Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter.
The 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.
Cordero
Julia B
JB
Beatson Institute for Cancer Research, Cancer Research UK, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Macagno
Juan P
JP
Stefanatos
Rhoda K
RK
Strathdee
Karen E
KE
Cagan
Ross L
RL
Vidal
Marcos
M
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006434:Hemocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D002273:Carcinogens; D029721:Drosophila Proteins; D008565:Membrane Proteins; C404683:Scrib protein, Drosophila; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D018631:ras Proteins