Mechanism incites early escape of tumor cells from new blood vessels

Researchers have found a novel mechanism through which epidermal growth factor receptor (EGFR) encourages blood vessel growth early in tumor development—not only feeding the primary tumor, but also providing routes for tumor cells to escape the primary tumor site, and enter the circulation. The study was published in the August 2015 issue of the journal Neoplasia.

Elevated expression of EGFR has long been known to be strongly associated with poor prognosis in many types of cancer.

“When cancer cells have high levels of EGFR, the tumor has a lot of new, angiogenic blood vessels,” explained the study’s senior author Elena Deryugina, PhD, Assistant Professor of Cell and Molecular Biology at The Scripps Research Institute (TSRI), in La Jolla, CA. “And these vessels are very welcoming for tumor cells and facilitate their dissemination from the very early stages of tumor development.”

In a previous study, the TSRI research team had shown that tumors with high levels of EGFR delivered 10- to 100-times more tumor cells to secondary organs than tumors with low levels of EGFR.

“When we downregulated EGFR so it wasn’t expressed anymore, the tumor cells were not able to disseminate efficiently,” said the study’s first author Petra Minder, Research Associate at TSRI. “This gave us a hint that EGFR plays a role in intravasation—we were just not sure how.”

In this study, the researchers performed experiments with EGFR levels in chick embryos. They found that EGFR signaling starts a chain reaction inside tumor cells that involves interleukin-8, matrix metalloproteinase-9, and ultimately results in the release of vascular endothelial growth factor (VEGF). Released VEGF then binds to endothelial cells, which both induces angiogenesis and regulates vascular permeability.

These new blood vessels do more than supply tumors with oxygen and nutrients, the researchers realized. “Now we have learned that these newly formed vessels are used by tumor cells for dissemination because of their certain structural properties,” Dr. Deryugina said.

That is, the new blood vessels are dilated and unusually permeable, so tumor cells can easily slip into them, escape from the primary tumor, and enter the circulation.

This study “implicates for the first time a specific mechanism involving EGFR in the development of a distinct intravasation-sustaining intratumoral vasculature,” the authors wrote.

The results may also explain why EGFR-inhibitors have had limited success in cancer patients. Although these drugs target EGFR’s effects in primary tumor growth, they don’t address EGFR’s role in blood vessel growth nor are they administered early enough to affect the initial seeding of metastatic tumor cells, the researchers concluded.