By David N. Leff

In one out of every three deaths from cancer, it isn't the tumor or the treatment that kills - it's cachexia. The patients literally waste away, until decayed muscle, depleted fat and extreme, irreversible weight loss leave their bodies unfit to stay alive.

"Cachexia is characterized by a dramatic loss of tryglycerides [fatty acids] from adipose tissue and proteins from skeletal muscle," observed biologist Michael Tisdale at Aston University in Birmingham, UK. "Although cachexia superficially resembles starvation," he went on, "it is refractory to nutritional intervention."

Tisdale made these points in an editorial titled "Protein loss in cancer cachexia," in today's issue of Science, dated Sept. 29, 2000. His commentary addresses two parallel research papers in Science. The first, from researchers at the University of Chicago, bears the heading: "Failure to regulate TNF-induced NF-kB and cell death responses in A20-deficient mice." Its senior author is immunologist Averil Ma.

"The A20 molecule," Ma told BioWorld Today, "was discovered 10 years ago, in a broad search for genes that were turned on by TNF - tumor necrosis factor. But since then it's been largely ignored. A20 has been studied only in a limited way at the cellular level, and never in a live animal. Investigators thought it was produced only by certain types of lymphocytes [white blood cells] in a few bodily tissues, such as the intestines.

"The overall finding of our Science paper," Ma observed, "might be that this relatively under-studied molecule, A20, that we found is critical for controlling inflammatory responses, and hence cachexia, in mice and people. And at least one of the ways it does that is to terminate the activity of a transcription factor called Nuclear Factor kappa B. And the second thing A20 does is protect them against TNF."

Cachexia Is Public Enemy Number One

This immune-response cytokine, he pointed out, is a key culprit in the etiology of cachexia. "TNF was originally cloned as 'cachetin,' found in excess in patients who were suffering from that wasting syndrome that accompanies certain malignancies. From a biological standpoint," Ma continued, "we studied how A20 shuts off inflammatory responses after they've been turned on. But A20's activity is not restricted to immune cells in the body. Nature has put that molecule there to protect all tissues globally - regulating inflammation in hearts, lungs, livers, intestines, which are not immune system organs.

"TNF triggers a number of pathways when it binds to a cell," Ma explained. "One is ultimately responsible for causing NF-kB to produce many different inflammatory genes. The NF-kB protein is normally bound to its inhibitor protein, I-kB. When TNF activates that pathway, several proteins cause I-kB to be degraded. So NF-kB becomes free to go to the cell nucleus, where it helps these new inflammatory genes express new inflammatory proteins. Two of those proteins are IkB again - and A20.

"We created mice that lacked the A20 gene," he recounted, "hoping to identify its function in intestinal lymphocytes. "Instead, we discovered that the molecule was much more widely spread than we had anticipated, and that A20 was a critical regulator of inflammation in multiple tissues of the body."

Within three to six weeks after birth, these A20 KO animals spontaneously incurred severe inflammation and widespread tissue damage. When administered even low doses of lipopolysaccharide (LPS), a toxin that mimics infection, they developed symptoms identical to septic shock - which in humans features plummeting blood pressure, diffuse inflammation, kidney damage, dampened heart function - and died within two hours. In contrast, normal A20-bearing mice had no symptoms after being administered 10-fold higher levels of the LPS toxin.

"These in vivo results," Ma suggested, "make A20 a novel, inviting target for potential anti-inflammatory drugs. Antibodies to TNF," he pointed out, "have received FDA approval for treating inflammatory disorders such as ulcerative colitis, Crohn's disease and arthritis. We can now hope to block cellular responses to TNF, in addition to trying to block TNF itself." But he hastened to add that "such therapies are not always effective."

Asked whether he or his associates are in touch with a pharmaceutical or biotechnology company, Ma replied, "Not yet."

A Second Wannabe Protective Molecule

Back to back with the Chicago-led team's paper in today's Science, immunologists at the University of North Carolina, Chapel Hill, present a different take on the cause and treatment of cachexia. Their paper is titled, "NF-kB-induced loss of MyoD messenger RNA: Possible role in muscle decay and cachexia." Its senior author is Albert Baldwin Jr., and first author, Denis Guttridge."

"MyoD," they explain, "regulates skeletal muscle differentiation and is essential for repair of damaged tissue. NF-kB, which turns genes on and off like a switch, prevents expression of MyoD from replenishing muscle tissue, as it does in healthy people.

"Cancer cachexia," Guttridge pointed out, "has been documented for at least 100 years, but it wasn't until about 20 years ago that researchers discovered the cytokine protein tumor necrosis factor, and that this TNF could elicit cachexia. What we have done," he added, "is identify a key part of what's happening mechanistically inside muscle cells to cause cachexia."

The team's in vitro and in vivo experiments show that TNF activates NF-kB, which in turn activates another factor that suppresses MyoD.

"NF-kB now becomes a very attractive new therapeutic agent for preventing cachexia," Guttridge said. Baldwin added that "on a scale of one to 10, the new findings could rate a 10 in importance, based on the novelty of the findings and their potential." He continued: "We're not saying that this is the only mechanism association with cachexia, but we believe that it is a very important one. Since we now know how to inhibit NF-kB - and we're getting better at it every day - this will lead to therapies for for reducing cachexia, which may well lead to significant improvement in the quality of life of patients who have chronic diseases, like cancer and AIDS."

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