Quick Test May Reveal Cancer

By William J. Cromie

Gazette Staff

Cancers secrete proteins that break down tough, fibrous tissue between cells and allow tumors to grow and spread. Such proteins have now been found in the urine of cancer patients, raising the possibility that the disease can be detected by a quick, inexpensive test.

"For the first time, we've established a link between the presence of certain enzymes in urine and the likelihood of either localized or metastatic cancer," says Marsha Moses, an assistant professor of surgery at Harvard Medical School. The enzymes are proteins known as MMPs, or matrix metalloproteinases.

Besides serving as a simple means for initial detection of malignant tumors, MMPs could be used to monitor the effectiveness of cancer treatments. It also may be possible to prevent growth and spread of tumors by blocking the activity of MMPs, a possibility being hotly pursued by drug companies.

"A previous study had detected fragments of MMPs in the urine of patients with bladder cancer," notes Michael Freeman, assistant professor of surgery. "But this is the first report to clearly demonstrate that MMPs can serve as independent predictors of a variety of cancers, including breast, prostate, kidney, and other tumors outside the urogenital tract. Our work suggests that an analysis of MMPs might serve as a first look at patients in whom a malignancy is suspected but not yet detected."

Refining the Test

Moses, Freeman, and their colleagues, working at Harvard-affiliated Children's Hospital in Boston, compared 117 patients who were either healthy, known to have cancer, or had been treated for cancer and thought to be free of the disease.

They found MMPs in 90 percent of those with metastatic (spreading) cancer and in 71 percent of those whose cancers were confined to one organ, such as the breast or prostate. Nine out of nine breast cancers had the revealing markers.

The test, however, is not perfect. Twenty percent of the healthy subjects, most of whom did not have cancer, tested positive for the proteins. Eleven percent of those treated for cancer and considered free of the disease also tested positive.

"Such levels of false readings are not surprising for a first experimental test of the MMP/cancer association," Moses says. "We expect that further refinements and additional testing will significantly reduce false positives and negatives."

The researchers found three large MMPs in their search for cancer markers. Two were known before, and one had not been previously identified. "We treated the presence of any one of these molecules as a positive indication of malignancy," explains Moses. "We need to do more tests to determine if one of the MMPs, or combination of MMPs, provides a more accurate indication of specific cancers."

"We want to examine different concentrations of MMPs and find out how they are related to specific cancers and to the aggressiveness of those cancers," adds David Zurakowski, a biostatistician on the research team.

"The bottom line," he continues, "is that the odds of someone having metastatic cancer are 30 times greater when the MMP marker is present than when it is absent. For organ-confined cancers, the probability of cancer reaches 96 percent when two of the three MMPs show up, but only 29 percent when none is detected."

"MMPs would not be used alone to diagnose cancer," points out Dmitri Wiederschain, another member of the team. "A positive MMP reading would be verified by other tests. The advantage of the MMP check would be as a first line of detection available with little expense, time commitment, or discomfort to patients."

It might, for example, be used to determine which women, particularly those under 50, should have a mammogram, a relatively expensive test that exposes a woman to radiation. It might also precede the standard blood test used to find prostate cancer.

If MMP assays prove to be successful, they might be used to screen people with no or inadequate health insurance. Before that happens, however, any MMP urine test must be refined and tested on many more people.

Blocking the Action

One of the most intriguing implications of this research involves using anti-MMP drugs to treat cancers. In order to grow and spread, tumors need a supply of blood. One of the first steps in obtaining that supply involves tunneling through the tough, stringy matrix that surrounds them. MMPs provide the machinery that makes this excavation possible. If their activity can be blocked, that, in turn, may inhibit growth of blood vessels that tumors need to become larger and more aggressive.

"A number of biotech and pharmaceutical companies are currently developing and testing anti-MMP drugs," Freeman notes.

To get an MMP urine test approved by the Food and Drug Administration, Freeman and his colleagues will need to develop a more sensitive assay and test it on thousands of patients. The team will not speculate on how long that might take, but they see no major obstacles in the way.

MMPs are relatively large molecules, and researchers want to know how they get into the urinary tract without being broken up by other biochemicals in the body.

"We were amazed that they survive intact," Moses admits. "It's not difficult to understand how MMPs might come through unscathed from the bladder or the prostate. But how do they travel from, say, a tumor in the breast?"

That's not a question of academic interest alone. Knowing as much as possible about those shifty MMP molecules can help in the design of smaller molecules that may be made into a drug that blocks their activity. Such a strategy would combine the best of two approaches: a cheap, simple test to detect cancer and a pill that can block the growth and spreading of malignant tumors.

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