Tumors in Touch: Cancer cells spur vessel formation through contact

Some tumor cells use a newfound mechanism to communicate with healthy cells next to them and prompt those neighbors into forming blood vessels. That discovery points a novel way toward drug treatments that could starve tumors of their all-important blood supplies.

Like roads built to support a suburban development, new blood vessels form in and around tumors, sustaining the cancerous cells. Tumors orchestrate vessel formation, or angiogenesis, by secreting various proteins called growth factors that can drift into contact with nearby cells that line blood vessels. Some cancer drugs inhibit secreted growth factors but have been only partially effective at blocking angiogenesis (SN: 6/7/03, p. 358: Available to subscribers at Cancer Advance: Treatment combinations stall colorectal cancer).

Cancer biologist Cun-Yu Wang of the University of Michigan in Ann Arbor and his colleagues set out to determine the role of growth factors in a cancer called head-and-neck squamous-cell carcinoma. They ultimately focused on the protein Jagged1, which differs from secreted growth factors in that it stays attached to the surface of cells.

In a series of laboratory experiments, the investigators observed that Jagged1 on a tumor cell binds to molecules called Notch receptors on adjacent blood vessel–lining, or endothelial, cells. Jagged1 signals those cells to initiate angiogenesis.

For example, the researchers grew human cancer cells and endothelial cells together in lab dishes. They coaxed some of the cancer cells to display Jagged1. Vessel-like tubes formed in dishes where the cancer cells displayed Jagged1 but not where Jagged1 was absent.

Wang and his team next implanted mixes of endothelial and cancer cells into mice. After 6 weeks, Jagged1-containing tumors were three times as large and twice as heavy as the tumors without Jagged1 were, Wang’s team found.

The researchers also determined that Jagged1 was more abundant on cells in malignant human tissues than in normal tissues. Furthermore, they report in the July Cancer Cell, there’s a correlation between Jagged1’s abundance and the amount of angiogenesis in the human tumors that the researchers examined.

The findings indicate that contact between Jagged1 on cancer cells and Notch receptors on endothelial cells contributes to tumor-related angiogenesis, Wang says. “This is a fundamental, new discovery [that] tumor cells can directly interact with endothelial cells,” he says.

Moreover, Wang says, the role his team has described for the Notch receptor in angiogenesis makes the molecule a potential target of drugs for head-and-neck cancers and perhaps for other solid tumors.

The new study “brings a lot of things together” in demonstrating that a protein binding to Notch receptors “is an important signal coming from the cancer cells to the endothelial cells,” says oncologist Adrian L. Harris of the University of Oxford in England and the nonprofit organization Cancer Research UK.

Some drugs being investigated as treatments for Alzheimer’s disease happen to block Notch signaling, among other actions, Harris says. Given Wang’s findings, these drugs might be useful as cancer medicines too, he suggests.

However, Harris cautions, blocking Notch signaling could have undesirable repercussions because that signal is known to have important effects, including one that appears to fight angiogenesis. Harris suggests that a Notch-blocking drug might need to be used in conjunction with one of the current anti-angiogenesis drugs to offset any such paradoxical effect.