R&D News: Conversion of brain tumor cells into blood vessels thwarts treatment efforts
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, said the researchers.
The researchers study 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 the findings may also spur the development of drugs aimed at novel targets.
â€œThis surprising effect of anti-angiogenic therapy with drugs such as Avastin tells us that we have to rethink glioblastoma combination therapy," says senior author Inder Verma, a professor in the Laboratory of Genetics and holder of the Irwin and Joan Jacobs Chair in Exemplary Life Science.
â€œDisrupting the formation of tumor blood vessels is not enough; we also have to prevent the conversion of tumor cells into blood vessels cells.â€
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 tumors overexpress growth factors, predominantly vascular endothelial growth factor, or VEGF. This led to the development of Avastin, a monoclonal antibody that intercepts VEGF.
â€œIn a recent phase II clinical trial, 60 percent of patients with glioblastoma responded to a combination of Avastin and Irinotecan, which directly interferes with the growth of cancer cells,â€ explains Mr Verma, â€œbut in most patients this effect was only transient.â€ In fact, studies have shown that tumor cells often become more aggressive after anti-angiogenic therapy, but the reason had been unclear.
To find out, postdoctoral researcher and first author Yasushi Soda took advantage of a mouse model of glioblastoma that recapitulates the development and progression of human brain tumors that arise naturally. â€œThe tumors in these mice closely resemble glioblastomas, including the typically messy and highly permeable tumor vessels, which allowed us to study the tumor vasculature in great detail,â€ he explains.
The glioblastoma mice, the concept for which was developed in the Mr Verma laboratory, grow brain tumors within a few months of being injected with viruses that carry activated oncogenes and a marker gene that causes all tumor-derived cells to glow green under ultraviolet light. By simply tracking the green glow under the microscope, the Salk researchers can then follow the fate of tumor cells.
When Mr 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 green. â€œThis indicated to us that they most likely originated from tumor cells,â€ he says.
Further experiments revealed that TDECs, short for tumor-derived endothelial cells, are not specific to mouse tumors but can also be found in clinical samples taken from human glioblastoma patients. â€œThis was really strong evidence for us that glioblastoma cells routinely transdifferentiate into endothelial cells,â€ Mr Verma explains.
The transformation is triggered by hypoxia, or low oxygen levels, which signals tumor cells that the time has come to start their shape-shifting stunt. But unlike regular vascular endothelial cells, TDECs don't require VEGF to form functional blood vessels. â€œThis might explain why, despite being initially successful, anti-angiogenic therapy ultimately fails in glioblastomas,â€ says Mr Verma.
Avastin interrupts normal blood vessels, but eventually they are replaced with tumor-derived vessels, which are now treatment-resistant. â€œOnce again, we are confronted with the versatility of tumor cells, which allows them to survive and thrive under adverse conditions,â€ says Mr Verma. â€œBut as we learn more about tumors' molecular flexibility, we will be able to design novel, tailor-made combination therapies to combat deadly brain tumors.â€
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