Keeping cells under control: enzyme suppression inhibits cancer spread.

Shutting down an enzyme can slow the spread of cancer in mice, scientists in Israel report. The finding suggests that further study of this enzyme, called heparanase, might lead to a treatment for cancer patients.

Normally, heparanase facilitates cell migration in the body. This enables immune cells, for example, to travel to sites of infection. To provide this service, heparanase cleaves a carbohydrate called heparan sulfate, one of the components of tough organic sheets located throughout the body.

These sheets, called basement membranes, typically serve as scaffolding for cells making up an organ. If those cells become cancerous, the membrane provides an added benefit: It keeps the tumor cells in place.

Unfortunately, excess heparanase can weaken the membrane and permit metastasis, the spread of malignant cells to other organs.

Scientists have been building a case against heparanase for years. They've noted that tumor cells often contain excess heparanase and that a high concentration of heparanase in the urine of cancer patients correlates with aggressive cancers.

Even more incriminating is evidence that when heparanase degrades heparan sulfate, the reaction releases growth factors. These include proteins that may stimulate growth of blood vessels that nourish tumor growth (SN: 7/24/99, p. 53).

In the new study, Israel Vlodavsky and his colleagues at the Israel Institute of Technology in Haifa short-circuited production of heparanase to clarify its role in cancer.

In laboratory-dish experiments, they compared the number of breast cancer cells--some with heparanase and some genetically engineered to lack it--that broke through a sheet resembling a basement membrane. Three times as many breast cancer cells producing heparanase penetrated the membrane as did those lacking the enzyme. The team got similar results when it used brain cancer cells.

Next, the researchers implanted lymphoma cells--some making heparanase and some not--under the skin of mice. The animals survived significantly longer before succumbing to the cancer when the lymphomas lacked the enzyme, the researchers report in the Aug. 18 Journal of the National Cancer Institute.

Autopsies revealed that, after the lymphomas metastasized to the liver, the tumors devoid of heparanase showed poor-quality blood vessel growth. Without heparanase, growth factors don't seem to escape the clutches of heparan sulfate to stimulate the vessel growth that strengthens the tumors, Vlodavsky and his colleagues assert.

Finally, Vlodavsky and his colleagues injected mice with melanoma cells with or without heparanase-making capability. Nine times as much metastasis occurred in the lungs of animals receiving melanoma with heparanase as in the others.

"This is an important study showing a necessary role for [heparanase] to drive cancer invasion, angiogenesis, and metastasis--the lethal aspects of cancer," says Lance A. Liotta, a pathologist at the National Cancer Institute in Bethesda, Md. "Heparanase constitutes a potential therapeutic target for cancer therapy."

While an anti-heparanase strategy holds promise, it's unlikely that inhibiting this enzyme alone will do the job, says Douglas D. Boyd, a molecular biologist at M.D. Anderson Cancer Center in Houston. "I'd be far more optimistic about multiple combinations [of enzyme inhibitors] being successful," he says.