MGH researchers unravel structure of a key protein involved in tumor angiogenesis and metastasis

Cancer cells need a blood supply to grow. A key receptor protein called the alpha V beta 3 integrin directs formation of new blood vessels by binding to other proteins, such as angiostatin and endostatin, produced by tumor cells. Scientists at Massachusetts General Hospital (MGH) have now deciphered the detailed structure of this protein as it interacts with its ligand (the protein that binds to a receptor). The work comes on the heels of findings published last year by the MGH investigators on the structure of the same protein in its resting unbound state. The new data, which will appear in a future issue of Science, are being published March 7 on the Science Express website (www.sciencexpress.org).

"By knowing the intricate molecular interactions between this receptor and its ligand, we are now in a better position to devise inhibitors that block this interaction and therefore prevent or forestall tumor angiogenesis and progression," says M. Amin Arnaout, MD, senior author, director of the MGH Structural Biology Program and chief of the MGH Renal Unit. Arnaout says this integrin receptor is also used by breast cancer cells to escape into the bloodstream and metastasize. "With this new information, we might be able to intercept that process as well," says Arnaout.

The MGH scientists also found that alpha V beta 3 integrin changes its shape when bound to its ligand, allowing it to send chemical signals instructing tumor cells to grow and spread. "Defining this shape-shift at the atomic level may also be harnessed therapeutically by designing more selective drugs with fewer side effects," says Arnaout.

There are 23 additional integrin receptors in humans, all with similar structural motifs. Some of these play important roles in other diseases -- such as osteoporosis, stroke, heart attack, diabetes, nephritis and rheumatoid arthritis -- and all bind to their protein ligands in a similar manner. "Catching an integrin in the act of binding to its ligand will offer new means of developing drugs to other debilitating diseases besides cancer," says Arnaout.

The other members of the research team include Jian-Ping Xiong, PhD, and Thilo Stehle, PhD, of the MGH -- who along with Arnaout are members of the MGH Structural Biology Program -- Matthias Frech, PhD, and Simon Goodman, PhD, of Merck KGaA in Germany, and Rongguang Zhang, PhD, and Andrzej Joachimiak, PhD, of the Argonne National Laboratory in Illinois. The study was supported by research grants from the National Institutes of Health and the U.S. Department of Energy.

The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.

---

---