New and more efficient target for antiangiogenic therapy

Scientists now have a more complete understanding of how cancer cells send signals to surrounding tissues to promote development of the blood supply needed to support tumor growth.

For the first time, it has been shown that signals expressed by tumor cells can directly interact with the outer membrane of adjacent blood vessel cells and influence growth and development.

The research, published in the July issue of Cancer Cell, may provide a new and more efficient target for antiangiogenic therapy.

Tumor cells, like other cells, require blood vessels to deliver oxygen and nutrients and to remove waste. Scientists have known for some time that tumor cells can stimulate blood vessel growth by secreting growth factors that promote angiogenesis. However, most human cancer therapies based on targeting these factors have been less than successful. Dr. Cun-Yu Wang from the University of Michigan and colleagues designed a series of studies to search for other signals that play a critical role in tumor angiogenesis.

The researchers examined factors that were upregulated when cancer cells were stimulated with a known growth factor. They found that angiogenic factors stimulated the mitogen-activated protein kinase (MAPK) pathway to induce the Notch ligand Jagged1 in head and neck squamous cell carcinoma cells. Jagged1 triggered Notch activation in neighboring blood vessel cells and promoted formation of new vessels. Notch signaling is known to be critical for specification of cell fate during development, and there is evidence that Notch plays a role in blood vessel formation. Angiogenesis and tumor growth was significantly enhanced in Jagged1-expressing cancer cells and high levels of Jagged1 were correlated with tumor size and blood vessel content.

Although Notch activation alone in tumor cells was not sufficient to induce angiogenesis, elevated levels of Jagged initiated crosstalk between tumor cells and blood vessel cells and stimulated tumor growth and new blood vessel formation. "Our studies suggest that in addition to the secretion of proangiogenic growth factors, tumor cells may express Notch ligands to guide angiogenesis which supports tumor growth and progression," explains Dr. Wang. "Our results elucidate a novel mechanism by which the direct interplay between tumor cells and blood vessel cells promotes angiogenesis through MAPK and Notch signaling pathways."

The researchers include Qinghua Zeng, Douglas B. Chepeha, Thomas J. Giordano, Jong Li, Honglai Zhang, Cun-Yu Wang, Peter J. Polverini, and Jacques Nor of School of Dentistry and Medicine, University of Michigan, Ann Arbor; Shenglin Li of Peking University School of Stomatology; and Jan Kitajewski of Columbia University, College of Physicians and Surgeons, New York. This work was supported by NIH grants and by the Chang Jiang Scholar Program.