We are interested in dissecting the molecular mechanisms governing blood vessel formation as it relates to tumor angiogenesis during cancer progression. Our lab uses the zebrafish as a model system to examine blood vessel formation. We are currently using a chemical genetic approach in combination with a mutagenesis screen to identify angiogenic mutants. Positional cloning of these mutants might reveal critical genes as novel targets for anti-angiogenic therapy.

Tumor growth is limited by its blood supply; thus, targeting blood vessels is a rational strategy for cancer treatment. During the formation of tumor vessels, many embryonic genes are reactivated. Our research focuses on using the zebrafish as a model system to examine genes that regulate endothelial cell function. The transparency and rapid development of fish embryos make it possible to detect many phenotypic changes. It is especially well suited for vascular biology studies as the transparency makes it easy to score blood flow as an indication of vessel function. As a vertebrate organism, zebrafish genes their encoded proteins are closely related to their human counterparts so that a small molecule kinase inhibitor designed against the human vascular endothelial growth factor (VEGF) receptor, also inhibits the function of the zebrafish receptor. The VEGF receptor is a major regulator of endothelial cell function in mammals and in the zebrafish. Both VEGF and its receptors are important targets for anti-angiogenic therapy. Recent success with the approval of an anti-angiogenic agent for clinical use has confirmed the feasibility of this approach.

In our work, we use a kinase inhibitor to block the function of the zebrafish VEGF receptor. This highly selective vascular blockade facilitated a chemical genetic dissection of angiogenic signaling in an intact vertebrate organism (Chan et al., 2002). We are currently combining this chemical approach with a mutagenesis screen to identify angiogenic mutants. Identification of the genes responsible for these mutations will further our understanding of the molecular determinants of blood vessel formation that could lead to improved cancer therapies.