Tumor necrosis factor: clinical use and mechanisms of action

Administration of high doses of TNF and IFNγ by isolated limb perfusion to patients affected by in transit melanoma metastases or inoperable soft tissue sarcoma of the limb, results in a high rate of complete response compared to chemotherapy alone. TNF/IFNγ induce apoptosis of angiogenic endothelial cells and selectively disrupt the tumor vasculature. The study of the cellular and molecular events mediating this effect has revealed that TNF and IFNγ inhibit the function of integrin αVβ3, an adhesion receptor expressed on angiogenic endothelial cells and essential for their survival, resulting in impaired endothelial cell adhesion, spreading, focal adhesion formation and cell survival. These and other recent findings may open new perspectives in the clinical use of TNF as anti-tumor agent as well as in the design of new anti-vascular strategies aimed to disrupt the tumor vasculature.