Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependant diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that control angiogenic responsiveness in several mouse models. We have identified the polymorphism responsible for two of these loci. Using composite interval mapping and multiple interval mapping in crosses involving C57BL/6J, A/J, and SJL/J strains, we have confirmed the existence of multiple angiogenesis-response loci on chromosome 7. One of these (AngVq4) localized to the middle of the chromosome and was centered on tyrosinase. Congenic animals confirmed this locus, but could not demonstrate that the classical tyrosinase albino (c) mutation was causative because of the existence of additional linked loci in the congenic. In 1970, a second tyrosinase albino mutation (c-2J) arose in the C57BL/6J background at Jackson Labs. Testing this strain (C57BL/6J<c-2J>) demonstrated that the albino mutation is sufficient to completely explain the alteration in angiogenic response that we observed in congenic animals. Thus, we conclude that the classical tyrosinase mutation is responsible for AngVq4. Similar methods have identified the classical pink-eyed dilution mutation as the genetic change responsible for AngFq5.

Characterizing novel angiogenesis regulating genes detected by QTL mapping may identify additional therapeutic targets for antiangiogenic agents. These experiments also reveal the important effect of the host genetics on angiogenesis and tumor growth. The identification of “high angiogenic” individuals which are at risk for angiogenesis dependent diseases will allow for increased monitoring and better clinical management. Further, new antiangiogenic therapies with low toxicity may allow for the pretreatment of such individuals rendering them “low angiogenic” and thereby increase survival.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 364.

©2010 American Association for Cancer Research
2010