Tumor angiogenesis and accessibility: role of vascular endothelial growth factor

Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through a process known as angiogenesis. Unlike normal blood vessels, tumor blood vessels are chaotic, irregular, and leaky, which leads to uneven delivery of nutrients and therapeutic agents to the tumor. Conventional therapies target neoplastic cells within a tumor; however, tumor vasculature is emerging as an important target for anticancer therapy. Antiangiogenic therapy offers several potential advantages as an approach to cancer treatment, notably physical accessibility and genetic stability of target cells. Vascular endothelial growth factor (VEGF), a central mediator of angiogenesis, has emerged as an important target for antiangiogenic therapy. In preclinical studies, treatment of human tumor xenografts in immunodeficient mice with the anti-VEGF monoclonal antibody A4.6.1 led to reduced tumor vessel permeability and caused vascular regression. The reduced vascular permeability, resulting from inhibition of VEGF, led to increased delivery of oxygen and therapeutic agents to tumors. Anti-VEGF therapy was effectively combined with other treatment modalities, including radiation, antihormonal, antibody, and chemotherapies in multiple preclinical models. Currently, several phase 3 clinical trials in various cancer types are under way to establish the efficacy of antiangiogenic therapy with a recombinant humanized anti-VEGF monoclonal antibody, bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA), in combination with chemotherapeutic agents.