The contribution of Harold F. Dvorak to the study of tumor angiogenesis and stroma generation mechanisms.

Abstract

In 1983, Harold Dvorak and his colleagues were the first to show that tumor cells secreted vascular permeability factor (VPF) and that a blocking antibody to VPF could prevent the edema and fluid accumulation that is characteristic of human cancers. In 1986, Dvorak went on to demonstrate that VPF was secreted by a variety of human tumor cell lines and proposed that VPF was in part responsible for the abnormal vasculature seen in human tumors. As a result, he and other investigators demonstrated that VPF was capable of stimulating endothelial cell growth and angiogenesis. These fundamental discoveries led to additional research conducted by Napoleone Ferrara and his laboratory, confirming the cloning of VPF and renaming the protein vascular endothelial growth factor (VEGF). In 1986, Dvorak proposed that by secreting VPF, tumors induce angiogenesis by turning on the wound healing response. He noted that wounds, like tumors, secrete VPF, causing blood vessels to leak plasma fibrinogen, which stimulates blood vessel growth and provides a matrix on which they can spread. Unlike wounds, however, that turn off VPF production after healing, tumors did not turn off their VPF production and instead continued to make large amounts of VPF, allowing malignant cells to continue to induce new blood vessels and so to grow and spread. Thus, tumors behave like wounds that fail to heal. This work is again extremely significant for patients worldwide, as Dvorak's scientific research is leading his colleagues all over the world to examine how to treat a tumor through its blood supply.