For the past several years, cancer researchers have been trying to develop therapies that work not by killing tumor cells directly, but by depriving them of the blood supply that they need to live and grow. New findings, published in the 16 May issue of Science, should boost the field. The work suggests that tumor responses to radiation therapy depend on whether the radiation kills the small blood vessels supplying the tumors. The finding may point the way to better therapies for treating radiation-resistant cancers.
Researchers had thought that radiation kills tumor cells directly. But 2 years ago, a team led by cancer biologist Richard Kolesnick and radiologist Zvi Fuks of Memorial Sloan-Kettering Cancer Center in New York City showed that one of the principal side effects of radiation therapy, damage to the gastrointestinal tract, occurs because the radiation triggers apoptosis, a form of cell suicide, in the cells of the small blood vessels of the tract. They also linked this apoptosis to radiation-induced production of a chemical called ceramide. They found that mice that don't make ceramide because they lack an enzyme called acid sphingomyelinase (asmase) are protected from the damage. Fuks and Kolesnick then decided to see whether the blood vessel cells of cancerous tumors are also vulnerable to radiation.
The current work shows that they are. Transplanted tumors, for example, grow much faster in mice in which the asmase gene has been knocked out than in normal mice. Tumors growing in the engineered mice are also much more resistant to radiation therapy, apparently because the cells of their blood vessels, unlike those of tumors in normal mice, undergo little apoptosis in response to radiation therapy.
Cancer researcher Robert Kerbel of Sunnybrook and Women's College Health Sciences Centre in Toronto describes the researchers' work as "elegant. By using the knockout mouse strain, they showed in a very conclusive way the validity of the concept" that therapies that target tumor blood vessels can improve tumor responses to therapy. Kerbel also notes that the results tie in with work from his group and others showing that something similar happens with cancer chemotherapies.
Fuks suggests that the findings might improve radiation therapy. He points out that cancers might be able to resist radiation because they pour out factors that stimulate blood vessel growth, thus countering the radiation-induced apoptosis. It may be possible to enhance apoptosis of the blood vessel cells, either with drugs that block the factors' activity or by boosting asmase activity.