May 22, 1998 ANN ARBOR---With cover stories in major news magazines and reports on national news, the tumor-fighting molecules called angiogenesis inhibitors have become overnight celebrities. University of Michigan researchers are among several groups around the country trying to understand and find ways of controlling the process of angiogenesis (blood vessel growth), which plays a key role in cancer and other diseases.
Research on this process not only may lead to improved cancer treatments, but also may offer new approaches to treating a wide range of other medical problems, says Peter Polverini, U-M professor of dentistry and pathology who has been doing research on angiogenesis for 20 years. Diabetes, rheumatoid arthritis, glaucoma, psoriasis and even obesity may someday be treated with drugs that control angiogenesis.
Most of the recent attention has focused on the potential of angiogenesis inhibitors to treat cancer by starving tumors. Tumors cannot grow to life-threatening sizes unless they are nourished by blood vessels. To ensure an adequate blood supply, tumors give off substances (angiogenic factors) that encourage nearby blood vessels to send branches to the tumors. Large tumors also give off substances (angiogenesis inhibitors) that prevent blood vessels from sending branches to smaller, more distant tumors. Researchers led by Judah Folkman at Children's Hospital in Boston have used these angiogenesis inhibitors to shrink tumors in mice.
But a number of other medical conditions also are influenced by angiogenesis and could be treated with drugs that control the process, says Polverini.
"Obviously, cancer represents the most extreme, life-threatening disease process in which blood vessel growth plays an important role, but there are many other diseases that we describe as 'angiogenesis-dependent,'" he says. "In disorders such as rheumatoid arthritis, psoriasis, and many ocular diseases---glaucoma and retinitis pigmentosa, for example---excessive blood vessel growth contributes greatly to the damage that the disease causes." Diabetes, too, has an angiogenesis link. Wounds heal more slowly in people with diabetes, because blood vessel growth is inadequate. Encouraging angiogenesis could speed healing in people with that disease.
Even melting away fat may someday be possible with help from drugs that control angiogenesis.
"There's evidence now that people who are overweight may have excessive blood vessel growth contributing to fat deposition," says Polverini. "So it's possible you could treat obesity by limiting angiogenesis."
Polverini's group is focusing on the relationship between angiogenesis and programmed cell death (apoptosis), a process that is important in normal growth and development. Jacques Nor, a doctoral student in Polverini's lab, has found that uncontrolled blood vessel growth may occur when blood vessel cells live longer than they should. Over their long life spans, these cells make blood vessels super-efficient at nourishing tumors and contributing to other disease processes. The U-M researchers' data suggest that the long-lived blood vessel cells also become resistant to substances that normally would suppress their growth and prevent them from contributing to disease.
These observations open the door to even more new approaches to treating disease by controlling blood vessel growth. For example, it may be possible to develop drugs that specifically target the cell death machinery in blood vessel cells, to suppress angiogenesis and limit solid tumor growth.
But in spite of their potential, drugs that control angiogenesis may not turn out to be the outright miracle cures that some media reports have suggested. Most likely these drugs will be used in combination with time-tested treatments such as surgery, radiation therapy and other novel anti-tumor strategies.
"As members of the armamentarium that will be used to treat tumors and other diseases, I think that they do have great promise," Polverini says. "There is every reason to believe that anti-angiogenesis will turn out to be a successful strategy for treating tumors. The only misconception about them is in setting expectations too high."
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