title: Multipotent mesenchymal stromal cells promote tumor growth in distinct colorectal cancer cells by a β1-integrin-dependent mechanism.
abstract: Tumor-stroma interactions play an essential role in the biology of colorectal carcinoma (CRC). Multipotent mesenchymal stromal cells (MSC) may represent a pivotal part of the stroma in CRC, but little is known about the specific interaction of MSC with CRC cells derived from tumors with different mutational background. In previous studies we observed that MSC promote the xenograft growth of the CRC cell-line DLD1. In the present study, we aimed to analyze the mechanisms of MSC-promoted tumor growth using various in vitro and in vivo experimental models and CRC cells of different mutational status. MSC specifically interacted with distinct CRC cells and supported tumor seeding in xenografts. The MSC-CRC interaction facilitated three-dimensional spheroid formation in CRC cells with dysfunctional E-cadherin system. Stable knock-downs revealed that the MSC-facilitated spheroid formation depended on β1-integrin in CRC cells. Specifically in α-catenin-deficient CRC cells this β1-integrin-dependent interaction resulted in a MSC-mediated promotion of early tumor growth in vivo. Collagen I and other extracellular matrix compounds were pivotal for the functional MSC-CRC interaction. In conclusion, our data demonstrate a differential interaction of MSC with CRC cells of different mutational background. Our study is the first to show that MSC specifically compared to normal fibroblasts impact early xenograft growth of distinct α-catenin deficient CRC cells possibly through secretion of extracellular matrix. This mechanism could serve as a future target for therapy and metastasis prevention.
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin IV, Hämatologie und Onkologie, Universitätsklinikum Halle, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Widder
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin IV, Hämatologie und Onkologie, Universitätsklinikum Halle, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Lützkendorf
authors.affiliation: Institut für Pharmazie, Institutsbereich Pharmazeutische Technologie und Biopharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Caysa
authors.affiliation: Institut für Medizinische Epidemiologie, Biometrie und Informatik, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Unverzagt
authors.affiliation: Institut für Pathologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.affiliation: Institut für Pharmazie, Institutsbereich Pharmazeutische Chemie und Klinische Pharmazie, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Benndorf
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin IV, Hämatologie und Onkologie, Universitätsklinikum Halle, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin IV, Hämatologie und Onkologie, Universitätsklinikum Halle, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin IV, Hämatologie und Onkologie, Universitätsklinikum Halle, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Universitätsklinik und Poliklinik für Innere Medizin IV, Hämatologie und Onkologie, Universitätsklinikum Halle, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Müller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000473:pathology*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D019012:Integrin beta1
keywords: CRC; MSC; growth promotion; tumor-stroma-interactions; β1-integrin