MERIT Award Recipient: David A. Cheresh, Ph.D.
VEGF and PDGF in Angiogenesis and Tumor Progression
The host vascular response to a tumor often dictates the growth rate of the primary tumor and the capacity of the tumor to invade. Inhibitors of angiogenesis (blood vessel growth and development) are beginning to show promise in the clinic. In fact, Avastin, an antibody that targets blood vessels by blocking Vascular Endothelial Growth Factor (VEGF), is clinically approved to treat a wide range of cancers. However, the clinical utility of Avastin is only realized when it is given in combination with more traditional chemotherapeutic agents. For this reason, it has been hypothesized that Avastin and perhaps other inhibitors of VEGF or its receptors on blood vessels act to normalize the host vascular response to the tumor and thereby facilitate more blood flow and better drug delivery to the tumor. Blood vessels are typically comprised of both endothelial cells that form a tube and pericytes that cover and stabilize the tube. These processes are coordinated by specific growth factors such as VEGF that stimulates endothelial cells and Platelet Derived Growth Factor (PDGF) that stimulates pericytes. We have discovered a new and surprising role for VEGF as an inhibitor of neovascularization, based on its capacity to disrupt pericyte function causing blood vessel destabilization. In fact, mice that show a reduced level of VEGF in tumors develop tumor-associated blood vessels that are more mature and better able to carry drugs to the tumor. Interestingly, while these tumors lacking VEGF grow at a faster rate, they are more sensitive to the effects of standard chemotherapy. These findings underscore the importance of pericytes in the neovascularization process and reveal a dichotomous role for VEGF both as a promoter of endothelial cell function and a negative regulator of pericytes and vessel maturation. These studies provide new insight into the mechanism by which drugs like Avastin influence tumor-associated blood vessels and reveal how specific anti-cancer therapies can synergize to maximize therapeutic benefit for cancer patients.