title: Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer.
abstract: The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill-Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD program.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: O'Rourke
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Janelle
authors.initials: J
authors.lastname: Simon
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY.|Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D016158:Genes, p53; D007417:Intestinal Polyps / Q000378:metabolism / Q000473:pathology; D007420:Intestine, Large / Q000378:metabolism / Q000473:pathology*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D034622:RNA Interference; D060449:Wnt Signaling Pathway
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D004318:Doxycycline
keywords: APC; FAP; Wnt; polyposis; shRNA; tumor regression