title: Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis.
abstract: 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.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Swann
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Vesely
authors.forename: Anabel
authors.initials: A
authors.lastname: Silva
authors.forename: Janelle
authors.initials: J
authors.lastname: Sharkey
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: 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
chemical_list: D053594:Myeloid Differentiation Factor 88; D008748:Methylcholanthrene