Researchers Explain How Protein Inhibits Angiogenesis

BOSTON – A new discovery led by a team of researchers at Beth Israel Deaconess Medical Center (BIDMC) offers one of the first explanations for how angiogenesis – the growth of small blood vessels – is inhibited in the body. The study, which appears in the Jan. 4 issue of Science, focuses on a protein called tumstatin, and could prove key to understanding how to stop the overgrowth of blood vessels that occur in cancerous tumors when the angiogenesis process goes awry.

“In a healthy individual, we know that angiogenesis is a ‘stop and go’ process, similar to the way an automobile runs” says senior author Raghu Kalluri, Ph.D., of the Department of Medicine and the Program in Matrix Biology at BIDMC and Associate Professor of Medicine at Harvard Medical School. “No matter how fast and powerful a car is, it is not useful if it can only accelerate and cannot stop.” The same principle applies to the growth of new blood vessels – in the absence of an effective set of brakes, what is an extremely useful tool under normal circumstances becomes a serious problem for patients with cancer.

During the process of angiogenesis, a single layer of endothelial cells lining the inside of blood vessels divide and break off from the vessels’ membrane, forming tubes that become new capillaries. In women, this process occurs monthly during the menstrual cycle, as the lining of the uterus is rebuilt. Angiogenesis is also important to both men and women to repair tissue following an injury.

In both of these cases, the process is maintained by a careful balance of proangiogenic and antiangiogenic factors. When this balance is disrupted, the capillaries grow unchecked, such as during tumor growth or in conditions such as macular degeneration, which leads to vision loss due to overgrowth of blood vessels in the eye.

“We know that when a tumor forms, the endothelial cells divide more rapidly and spread much more quickly than they would during the normal course of blood vessel formation,” explains Kalluri, who with colleagues at BIDMC, first identified tumstatin two years ago. A naturally occurring protein found in tissue, tumstatin was shown to be capable of specifically halting the growth of a tumor’s dividing endothelial cells in a mouse model. Following this discovery, says Kalluri, “Our next question was, ‘How was this happening?’”

The answer, as described in the new study, is that tumstatin appears to specifically inhibit protein synthesis in the dividing vascular endothelial cells; in other words, it becomes the “brakes” needed to halt the abnormal angiogenesis process.

The researchers found that the tumstatin protein binds to an integrin molecule, specifically aVb3 integrin, which is found in abundance among dividing endothelial cells, and typically serves as a proangiogenic factor to help construct new blood vessels. However, Kalluri and his colleagues discovered that in the presence of tumstatin, the aVb3 integrin molecule had the opposite effect – it became the mediating factor necessary to halt the growth and spread of the tumor’s endothelial cells.

“This integrin molecule normally functions as an ‘accelerator’ of angiogenesis,” explains Kalluri. “But when tumstatin connects with integrin, it “brakes” the acceleration and, by exerting a negative force, stops the production of proteins.” As a result, the endothelial cells die, angiogenesis is halted, and the spread of tumors or other abnormal blood vessels is prevented.

“This is a very important advance in the fields of angiogenesis research and cancer biology,” notes Judah Folkman, M.D., of Children’s Hospital Boston and Harvard Medical School, who 30 years ago first developed the paradigm that tumors are angiogenesis-dependent. “This discovery of the novel protein tumstatin in the body’s extracellular matrix is fundamental because it enlarges our view of the family of proteins which guard against abnormal angiogenesis.”

“There are currently more than 20 angiogenesis inhibitors in clinical trials for the treatment of cancer,” Kalluri writes in Science. “These inhibitors fall into two general categories: Small molecules or antibodies that target proangiogenic products of a tumor cell [such as vascular endothelial growth factor] and naturally occurring proteins in the blood or tissues that target vascular endothelial cells.” The latter group – which in addition to tumstatin includes the endostatin protein – has displayed great precision in singling out endothelial cells to prevent angiogenesis. But until now it was unknown how they worked.

“For the first time we were able to show what is happening that enables the angiogenesis inhibitor tumstatin to halt the growth of blood vessels,” says Kalluri. “Understanding the mechanism behind this process will help in developing these molecules as effective cancer drugs.”

Study co-authors include Yohei Maeshima, M.D., Ph.D. and Akulapalli Sudhakar, Ph.D. of Beth Israel Deaconess Medical Center; Julie C. Lively, and Richard O. Hynes, Ph.D., of the Massachusetts Institute of Technology; Kohjiro Ueki, M.D., Ph.D. and C. Ronald Kahn, M.D. of Joslin Diabetes Center, Boston; Surender Kharbanda, Ph.D. of the Dana-Farber Cancer Institute, Boston; and Nahum Sonenberg, Ph.D., of McGill University, Quebec, Canada.

The study was supported in part by grants from the National Institutes of Health (NIH) and research funds from Beth Israel Deaconess Medical Center. Beth Israel Deaconess Medical Center has licensed tumstatin to ILEX Oncology for human clinical trials. Raghu Kalluri serves as a consultant for ILEX Oncology.

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 fourth largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.

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