Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis.
Here we report the effects of loss of the Toll-like receptor-associated signaling adaptor myeloid-differentiation factor 88 (MyD88) on tumor induction in two distinct mouse models of carcinogenesis. The 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin papilloma model depends on proinflammatory processes, whereas the 3'-methylcholanthrene (MCA) induction of fibrosarcoma has been used by tumor immunologists to illustrate innate and adaptive immune surveillance of cancer. When exposed to a combination of DMBA/TPA, mice lacking MyD88 formed fewer skin papillomas than genetically matched WT controls treated in a similar manner. Unexpectedly, however, fewer MyD88-/- mice formed sarcomas than WT controls when exposed to MCA. In contrast, MyD88-deficient mice did not show a defective ability to reject highly immunogenic transplanted tumors, including MCA sarcomas. Despite the reported role of TNF in chronic inflammation, TNF-deficient mice were significantly more susceptible to MCA-induced sarcoma than WT mice. Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model.
Swann
Jeremy B
JB
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
Vesely
Matthew D
MD
Silva
Anabel
A
Sharkey
Janelle
J
Akira
Shizuo
S
Schreiber
Robert D
RD
Smyth
Mark J
MJ
D000818:Animals; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007107:Immune System / Q000378:metabolism; D007249:Inflammation; D008297:Male; D008748:Methylcholanthrene / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D012878:Skin Neoplasms / Q000378:metabolism
D053594:Myeloid Differentiation Factor 88; D008748:Methylcholanthrene