New finding has potentially major implications for anti-angiogenic therapy

Scientists supported by the National Institute of Dental and Craniofacial Research (NIDCR) have added a key new piece to the puzzle of how tumor cells induce new blood vessels to form and fuel their abnormal growth, a well-known process called angiogenesis.

As published in this month's issue of the journal Cancer Cell, the scientists found that in addition to the well-known strategy of secreting proteins to trigger angiogenesis, tumor cells also physically attach to a protein displayed on the surfaces of cells that line the walls of our blood vessels. This physical interaction, like a finger pushing a button, sends a signal within these cells to grow and sprout new capillaries.

The finding, while technical in nature, has potentially major implications for anti-angiogenic therapy, one of the hottest areas in cancer research. Dr. Cun-Yu Wang, a scientist at the University of Michigan and senior author on the paper, said the finding suggests a future anti-angiogenic strategy of blocking not only the secreted molecules but also the cell-to-cell contact.

Wang said these early data also suggest the intriguing possibility of directing growth-inhibiting drugs at the normal blood vessel cells to stop angiogenesis. "It's well established that tumor cells can become resistant to chemotherapy," said Dr. Wang. "For endothelial cells, which are the cells that line the walls of the blood vessels, there is no indication that resistance is a problem. It's an intriguing idea, and one that we think might be well worth pursuing."

This month's paper, as is often the case in the world of science, involves a great deal of hard work - and a little luck. Wang said his group began a few years ago studying a secreted protein called hepatocyte growth factor, or HGF, and its role in helping head and neck tumors to turn cancerous. HGF does so, in part, by helping to induce nearby blood vessels to grow misguidedly toward and eventually into the developing tumor for nourishment. "Still unanswered was exactly how HGF sets the angiogenic process in motion," said Dr. Qinghua Zeng, lead author on the paper and a researcher at the University of Michigan, noting that HGF also has a pro-angiogenic effect in other tumor types. "We needed to connect the molecular dots."

Zeng and his colleagues conducted a series of experiments under carefully controlled laboratory conditions to determine whether, as they suspected, HGF stimulates head and neck tumor cells to release pro-angiogenic proteins. To their surprise, they found that was not the case. Tumor cells stimulated by HGF strongly promoted the formation of a capillary-like network compared with secreted factors induced by HGF alone. "At this point, we didn't have any idea of what was going on," said Wang. "But we started to think that it must involve the direct interaction between the tumor and endothelial cells."

Wang said that's where luck entered the picture. He and his colleagues decided to take a closer look at a vast body of data that they had generated a few years earlier showing thousands of genes that HGF activates in head and neck tumor cells. The gene that was among the most expressed is called jagged1, which is known to bind to a specific protein on the surface of endothelial cells. "I thought, 'Oh, this makes sense,'" said Wang. "The jagged1 protein is not secreted but is displayed on the surface of the tumor cells. I speculated that HGF induced jagged1 levels to increase, leading to a direct surface to surface interaction between the tumor and endothelial cells."

Wang's hunch also made good intuitive sense for another reason. The jagged1 protein bound in a hand-in-glove manner to a protein on the endothelial cells called notch. Other laboratories have shown that notch plays a key role during human development in forming blood vessels. Oddly, Wang noted, the possible role of notch in tumor angiogenesis has not been well studied.

After further laboratory and mouse experiments, Wang said the data supported their hypothesis. "Over the past several years, various compounds have been developed to inhibit secreted proteins such as the much-studied vascular endothelial growth factor, or VEGF, which clearly plays a role in tumor angiogenesis," said Wang. "To date, though, none of these compounds have been very effective as cancer therapies, suggesting that other factors may play a role. We think that we have found one of these additional factors."

Zeng added that because the research involved cells from head and neck tumors, the discovery could provide further insight into the uniquely invasive character of these cancers. He explained that cells in head and neck tumors tend to be mobile, shifting within the developing mass and possibly establishing tumor-to-endothelial cell contact to prompt angiogenesis. "We have some evidence that inflammatory factors, and even some infectious agents, can induce jagged1 expression," said Wang. "That's what we plan to study next."

The article is titled, "Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling." The article was published in the July issue of Cancer Cell, and its authors are: Qinghua Zeng, Shenglin Li, Douglas B. Chepeha, Jong Li, Honglai Zhang, Peter J. Polverini, Jacques Nor, Jan Kitajewski, and Cun-Yu Wang.