title: Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells.
abstract: Within primary colorectal cancer (CRC) a subfraction of all tumor-initiating cells (TIC) drives long-term progression in serial xenotransplantation. It has been postulated that efficient maintenance of TIC activity in vitro requires serum-free spheroid culture conditions that support a stem-like state of CRC cells. To address whether tumorigenicity is indeed tightly linked to such a stem-like state in spheroids, we transferred TIC-enriched spheroid cultures to serum-containing adherent conditions that should favor their differentiation. Under these conditions, primary CRC cells did no longer grow as spheroids but formed an adherent cell layer, up-regulated colon epithelial differentiation markers, and down-regulated TIC-associated markers. Strikingly, upon xenotransplantation cells cultured under either condition equally efficient formed serially transplantable tumors. Clonal analyses of individual lentivirally marked TIC clones cultured under either culture condition revealed no systematic differences in contributing clone numbers, indicating that phenotypic differentiation does not select for few individual clones adapted to unfavorable culture conditions. Our results reveal that CRC TIC can be propagated under conditions previously thought to induce their elimination. This phenotypic plasticity allows addressing primary human CRC TIC properties in experimental settings based on adherent cell growth.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Taronish D
authors.initials: TD
authors.lastname: Dubash
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hoffmann
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Oppel
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Klara M
authors.initials: KM
authors.lastname: Giessler
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weber
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Dieter
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hüllein
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Herbst
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Institute for General Pathology and Pathological Anatomy, Technical University of Munich; German Consortium for Translational Cancer Research (DKTK), Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Werft
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany; German Consortium for Translational Cancer Research (DKTK), Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany; German Consortium for Translational Cancer Research (DKTK), Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany; German Consortium for Translational Cancer Research (DKTK), Germany. Electronic address: claudia.ball@nct-heidelberg.de.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Ball
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D061251:Primary Cell Culture; D018874:Spheroids, Cellular; D013997:Time Factors; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor
keywords: Colon cancer; Phenotypic differentiation; Tumor initiating cells