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Front Page

Body’s Own Angiogenesis Inhibitors Check Tumor Growth

Cancer is like a bomb with a thousand triggers; even as researchers uncover details about how tumors grow and spread, the reason some tumors are set off and others remain dormant is still a mystery. A new study by Raghu Kalluri, HMS associate professor of medicine at Beth Israel Deaconess Medical Center, suggests that our own ability to keep tumors from building blood vessels may be a factor in keeping tumors at bay. This line of research is bringing about a new approach to cancer treatment and prevention that focuses on boosting our natural defense against cancer’s spread.

From left, Raghu Kalluri (inset), Hikaru Sugimoto, Malin Sund, and Mary Soubasakos demonstrated in mice that angiogenesis inhibitors are needed to keep tumor growth in check. (Photo by Steve Gilbert; inset photo by Graham Ramsay)

The study, published online Feb. 14 in Proceedings of the National Academy of Sciences, offers genetic evidence in mice that normal circulating levels of the naturally occurring angiogenesis inhibitors endostatin, tumstatin, and thrombospondin-1 (TSP-1) can have a powerful effect on the progression of tumors. Without these natural defensive molecules, tumors progress much more rapidly than they normally would.

Tumors Without Disease
Kalluri’s interest in natural defenses against cancer came from a striking observation about human cancer and disease. A 1993 New England Journal of Medicine paper by two researchers at Dartmouth brought to many researchers’ attention a fact that pathologists already knew: when bodies of healthy people who had died of trauma are closely examined, they contain a lot of tumors. Not cancer, not disease, just small in situ tumors that seem to be doing little harm. For instance, one autopsy study found a tumor in the thyroids of more than one third of the adults aged 50 to 70. Another study found tiny tumors in the breasts of nearly 40 percent of women aged 40 to 50.

“The goal is to use our body’s own defense mechanism against angiogenesis to significantly delay cancer progression, to prolong the ‘cancer without disease’ phase.”

For Kalluri, who is a member of the Dana–Farber/Harvard Cancer Center, the findings were provocative. They implied that cancer itself is not the aberration—the progression to disease is. Last year, he and Judah Folkman authored an essay for Nature in which they explain the concept of “cancer without disease.” The genetic mutations that turn a cell into a tumor, they say, are only the first step. Most of the tumors that form in our bodies are kept quiet and contained by a troop of circulating inhibitory molecules that prevent the tumors from recruiting blood vessels. To switch on angiogenesis, the tumor must overcome this natural defense system.

In the current study, Kalluri’s team, led by postdoctoral fellows Malin Sund, Yuki Hamano, and Hikaru Sugimoto, used three lines of mice that each lacked either endostatin, tumstatin, or TSP-1. In each case, adding tumor cells to the mice resulted in tumors that grew two- to threefold faster than normal. The growth spurt was not a result of the tumors themselves, which typically follow a predictable growth rate. “It’s not only the cancer cell that determines the ceiling rate of tumor growth,” said Kalluri. Instead, cancer progression is determined in part by the host’s ability to keep tumor growth in check.

When the team studied mice that lacked both tumstatin and TSP-1, the tumors grew twice as fast as they did when one inhibitor was missing, showing that the proteins work in different ways and are not redundant. “The body has these different molecules to function in different contexts to inhibit angiogenesis,” Kalluri said.

Body Armor
Angiogenesis inhibitors first gained fame as potential cancer therapies; it was only later that researchers began paying more attention to the natural role that some of these proteins play in the body. Though accumulating evidence has shown that delivering these inhibitors could slow tumor growth, it was still questionable whether the molecules served as natural defenses.

Folkman, the Julia Dyckman Andrus professor of pediatric surgery at Children’s Hospital Boston, said that Kalluri’s paper provides “genetic proof that angiogenesis inhibitors that are in circulation in the body actually are suppressing abnormal angiogenesis.” It remains to be seen whether differences in angiogenesis inhibitors can account for why some people develop cancer and some don’t. But with this proof of principle in mice, Kalluri would like to begin to examine the inhibitors’ role in humans.

Boosting these natural defenders may also point to a new preventive approach to cancer. Kalluri’s team engineered a mouse that overproduced endostatin, similar to the levels seen in people with Down syndrome (see sidebar). With this small adjustment, tumors grew threefold more slowly in the mice. Because these endogenous molecules are nontoxic, Kalluri believes they potentially could be administered at low levels to prevent angiogenesis, keeping tumors in perpetual stasis. “The goal is to use our body’s own defense mechanism against angiogenesis to significantly delay cancer progression, to prolong the ‘cancer without disease’ phase,” Kalluri said.

—Courtney Humphries

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