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Shape-shifting brain tumor cells thwart treatment

Glioblastoma tumor cells

Glioblastoma tumor cells (shown in green) can transform into endothelial cells (shown in red), which line the interior surface of a tumor vessel.
Image courtesy of Yasushi Soda

"To grow beyond one to two millimeters in diameter—roughly the size of a pinhead—tumors need their own independent blood supply. To recruit new vasculature from existing blood vessels, many overexpress growth factors, predominantly vascular endothelial growth factor (VEGF). This led to the development of Avastin, a monoclonal antibody that intercepts VEGF.

Glioblastoma, however, the most common and lethal form of brain cancer, resists nearly all treatment efforts, even when attacked simultaneously on several fronts. In fact, studies have shown that tumor cells often become more aggressive after anti-angiogenic therapy, but the reason had been unclear.

One explanation can be found in the tumor cells' unexpected flexibility, discovered researchers the lab of Inder Verma. When faced with a life-threatening oxygen shortage, glioblastoma cells can shift gears and morph into blood vessels to ensure the continued supply of nutrients. The study, published in the Proceedings of the National Academy of Sciences, not only explains why cancer treatments that target angiogenesis—the growth of a network of blood vessels that supplies nutrients and oxygen to cancerous tissues—routinely fail in glioblastoma, but may also spur the development of drugs aimed at novel targets.

Postdoctoral researcher Yasushi Soda studied a mouse model of glioblastoma that recapitulates the development and progression of human brain tumors that arise naturally. The glioblastoma mice grow brain tumors within a few months of being injected with viruses that carry activated oncogenes. When Soda peered at the tumor cells, he found—much to his surprise—that about 30 percent of vascular endothelial cells— specialized cells that line the interior surface of blood vessels—appeared to have originated from tumor cells. Further experiments revealed that these tumor-derived endothelial cells are not specific to mouse tumors but can also be found in clinical samples taken from human glioblastoma patients.

"This surprising effect of anti-angiogenic therapy with drugs such as Avastin tells us that we have to rethink glioblastoma combination therapy," says Verma. "Disrupting the formation of tumor blood vessels is not enough; we also have to prevent the conversion of tumor cells into blood vessel cells. But as we learn more about tumors' molecular flexibility, we will be able to design novel, tailor-made combination therapies to combat deadly brain tumors."