Some cancers are fueled by more than genetic mutations. About two out of three breast cancers, for example, are aided by estrogen, so blocking the hormone helps stop those tumors. Inhibiting these cancer enablers is a growing discipline in oncology research.

One such class of therapies is called protease inhibitors—drugs that block a protease necessary for a cancer cell to invade and metastasize. Proteases are enzymes that cleave, or split, proteins, and researchers know they play a role in the growth and spread of cancer.

“There is a widely accepted dogma that proteases are bad,” says Jaime R. Merchan, M.D., M.M.Sc., assistant professor and a hematologist-oncologist at the University of Miami Sylvester Comprehensive Cancer Center. “Block the enzyme and the cell can’t spread.”

Merchan and colleagues have recently published a study that challenges this dogma. He conducted experiments where breast cancer cells were genetically “forced” to produce an excess of two proteases—tissue plasminogen activator, or tPA, and urokinase, or uPA. When they injected the cancer cells into mice, the modified tumors were less likely to grow or metastasize compared with mice having unmodified control tumors. They also found that in the protease-overexpressing tumors, overall survival was one-third longer in the tPA group and twice as long in the uPA group compared with controls.

The researchers then tested whether the anti-tumor effects were due to the enzymatic activity of the proteases. They genetically modified urokinase to make it “proteolytically inactive,” switching off its ability to decompose proteins. Tumors expressing the proteolytically inactive urokinase grew faster than tumors exposed to “active” urokinase and at about the same rate as untreated control tumors.

Curiously, the proteases stopped tumors only in animal models (in vivo), not in isolated cancer cells in the lab (in vitro). “That led us to conclude that the proteases overexpressed by the tumors are not directly toxic to the tumor cells, but that they block tumor growth indirectly.” Merchan published an earlier study showing that proteases of the plasminogen activator system can cleave blood proteins and generate peptides that inhibit angiogenesis, starving the tumors of blood.