Tumors are like smoothtalking scam artists. Through the messages they send out, they convince other cells to do their bidding. Vascular endothelial cells, in particular, are duped into providing tumors with the blood supply they need to grow. Decades ago, cancer pioneer Judah Folkman realized that without sufficient vascularization tumors would starve. His insight spurred the development of several angiogenesis inhibitors now in clinical use.
These inhibitors have yet to fulfill the potential of this promising approach, and their use may be complicated by serious side effects (see Ophthalmology). So the search continues for “new ways to starve tumors out,” according to Xandra Breakefield, HMS professor of neurology at Massachusetts General Hospital.
In a study published in the Nov. 4 issue of Cancer Cell, Breakefield and her colleagues identify a new anti-angiogenesis target, the microRNA miR-296, which they found regulates glioma-induced angiogenesis.
Thomas Würdinger, a postdoctoral fellow in Breakefield’s lab, discovered that by secreting well-known growth factors like vascular endothelial growth factor (VEGF), glioma cells not only induce endothelial cells to form blood vessels, they also enhance endothelial expression of the receptors that respond to these angiogenic signals. Würdinger, who is also a member of the neuro-oncology research group at the VU University Medical Center in the Netherlands, determined that both of these angiogenic effects are stimulated by miR-296 in endothelial cells.
“Other miRNAs are known to be involved in angiogenesis,” said Anna Krichevsky, HMS assistant professor of neurology at Brigham and Women’s Hospital and senior author of the study. “But what makes this miRNA different is that it is upregulated within endothelial cells in response to soluble signals from the glioma.”
Like most miRNAs, miR-296 has hundreds of bioinformatically predicted mRNA targets. The researchers focused their validation efforts on a target with a known role in growth factor signaling.
“Hepatocyte growth factor–regulated tyrosine kinase substrate [HGS] facilitates the degradation of internalized growth factor receptors,” said Krichevsky. “We found that when it is silenced by miR-296, more receptors return to the cell surface and amplify the angiogenic signal.”
To determine how miR-296 affects tumor-induced angiogenesis in vivo, the researchers developed an antisense inhibitor of miR-296, which they injected into a mouse model of glioma. Mice injected with this antagomir showed a marked decrease in angiogenesis at the tumor site.
“It is too early to say whether inhibiting miR-296 would ultimately limit tumor size or enhance survival,” said Breakefield, who is also a geneticist at MGH. “Further studies are needed to address that question.”
“We would like to test antagomirs in combination with standard cancer therapies, such as chemotherapy,” said Würdinger by e-mail, suggesting that antagonizing the activity of an angiogenic factor, like miR-296, might restrain a tumor while genotoxic drugs do their work.
“In gliomas new targets are badly needed,” said Krichevsky. “I don’t believe that inhibiting a single miRNA will stop gliomas, but combinational therapy could be very promising.”
Breakefield, Krichevsky, and their colleagues have published a related paper, which appeared online Nov. 16 in Nature Cell Biology, describing another way that glioma cells manipulate their environment. The researchers, including first author Johan Skog, an instructor in neurology in Breakefield’s lab, found that glioma cells shed vesicles, called exosomes, that contain mRNA, miRNA, and proteins. These exosomes are taken up by vascular endothelial cells and alter their physiology, causing them to form new blood vessels, for example, which benefits the blood-thirsty glioma.
These vesicles could be harnessed to benefit patients, too. The researchers found that because the vesicles enter the bloodstream, they provide accessible information about the glioma that could help physicians design tailored therapies and monitor progress without invasive brain surgery.
