Cancer cells combine tools to increase invasivenessDec. 19, 2013, 9:30 AM
Two features of invasive cancer cells — invadopodia and exosomes — are linked together, Vanderbilt University investigators have discovered. They report in the Dec. 12 issue of Cell Reports that invadopodia — cell surface structures that “drill” into the surrounding matrix — act as docking and secretion sites for exosomes, bubble-like packets that carry tumor growth and survival factors.
“Exosomes are a focus of intense interest in the cancer research community,” said Alissa Weaver, M.D., Ph.D., associate professor of Cancer Biology.
“It has become apparent that tumors secrete a lot of exosomes, and that they are important for tumors to survive and become aggressive,” she said.
Because exosomes end up in blood and other body fluids, they may provide useful biomarkers to track tumors using blood samples. Multiple studies have focused on defining the “cargoes” that these vesicles carry, but little is known about how the exosome secretion and cargo content are regulated.
“We wanted to know how exosomes are secreted, and why cancer cells seem to secrete more of them than normal cells,” Weaver said.
Weaver and her team have focused for several years on invadopodia and their secretion of matrix-degrading enzymes. Because exosomes have been reported to carry some of the same matrix-degrading enzymes, they used cultured cells and live cell imaging to test whether invadopodia are specific subcellular sites of exosome secretion.
“It was really exciting to find that invadopodia are docking sites for exosomes,” Weaver said. “We think that’s one potential reason why tumors secrete so many exosomes — as tumors become more aggressive, they make more invadopodia structures, which means they have more docking and release sites for exosomes.”
The team also showed that invadopodia and exosomes are interdependent. Blocking the formation of invadopodia greatly reduced the secretion of exosomes. Likewise, blocking exosome production affected formation and stabilization of invadopodia.
“There’s a synergy where exosomes help induce the signaling that starts an invadopodia, and then after the exosomes are secreted, they play a role in invadopodia stabilization and activity regulation as well,” Weaver said.
“The deregulated signaling in the cancer cell probably sets up a positive feedback loop that promotes invasiveness, and exosome secretion is a major part of that.”
Understanding the molecular details of invadopodia and exosome generation and regulation may offer new therapeutic opportunities.
“If you could block invadopodia, that would greatly diminish the secretion of exosomes and limit the aggressiveness of tumors,” Weaver said.
Research collaborators included first author Daisuke Hoshino, Ph.D., Kellye Kirkbride, Ph.D., Kaitlin Costello, Emily Clark, Ph.D., Seema Sinha, Nathan Grega-Larson and Matthew Tyska, Ph.D. The research was supported by grants from the National Institutes of Health (CA163592, DK095811, DK075555, AI060729, MH018917), the American Cancer Society and the American Heart Association.