another.

To examine the consequences of excess amounts of hepsin, Vasioukhin's group developed a strain of mice that produced elevated amounts of hepsin in the prostate gland. The mice with elevated hepsin levels had defects in the basement membrane that separates different populations of cells. This finding was interesting because disorganization and disruption of the basement membrane is a mandatory step that occurs in early phases of metastasis.

Next, the researchers bred this mouse with a type of mouse that develops a form of prostate cancer that does not metastasize in order to generate cancer-susceptible mice that overproduce hepsin. They found that these mice developed more highly advanced prostate tumors and metastases in the liver, lung, and bone. These data provide strong evidence that hepsin promotes prostate-cancer progression and metastasis.

Vasioukhin said that hepsin is not normally produced in the mouse prostate. Hepsin overproduction was not observed in other mouse models of prostate cancer.

"One simplified way to explain our observations in mice is that overproduction of hepsin is what's necessary to drive prostate cancer metastasis to the bone," he said.

Although the absence of hepsin may prevent metastasis, Vasioukhin said that studies from human cancers suggest that very high levels might also prevent cancer from spreading.

"There have been controversial results about hepsin levels in human cancer," he said. "It may be that the change from very low levels to elevated levels of hepsin will promote metastasis. But in a few cases when the levels are too high, it may cause enough disruption to the cell's gripping abilities so that they can't form new attachments at sites in the body distant from the original tumor."

In addition to searching for inhibitors of hepsin, Vasioukhin's lab also plans to study mechanisms of hepsin function in prostate-cancer metastasis. Specifically, the researchers will try to determine how hepsin causes disorganization of the basement membrane.

Research in Vasioukhin's lab is funded by the V Foundation for Cancer Research and the National Cancer Institute.