It has been known for more than a century that tumors have their own blood supply and, for the better part of that time, that the tumor vasculature is highly abnormal, differing from that of normal tissues with respect to organization, structure, and function (1). At one time it was thought that tumors had a vasculature that was superior to that of normal tissues; this misconception arose because tumor vessels are often of large size and were therefore more readily visualized by angiography and macroscopy than the smaller but more numerous and functionally superior capillaries of normal tissues. By the late 1970s, it also was clear that tumor vessels were heterogeneous, hyperpermeable to plasma and plasma proteins, and that tumor blood flow was unevenly distributed and, overall, significantly lower than that in normal tissues. Further, it was known that tumor vessels were induced by tumor-secreted products, although the tumor angiogenic factor(s) responsible were just beginning to be investigated. In the years that followed, much has been learned about the molecules responsible for angiogenesis, particularly vascular endothelial growth factor (VEGF)-A, and about the steps and mechanisms by which tumors induce the new vascular supply that they require to grow beyond minimal size. Recent successes with blocking agents against VEGF-A suggest that antiangiogenesis may provide a valuable new approach to tumor therapy (2). This chapter reviews the properties of tumor blood vessels, their differences from normal vessels, and the steps and mechanisms by which they form.

THE NORMAL MICROVASCULATURE AND STROMA

Before discussing tumors, it is important to review the structure of normal tissues to provide a standard of comparison.