Cutting off the vascular supply to solid tumors to promote regression has not proven singularly effective in cancer patients because “in practice you can’t get rid of all of the blood vessels in the tumor,” explained Dai Fukumura, HMS associate professor of radiation oncology at Massachusetts General Hospital. “It is better to use an approach of normalizing the blood vessels to improve chemotherapy and radiation treatment.”
The tortuous, leaky vessels found in solid tumors have abnormal organization, structure, and function, posing barriers to delivery of antitumor agents. Inducing normal vessel morphology could enhance vascular function, thereby improving the efficacy of tumor drug therapy.
Fukumura and his colleague Rakesh Jain, HMS professor of radiation oncology (tumor biology) at MGH—and the person who first proposed the normalization concept using anti-angiogenic agents (see Focus, Feb. 2, 2007)—published a study online Feb. 17 in Nature Medicine detailing a novel mechanism for vascular normalization of solid tumors. They determined that creating an endothelial gradient of nitric oxide (NO), a gaseous mediator of neovascularization, was sufficient to normalize blood vessels in a mouse model of glioma, a brain tumor arising from glial tissue.
These tumors have diffuse NO expression resulting from two different forms of nitric oxide synthase, neuronal NOS (nNOS), generated by tumor cells, and endothelial NOS (eNOS), made by cells lining the vascular wall.
In tumors, NO made by nonvascular cells can hinder vessel maturation, contributing to abnormal structure and function. The authors hypothesize that “if NO could be localized selectively around blood vessels, the morphology and function of the tumor vasculature would be improved,” making a better vehicle for antitumor therapies.
The team used short hairpin RNA to block expression of nonvascular nNOS in glioma cells and evaluated the morphology and function of the blood vessels in the resulting tumors. The remaining vascular eNOS created an NO gradient that was restricted to blood vessels, causing them to be more numerous and less permeable than those found in tumors where nNOS was not silenced. In addition, tissue oxygenation was improved in the nNOS-silenced tumors. Together, these vascular alterations improved suppression of glioma growth and overall survival of tumor-bearing mice after they received radiation therapy.
“This is a proof of concept model that worked nicely with gliomas,” said Fukumura. “This may be useful in other diseases where abnormal blood vessels are involved.”
