Novel angiogenesis mechanism

Tumor stimulation of blood vessel growth may involve the Notch pathway, researchers show

By | July 18, 2005

Tumor cells can trigger angiogenesis by a process involving physical contact with neighboring endothelial cells, scientists report in this month's issue of Cancer Cell. This is the first time, according to the paper, that such a mechanism has been described involving the Notch pathway, which is known to play key roles in embryonic vascular development and angiogenesis, but whose participation in tumor angiogenesis has been unclear.

There are several ways by which a tumor might stimulate angiogenesis, said coauthor Jan Kitajewski, from Columbia University in New York, including the well-documented paracrine mechanism and some emerging contact-dependent mechanisms. "Here Notch seems to act as a proangiogenic factor in head and neck tumors," he told The Scientist, "and it probably does so in other tumors."

The team, led by Cun-Yu Wang from the University of Michigan, Ann Arbor, conducted a microarray analysis of head and neck squamous cell carcinoma cells. "We discovered that in the presence of common tumor stimulating growth factors, the Notch ligand Jagged1 is overexpressed," Wang told The Scientist. "This expression depends on the mitogen-activating protein kinase (MAPK) pathway, which is already implicated in other angiogenic routes."

Because endothelial cells possess Notch receptors on their surface, the researchers hypothesized that a cell-to-cell mechanism involving Notch might participate in angiogenesis, as it does during embryogenesis.

To test this hypothesis, they induced Jagged1 expression by retrovirus-mediated transduction of human SCC9 squamous cell carcinoma cell lines in which Jagged1 is endogenously undetectable. In cocultures with human endothelial cells, the comparison of wild SCC9 cell lines with the mutated strain revealed that Jagged1 is necessary to activate the Notch-dependent luciferase reporter in endothelial cells and to induce capillary sprout formation. The team then implanted wild SCC9 cell lines, the mutated strains, and endothelial cells into mice. After histology and immunostaining testing, they reported similar results in vivo.

Warren Pear from the University of Pennsylvania, Philadelphia, told The Scientist that the group's hypothesis was intriguing. "But I think they still have a long way to go to show whether this process is relevant in naturally arising tumors," said Pear, who did not participate in the study.

In the future, it will also be important to understand the different ways in which Notch might be implicated in cancer cell growth, the authors said. "If we hypothesize from what occurs during embryogenesis, Notch could have antiangiogenic effects in other settings," said Kitajewski. "Studies have shown that Notch is also commonly overexpressed in cancer cells themselves, where it could play a role in dedifferentiating cells or in the tumor cell's survival."

Meanwhile, this new discovery represents a potential additional target for antiangiogenic therapy. "Notch could be an alternative pathway that tumors use to escape control by angiogenesis inhibitors that target paracrine factors such as [vascular endothelial growth factor]," Judah Folkman, from Harvard Medical School, who did not participate in the study, told The Scientist.

"If you need to completely shut down Notch signaling in the body to inhibit tumor angiogenesis, then it's not a viable treatment," added Pear. "If you can lower the dosage to maintain Notch in the gut for instance, and still act upon the tumor, then there may be a therapeutic window in which toxicity is minimal."

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