Nanoparticle delivery of anti miR-132 blocks neovasculature and tumor burden in mice.
Investigators state that an miRNA known as miR-132 acts as the molecular switch responsible for triggering angiogenesis in tumor formation. Early studies by a team led by David A Cheresh, Ph.D., professor of pathology at the University of California San Diego School of Medicine, have shown that blocking miR-132 through the use of neutralizing miRNAs effectively controls disease severity in animal models of cancer and retinal disorders. Conversely, ectopic expression of miR-132 in endothelial cells in vitro was found to increase cellular proliferation and tube-forming capacity.
Their research is published online in Nature Medicine in a paper titled “MicroRNA-132–Mediated Loss of p120RasGAP Activates the Endothelium to Facilitate Pathological Angiogenesis.”
miR-132 is a highly conserved miRNA transcribed from an intergenic region on human chromosome 17, the authors explain. The team subsequently confirmed that miR-132 is highly upregulated in a human embryonic stem cell model of vasculogenesis and highly expressed in the endothelium of human tumors and hemangiomas but was undetectable in normal endothelium. Further investigation showed that miR-132 acts as an angiogenic switch by targeting p120RasGAP in the endothelium and thereby inducing neovascularisation.
To evaluate the effects of blocking miR-132 activity the researchers used a nanoparticle delivery platform to systemically deliver anti-miR-132 in cancer-bearing mice. The nanoparticles not only blocked angiogenesis induced by a VEGF-secreting ovarian carcinoma but also significantly decreased tumor burden and angiogenesis in an orthotopic xenograft mouse model of human breast carcinoma, they claim. After treatment with anti-miR-132 nanoparticles the vasculature of the mice showed increased endothelial p120RasGAP, which appears to confirm the hypothesis that antagonism of miR-132 can restore p120RasGAP expression during neovascularisation in vivo.
The researchers hope that the technology will provide a new approach to either promotie angiogenesis in patients with diseases such as stroke, heart attacks, or diabetes or inhibit blood vessel development in cancer patients. “To our knowledge, the findings reported here provide the first description of a miRNA-regulated angiogenic switch,” they conclude. “Our studies show that this switch can be regulated to both disrupt and facilitate neovascularization. The possibility of delivering miRNAs or antagomirs to activated endothelium, as demonstrated here using miR-132–containing nanoparticles targeted to integrin αVβ3, suggests opportunities for manipulating miRNA levels in the endothelium to control pathological neovascularization.”