In vivo sensitivity of human melanoma to tumor necrosis factor (TNF)-alpha, is determined by tumor production of the novel cytokine endothelial-monocyte activating polypeptide II (EMAPII)

Tumor necrosis factor (TNF)-alpha is a potent anticancer agent that seems t o selectively target tumor-associated vasculature resulting in hemorrhagic necrosis of tumors without injury to surrounding tissues. The major limitat ion in the clinical use of TNF has been severe dose-limiting toxicity when administered systemically, However, when administered in isolated organ per fusion it results in regression of advanced bulky tumors. A better understa nding of the mechanisms of TNF-induced antitumor effects may provide valuab le information into how its clinical use in cancer treatment may be expande d. We describe here that the release of a novel tumor-derived cytokine endo thelial-monocyte-activating polypeptide II (EMAPII) renders the tumor-assoc iated vasculature sensitive to TNF, EMAPII has the unique ability to induce tissue factor production by tumor vascular endothelial cells that initiate s thrombogenic cascades, which may play a role in determining tumor sensiti vity to TNF, We demonstrate here that constituitive overexpression of EMAPI I in a TNF-resistant human melanoma line by retroviral-mediated transfer of EMAPII cDNA renders the tumor sensitive to the effects of systemic TNF in vivo, but not in vitro. This interaction between tumors and their associate d neovasculature provides an explanation for the focal effects of TNF on tu mors and possibly for the variable sensitivity of tumors to bioactive agent s.