Oncogenic Ras Diverts a Host TNF Tumor Suppressor Activity into Tumor Promoter

SummaryThe roles of inflammatory cytokines and the immune response in cancer remain paradoxical. In the case of tumor necrosis factor (TNF), there is undisputed evidence indicating both protumor and antitumor activities. Recent work in Drosophila indicated that a TNF-dependent mechanism eliminates cells deficient for the polarity tumor suppressors dlg or scrib. In this study, however, we show that in tumors deficient for scrib that also expressed the Ras oncoprotein, the TNF signal was diverted into a protumor signal that enhanced tumor growth through larval arrest and stimulated invasive migration. In this case, TNF promoted malignancy and was detrimental to host survival. TNF was expressed at high levels by tumor-associated hemocytes recruited from the circulation. The expression of TNF by hemocytes was both necessary and sufficient to trigger TNF signaling in tumor cells. Our evidence suggests that tumors can evolve into malignancy through oncogenic Ras activation and the hijacking of TNF signaling.

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► Elimination of dlg mutant cells in larvae requires TNF/Eiger
► Oncogenic Ras converts TNF signaling from anti- to pro-tumor in scrib cells
► Tumor-associated hemocytes recruited from the circulation express TNF
► Hemocyte TNF expression is necessary and sufficient for TNF signaling