title: Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling.
abstract: A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: J
authors: J
authors: Zeilstra
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: S P J
authors: SP
authors: Joosten
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: H
authors: H
authors: van Andel
authors: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: C
authors: C
authors: Tolg
authors: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: A
authors: A
authors: Berns
authors: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: M
authors: M
authors: Snoek
authors: Hubrecht Institute and University Medical Center Utrecht, Utrecht, The Netherlands.
authors: M
authors: M
authors: van de Wetering
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: M
authors: M
authors: Spaargaren
authors: Hubrecht Institute and University Medical Center Utrecht, Utrecht, The Netherlands.
authors: H
authors: H
authors: Clevers
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: S T
authors: ST
authors: Pals
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C117722:CD44v10 antigen; D018960:Hyaluronan Receptors; C493597:Lgr5 protein, mouse; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled