Compound may cause wasting seen in cancer.

Cancer kills, but often in more subtle ways than one might imagine. Large tumors can savagely destroy organs, yet small tumors may cause a wasting of the body that leaves patients too weak to fight pneumonia and other illnesses.

Now, investigators working with mice have found a compound, apparently made by cancer cells, that causes this mysterious wasting by attacking the body's muscles.

"It produces a syndrome in mice similar to that seen in cancer patients," says Michael Tisdale of Aston University in Birmingham, England.

More important, the compound appears in the urine of cancer patients suffering from the wasting, or cachexia, but not in the urine of other cancer patients or healthy individuals, Tisdale and his colleagues report in the Feb. 22 Nature.

"It's exciting because they may have found a compound involved in cachexia.

The important thing now is for someone to confirm [the result]," says David Kritchevsky of the Wistar Institute in Philadelphia, who helped organize a meeting on cachexia last December.

"If this agent can be established as a key player in cachexia, this would be a major advance," agrees Michael C. Perry, who studies the wasting phenomenon at University of Missouri in Columbia.

Perry notes that about 50 percent of patients have an unexplained weight loss by the time they're diagnosed with cancer. "It's a very common problem in malignancy," he says.

In addition to making patients vulnerable to illness, wasting can severely reduce their tolerance for radiation and chemotherapy, adds Perry.

To find what causes the wasting, Tisdale and his colleagues transplanted a cachexia-causing tumor into healthy mice. The mice developed antibodies, which the investigators used to identify and purify a compound circulating in the blood of cachexic mice but not in that of normal mice.

The agent turned out to be a protein fragment decorated with an unusual jumble of carbohydrate groups and other side chains. Tisdale suggests that the protein fragment has a role in normal cells, but cancer cells tack on the extra clusters of atoms.

The compound degrades existing muscle proteins and inhibits the creation of new proteins, reports the British group. "The material acts directly on skeletal muscles," says Tisdale.

The researchers found the compound in the urine of cachexic patients with lung, breast, ovarian, or pancreatic cancers. "They all show this material in the urine if they're losing weight," says Tisdale.

He also told Science News about two observations not reported in the Nature article. First, injections of antibodies to the compound inhibited tumor growth in mice, suggesting that cancer cells may depend on the substance in some manner.

Second, the compound's discovery may explain the activity of a cachexia drug now under development. One of Tisdale's colleagues, Kenneth Fearon of the University of Edinburgh, is giving pancreatic cancer patients with cachexia a fatty acid derived from fish oil.

Though the trial involves only a few patients, the acid has demonstrated an ability to thwart cachexia, says Tisdale. This promising result may stem from the acid's ability to counteract the compound his group has discovered. When the investigators treat mice with the fatty acid before giving them the cachexia compound, the rodents suffer no wasting, says Tisdale.