title: Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research.
abstract: Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1CreERknock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1CreERKI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1CreERKI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Tetteh
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: Kretzschmar
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Begthel
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Korving
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Morsink
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Henner
authors.initials: H
authors.lastname: Farin
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences (KNAW), 3584 CT Utrecht, The Netherlands; University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands; h.clevers@hubrecht.eu.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor; D024401:Carbonic Anhydrase I / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D018390:Gene Targeting; D017491:Genes, APC; D011905:Genes, ras; D056426:Genetic Loci; D006801:Humans; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D012106:Research
chemical_list: D014408:Biomarkers, Tumor; C045073:Cre recombinase; D019426:Integrases; D024401:Carbonic Anhydrase I
keywords: Car1; colorectal cancer; differentiated epithelial cells; gastrointestinal tract; mouse model