Stopping VEGF, a Cancer Super-Villain

For years, a protein called vascular endothelial growth factor (VEGF) has been known for its ability to generate new blood vessels. As tumors grow, and need more oxygen and nutrients, they secrete VEGF to increase their blood supply.

Micrograph of breast cancer metastasis to lymph node.

That was a radical discovery 20 years ago, and some believed it would create many therapeutic opportunities against cancer. Perhaps, by cutting off VEGF, we could starve tumors into submission. A number of drugs were developed to do just that. Unfortunately, cancer had other ideas.

“If you interfere with a tumor’s blood supply by blocking VEGF, tumor cells become starved of oxygen and crank up VEGF production,” said Joyce Slingerland, M.D., Ph.D., director of the Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, part of the University of Miami Health System. “The tumor has a built-in resistance mechanism.”

Slingerland’s lab has been working for years to better understand VEGF and the molecular pathways it influences. Now, two recent papers, published in the journals EMBO Molecular Medicine and Oncogene, have shown that VEGF plays a much larger role in cancer. In addition to recruiting blood vessels, it also helps drive tumor invasion and metastasis and helps cancer cells resist treatment.

Tumor-initiation cells
One of the keys to VEGF’s virtuosity is its effect on tumor-initiating cells (also called cancer stem cells). These rare cells can both copy themselves and differentiate into more-common tumor cells. They’re also difficult to kill and especially resistant to chemotherapy and radiation. Even when aggressive treatments kill most of a tumor, small populations of cancer stem cells can rapidly regenerate the tumor.

“These cells are really good at self-protection,” said Slingerland. “We wanted to figure out what stimulates them, how they differ from other cancer cells, and how we can kill them.”

Slingerland and colleagues showed that VEGF triggers cellular communications that ultimately drive cancer stem cells.

In the Oncogene breast cancer paper, VEGF turns on a signaling messenger protein called Stat3, which not only helps increase the cancer stem cell population, but it also initiates the epithelial to mesenchymal transition (EMT) — the biological program that allows cancer cells to invade other tissues.

The ovarian cancer study, published in EMBO Molecular Medicine, tells a similar story. VEGF activates a protein called Src that makes cancer cells more aggressive by activating cancer stem cell pathways.

“VEGF is not only a driver of blood vessel formation,” said Slingerland. “We’ve shown, for the first time in breast and ovarian cancer, that it drives cancer stem cells. We’ve also linked the pathways that turn on cancer stem cells with those that increase metastasis.”

New knowledge, new targets
Slingerland believes these findings could lead to better treatments. Since inhibiting VEGF causes the tumor to produce more of the protein, perhaps the answer is to block the VEGF receptor. If VEGF can’t reach its receptor, it doesn’t matter how many molecules the tumor makes.

“We have a perfectly good rationale for combining VEGF receptor inhibitors with Src inhibitors in an ovarian cancer clinical trial,” says Slingerland.

A similar strategy — VEGF receptor inhibitors combined with Stat3 inhibitors — might also be useful against breast cancer.

“By understanding these pathways, we can figure out where the tumor’s Achilles heel is,” said Slingerland. “We can use that information to design trials for drugs that are currently in development and, hopefully, do a better job against breast and ovarian cancer.”

Tags: Braman Family Breast Cancer Institute, cancer metastasis, EMBO Molecular Medicine, Joyce Slingerland, Miller School of Medicine, Oncogene journal, Sylvester Comprehensive Cancer Center, University of Miami, VEGF protein