Applied Vascular Biology: Can Angiogenesis Inhibitors Help Control Malignant Growth?

A primordial event in the young fetus is vasculogenesis: the transformation of progenitor cells into interconnecting tubes of endothelial cells that act as conduits for the circulating blood, enabling it to perfuse all body tissues. Starting nearly at the same time, new capillaries sprout from existing vessels in what is aptly called angiogenesis, which literally means the “birth of vessels.” These new vessels eventually are pruned and remodeled, developing into the adult circulatory system. Endothelial cells are ordinarily quiescent-their turnover time is measured in years-unless activated by a situation that increases the body's need for blood, such as the menstrual cycle, a healing wound, and certain ocular diseases. Another situation, which has attracted much interest in recent years, is the formation and growth of tumors.

The field of angiogenesis research, an exotic concept to most physicians a quarter century ago, now commands two journals devoted exclusively to answering such questions as how growth factors and other molecules regulate vessel growth and how this process is altered in early neoplasms and again during metastasis. Another intriguing question is how to control and possibly even reverse new vessel formation.

Efforts to curtail growth of the new vessels that nourish tumors and support tumor growth have taken three major directions:

- Countering the actions of the numerous factors (> 15 at last count) that maintain endothelial cell growth and proliferation. Two of the best known are vascular endothelial growth factor and what may be the most potent of all angiogenic substances, the misnamed basic fibroblast growth factor. It might prove possible genetically to alter growth factor receptors in tumor cells.

- Inhibiting matrix metalloproteases, enzymes that break down normal tissues to clear a path for new “tumor vessels.”

- Using angiogenesis inhibitors, substances that paradoxically are produced by tumor cells but strongly suppress …