The growth of blood vessels that supply tumors with essential nutrients may be regulated in endothelial cells by a small RNA molecule, or microRNA, a new study suggests. Researchers identified a microRNA called miR-132 that appears to act as a molecular switch for endothelial cell growth, causing the cells to transition out of their normal resting state and form new blood vessels (angiogenesis). The study, which could lead to a strategy for preventing angiogenesis and potentially for treating cancer, was published online by Dr. David Cheresh of the University of California, San Diego, and his colleagues August 1 in Nature Medicine.

Endothelial cells are among the least proliferative types of cells in adults, but they can be activated in response to certain cues, such as growth factors. Suspecting that microRNAs, which are known to regulate genes, might play a role, the researchers profiled microRNAs in a stem cell model of human vascular development and identified miR-132 as highly upregulated during the development of blood vessels. They then confirmed that miR-132 expression was also highly elevated in benign lesions of blood vessels, or hemangiomas, and in the blood vessels of human tumors, but was not detectable in normal blood vessels.

A molecular pathway analysis revealed that miR-132 suppresses the expression of a gene that encodes the protein p120RasGAP, which is a negative regulator of the protein Ras. Ras is frequently altered in cancer, so targeting miR-132 could be a way to intervene in an important pathway, the researchers said. And because miR-132 is found primarily in endothelial cells, these strategies would likely be specific to these cells, they noted.

As a proof of principle, the researchers used nanoparticle technologies they have developed to deliver an inhibitor of miR-132 directly to the vasculature of tumor-bearing mice. This treatment resulted in the blockade of tumor angiogenesis and tumor growth. Moreover, in mice with retinal disease that featured the growth of new blood vessels, direct injection of the anti-miR-132 into the eye was able to suppress angiogenesis in the retina.

“We essentially turned off the angiogenic switch during angiogenesis,” said Dr. Cheresh. The preponderance of growth in these cells was reduced, making it feasible to apply this kind of approach to patients with cancer and retinal diseases characterized by extensive angiogenesis, he added.

source:NCI