Study offers new insights into angiogenesis inhibitors

In working to halt the overgrowth of blood vessels that feed cancerous tumors, the antiangiogenic molecules endostatin and tumstatin take two distinct and very different tactics, according to a study in the April 15 issue of the Proceedings of the National Academy of Sciences (PNAS).

These findings, which currently appear on-line, suggest for the first time that these two agents combined may prove more effective in battling cancer than either one used separately.

“Just as aspirin, acetaminophen and ibuprofen each work in different ways to relieve pain, it now appears that endogenous inhibitors like endostatin and tumstatin work in different ways to halt angiogenesis,” explains the study’s senior author Raghu Kalluri, Ph.D., of the Center for Matrix Biology at Beth Israel Deaconess Medical Center (BIDMC). “These findings may help us to be more informed in the ways we use these molecules as potential drug candidates in the future.”

Angiogenesis has been the focus of attention among cancer researchers for more than 30 years. The angiogenesis process takes place when a single layer of endothelial cells – which line the inside of the small blood vessels – break off from the vessels’ membrane and develop into new capillaries. In a number of diseases – including psoriasis, rheumatoid arthritis and diabetic retinopathy, as well as cancer – it is the unchecked growth of these capillaries that contributes to disease pathogenesis.

Over the years, scientists have identified a number of endogenous protein fragments which can put a halt to this process. Known as endogenous angiogenesis inhibitors, these include endostatin and tumstatin. Subsequent investigations have shown that these angiogenesis inhibitors might function by binding to a group of cell surface associated molecules known as integrins.

In this new study, Kalluri and his colleagues discovered that these two inhibitory molecules were binding to two separate and distinct integrins – endostatin to a5b1 integrin and tumstatin to aVb3 integrin – thereby achieving the same end effect of inhibiting angiogenesis, but by diverse mechanisms.

“While human endostatin targets the endothelial cells’ migratory abilities, human tumstatin prevents endothelial cells from proliferating,” says Kalluri, who is an associate professor of medicine at Harvard Medical School. “These two different approaches lead to the same outcome – halting the outgrowth of the blood vessels and inhibition of tumor growth.”

With this discovery, he adds, clinicians may be able to use these molecules in a more targeted fashion. “In order for endostatin to work, it has to be targeting tumors with the a5b1 positive tumor vasculature. Likewise, tumstatin must target tumors with aVb3 positive tumor vasculature,” he explains. “Future clinical trials of these antiangiogenic therapies may benefit by building in these considerations.”

“This is a very important piece of work,” notes Judah Folkman, M.D., of Children’s Hospital Boston and Harvard Medical School, in whose laboratory endostatin was first discovered with Michael O’Reilly in 1997. “This paper shows an emerging set of proteins in the body which guard against abnormal angiogenesis, similar to the set of proteins that guard against blood clotting.” This new finding, he adds, “suggests that because these two proteins inhibit angiogenesis by two separate pathways, they could eventually be used together for the treatment of cancer.”

Study co-authors include Beth Israel Deaconess Medical Center researchers Akulapalli Sudhakar, Ph.D., Hikaru Sugimoto, M.D., Ph.D., Changqing Yang, M.D., Ph.D., Julie Lively, Ph.D., and Michael Zeisberg, M.D.

This study was funded by grants from the National Institutes of Health and funds from the Program in Matrix Biology at BIDMC. BIDMC owns patent rights to human tumstatin, which are exclusively licensed to Ilex Oncology, Inc. Raghu Kalluri and BIDMC hold equity in Ilex.

Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.