title: The immune response to sporadic colorectal cancer in a novel mouse model.
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-ER(T2) × 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-ER(T2) × 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-ER(T2) × 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.
authors.affiliation: Institute of Immunology, Charité Campus Benjamin Franklin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Czéh
authors.forename: C
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: S
authors.initials: S
authors.lastname: Shalapour
authors.forename: C
authors.initials: C
authors.lastname: Schön
authors.forename: S
authors.initials: S
authors.lastname: Robine
authors.forename: E
authors.initials: E
authors.lastname: Goldscheid
authors.forename: H
authors.initials: H
authors.lastname: Stein
authors.forename: T
authors.initials: T
authors.lastname: Schüler
authors.forename: G
authors.initials: G
authors.lastname: Willimsky
authors.forename: T
authors.initials: T
authors.lastname: Blankenstein
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology; D002277:Carcinoma / Q000276:immunology* / Q000556:secondary; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D007078:Ileal Neoplasms / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000912:Antibodies, Neoplasm; D000952:Antigens, Polyomavirus Transforming