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Tumor Blocker May Fight Fibrosis

30 May 2012 2:00 pm
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Feghali-Bostwick Laboratory

Thick-skinned. Fragments of the anticancer drug endostatin can halt fibrosis in a slab of human skin.

Connective tissue holds our bodies together, but in a condition called fibrosis, an overabundance of the material devastates organs such as the liver, heart, and lungs. A new study suggests that fragments of a promising cancer drug can rein in fibrosis, which is currently untreatable.

Fibrosis occurs when cells pump out excess collagen and other connective tissue proteins, which harm organs. Pulmonary fibrosis, for example, stiffens the lungs, eventually suffocating patients unless they receive a lung transplant. In people with cirrhosis, connective tissue crams into the liver. Heart and kidney disease can also be caused by fibrosis. So far, no drugs to stop or reverse fibrosis have won approval in the United States.

Cell and molecular biologist Carol Feghali-Bostwick of the University of Pittsburgh School of Medicine in Pennsylvania and colleagues decided to test whether endostatin, a drug undergoing clinical trials as a treatment for various cancers, also has an effect on fibrosis. Endostatin is one of the so-called angiogenesis inhibitors, a group of much-touted drugs that block the formation of new blood vessels that tumors need for growth. Endostatin also occurs naturally in the human body, and patients with lung fibrosis have up to 20 times the normal levels in their blood or lungs. That observation raised the possibility that the protein is a natural defense against connective-tissue overgrowth, says Feghali-Bostwick.

To test that hypothesis, she and her colleagues studied swatches of human skin that they nurtured in the lab. They dosed the skin with TGF-β, a cellular signal that promotes fibrosis and causes the skin to thicken as connective tissue builds up. Adding endostatin prevented the skin patches from growing thicker, the team discovered.

Because endostatin thwarts blood vessel growth, an undesirable quality for a fibrosis treatment, the researchers next tested three shards of the molecule, or peptides. After a little tinkering to improve its stability, one of the peptides by itself reversed fibrosis spurred by TGF-β in the skin patches, the researchers report online today in Science Translational Medicine. Moreover, this portion of endostatin had little effect on blood vessel growth in the culture dish, the team showed.

The peptide also worked in mice, reducing skin fibrosis caused by TGF-β and by the drug bleomycin. After a dose of bleomycin, the peptide also curtailed lung fibrosis in the animals.

"It makes a lot of sense that the body would try to mount an opposing process to fibrosis," says Feghali-Bostwick. Scientists think that naturally produced endostatin can't counteract the accumulation of connective tissue in fibrosis patients, perhaps because another molecule inhibits it. But the peptide might be able to do the job, and it might overcome some of the limitations that have bedeviled endostatin's use in cancer treatment, such as its rapid deterioration in the body. The researchers now want to nail down how their peptide short-circuits fibrosis and determine if they can make it more potent, says Feghali-Bostwick.

"I think the peptides are a novel approach to targeting the TGF-β pathway," says immunologist Thomas Wynn of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who wasn't involved in the research. However, he cautions that so far, other compounds that block this pathway in mice haven't panned out in clinical trials, and he'd like to see further research with different mouse versions of fibrosis. "It's not certain how generally applicable the findings will be."

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