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The immune response to sporadic colorectal cancer in a novel mouse model

Oncogene volume 29, pages 6591–6602 (2010)Cite this article

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Abstract

Current mouse models do not reflect the sporadic nature of colon cancer and do not allow the analysis of antitumor immune response because of the lack of known tumor-specific antigens. Two transgenic mouse models with spontaneous tumor development were generated, directing the expression of SV40T antigen (Tag) either constitutively (Vil-Cre × LoxP-Tag-transgenic mice) or stochastically (Vil-Cre-ERT2 × LoxP-Tag-transgenic mice) into the putative stem cell region of the crypt of Lieberkühn. Tumor development and antitumor immune response were monitored. Vil-Cre × LoxP-Tag mice developed multiple adenocarcinomas of the small intestine and colon at an average age of 6 months. During the tumor development, Tag-specific immunoglobulin G (IgG) antibodies were induced in half of the mice, although they had developed neonatal cytotoxic T lymphocyte (CTL) tolerance. This model shows similarity to hereditary colon cancer but not to the sporadic tumor development. Therefore, the conditional Vil-Cre-ERT2 × LoxP-Tag mice were established, in which expression of the dormant Tag was induced by stochastic, tissue-specific activation of Cre recombinase. These mice spontaneously developed highly invasive, metastasizing colon carcinomas at an average age of 20 months. Colon carcinomas expressed epithelial and/or neuroendocrine markers depending on the grade of differentiation. Young Vil-Cre-ERT2 × LoxP-Tag mice had retained CTL responses against epitope IV of Tag. The tumors induced strong anti-Tag IgG responses. We report, for the first time, a mouse model based on stochastic, tissue-specific activation of a dormant oncogene in the colon allowing the analysis of antitumor immune response against primary colorectal cancer.

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Acknowledgements

We thank S Spieckermann, M Rösch, C Westen and S Horn for excellent technical assistance and JC Schmollinger for reading the paper. This study was supported by the Research grants Sonderforschungsbereich SFB 633 and TR 36.

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Author notes

  1. M Czéh

    Present address: 6Current address: Department of Neuropediatrics, Charité Campus Virchow, Augustenburger Platz 1, Berlin 13535, Germany.,

Authors and Affiliations

  1. Institute of Immunology, Charité Campus Benjamin Franklin, Berlin, Germany

    M Czéh, S Shalapour, C Schön, T Schüler, G Willimsky & T Blankenstein

  2. Institute of Pathology, Charité Campus Benjamin Franklin, Berlin, Germany

    C Loddenkemper & H Stein

  3. Research Center ImmunoSciences, Charité Campus Benjamin Franklin, Berlin, Germany

    C Loddenkemper

  4. Department of Morphogenesis and Intracellular Signaling, Institut Curie-Centre National de la Recherche Scientifique, Paris Cedex, France

    S Robine

  5. Max-Delbrück-Center for Molecular Medicine, Robert-Rössle Strasse, Berlin, Germany

    E Goldscheid, G Willimsky & T Blankenstein

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Correspondence to T Blankenstein.

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Czéh, M., Loddenkemper, C., Shalapour, S. et al. The immune response to sporadic colorectal cancer in a novel mouse model. Oncogene 29, 6591–6602 (2010). https://doi.org/10.1038/onc.2010.388

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