Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 2; pp. 652 - 656
• Main Authors: Swann, Jeremy B, Vesely, Matthew D, Silva, Anabel, Sharkey, Janelle, Akira, Shizuo, Schreiber, Robert D, Smyth, Mark J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15-01-2008; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cancer; Carcinogenesis; Cell Line, Tumor; Cytokines; Fibrosarcoma; Fibrosarcoma - metabolism; Gene Expression Regulation, Neoplastic; Genetics; Immune System - metabolism; Inflammation; Inoculation; Male; Methylcholanthrene - chemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Myeloid Differentiation Factor 88 - metabolism; Myeloid Differentiation Factor 88 - physiology; Neoplasm Transplantation; Neoplasms - genetics; Neoplasms - immunology; Papilloma; Proteins; Receptors; Rodents; Sarcoma; Skin Neoplasms - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0708594105

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.