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 to selectively target tumor-associated vasculature resulting in hemorrhagic necrosis of tumors without injury to surrounding tissues. The major limitation in the clinical use of TNF has been severe dose-limiting toxicity when administered systemically. However, when administered in isolated organ perfusion it results in regression of advanced bulky tumors. A better understanding of the mechanisms of TNF-induced antitumor effects may provide valuable information into how its clinical use in cancer treatment may be expanded. We describe here that the release of a novel tumor-derived cytokine endothelial-monocyte-activating polypeptide II (EMAPII) renders the tumor-associated vasculature sensitive to TNF. EMAPII has the unique ability to induce tissue factor production by tumor vascular endothelial cells that initiates thrombogenic cascades, which may play a role in determining tumor sensitivity to TNF. We demonstrate here that constitutive overexpression of EMAPII 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 associated neovasculature provides an explanation for the focal effects of TNF on tumors and possibly for the variable sensitivity of tumors to bioactive agents.
Wu
P C
PC
Surgical Metabolism Section, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Alexander
H R
HR
Huang
J
J
Hwu
P
P
Gnant
M
M
Berger
A C
AC
Turner
E
E
Wilson
O
O
Libutti
S K
SK
D000818:Animals; D016207:Cytokines; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D012190:Retroviridae; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C077219:small inducible cytokine subfamily E, member 1