Tumor necrosis factor induces tumor necrosis via tumor necrosis factor receptor type 1-expressing endothelial cells of the tumor vasculature

Activation of endothelial cells, fibrin deposition, and coagulation within the tumor vasculature has been shown in vivo to correlate with the occurren ce of tumor necrosis factor (TNF)-induced tumor necrosis in mice. In the pr esent study we investigated which target cells mediate the TNF-induced necr osis in fibrosarcomas grown in wild type (wt), TNF receptor type I-deficien t (TNFRp55-/-), and TNF receptor type 2-deficient (TNFRp75-/-) mice. TNF ad ministration resulted in tumor necrosis exclusively in wt and TNFRp75-/-, b ut not in TNFRp55 -/- mice, indicating a dependence of TNF-mediated tumor n ecrosis on the expression of TNF receptor type 1, However, using wt and TNF Rp55-/- fibrosarcomas in wt mice, we found that TNF-mediated tumor necrosis was completely independent of TNF receptor type 1 expression in tumor cell s. Thus we could exclude any direct tumoricidal effect of TNF in this model . Soluble TNF induced leukostasis in wt and TNFRp75-/- mice but not in TNFR p55-/- mice. TNF-induced leukostasis in TNFRp55-/- mice was restored by ado ptive bone marrow transplantation of wt hematopoietic cells, but TNF failed to induce tumor necrosis in these chimeric mice. Because TNF administratio n resulted in both activation and focal damage of tumor endothelium, TNF re ceptor type 1-expressing cells of the tumor vasculature, likely to be endot helial cells, appear to be target cells for mediating TNF-induced tumor nec rosis.