Targeting Coagulation to the Tumor Microvasculature: Perspectives and Therapeutic Implications From Preclinical Studies

Abstract

Pioneering studies at the National Cancer Institute by Glenn Algire in 1945 led to the conclusion that “ the rapid growth of tumor explants is dependent on the development of a rich vascular supply ” ( 1 ) . There is now little doubt that most tumors are dependent on neovascularization for oxygen and nutrients to sustain progressive growth ( 2 ) . In 1971, Judah Folkman ( 3 ) proposed the innovative idea that angiogenesis inhibitors could be used to treat cancer. In 2004, the U.S. Food and Drug Administration approved the fi rst antiangiogenic drug for the treatment of cancer, a humanized monoclonal antibody against VEGF-A named Avastin (bevacizumab). Other drugs in this category are under development. There are at least two general approaches to depriving tumors of their blood supply. One approach is to inhibit tumor-induced neovascularization from both the sprouting neighboring vessels and the recruitment of endothelial cell precursors from the bone marrow ( 4 – 8 ) . The essential role of vascular endothelial growth factor (VEGF) in this process is well established, and several angiogenesis inhibitors have shown effi cacy at reducing tumor neovascularization and tumor growth, at least in preclinical models ( 9 – 11 ) . In some cases, rapidly growing lesions were converted into dormant lesions ( 12 ) . A second approach to reducing the tumor blood supply is to cause zonal tumor necrosis by targeting the preexisting vasculature ( 13 , 14 ) . This approach is used successfully in the clinic, where transarterial embolization is used to obstruct vessels, particularly in hepatocellular carcinoma ( 15 ) . Recently, randomized controlled trials have shown increased survival of patients treated in this way ( 16 , 17 ) . As elegantly illustrated by Dienst et al. in this issue ( 18 ), recent advances in the molecular characterization of tumor endothelium have permitted an evolution of this catheter-based approach to vessel occlusion. The targeting of vascular endothelial cells presents several advantages compared with tumor cell targeting. First, effective and uniform delivery of anticancer drugs to solid tumors has proved challenging: Drugs do not reach deep beyond the perivascular region due to physical barriers by fi brous tumor tissue and to elevated interstitial pressure, which reduces fl uid convection ( 19 ) . By contrast, endothelial cells lining the vessels are easily accessible to the bloodstream. Second, vascular endothelial cells are less heterogeneous than tumor cells and, as generally normal, nontransformed cells, are less likely than tumor cells to acquire mutations leading to drug resistance ( 7 ) . Third, complete cell death in all endothelial cells lining a vessel is not necessary; rather, interruption of the blood stream for a period of hours may suffi ce. At the same time, these advantages are the base of diffi culties to overcome. The most critical point is specifi city of tumor vascular targeting to avoid undesirable effects to normal tissue blood supply. Thus, selection of tumor-specifi c target molecules is the key to the success of this approach. Fortunately, tumor and normal tissue vasculature differ in morphology and function.