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 pap...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-01, Vol.105 (2), p.652-656
Main Authors: Swann, Jeremy B, Vesely, Matthew D, Silva, Anabel, Sharkey, Janelle, Akira, Shizuo, Schreiber, Robert D, Smyth, Mark J
Format: Article
Language:English
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0708594105