title: Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors.
abstract: Mesenchymal stromal cells (MSCs) are inherently tumor homing and can be isolated, expanded, and transduced, making them viable candidates for cell therapy. This tumor tropism has been used to deliver anticancer therapies to various tumor models. In this study, we sought to discover which molecules are the key effectors of human MSC tumor homing in vitro and using an in vivo murine model. In this study, we discover a novel role for macrophage migration inhibitory factor (MIF) as the key director of MSC migration and infiltration toward tumor cells. We have shown this major role for MIF using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Additionally, we demonstrate physical interaction between MIF and three receptors: CXCR2, CXCR4, and CD74. CXCR4 is the dominant receptor used by MIF in the homing tumor context, although some signaling is observed through CXCR2. We demonstrate downstream activation of the MAPK pathway necessary for tumor homing. Importantly, we show that knockdown of either CXCR4 or MIF abrogates MSC homing to tumors in an in vivo pulmonary metastasis model, confirming the in vitro two-dimensional and three-dimensional assays. This improved understanding of MSC tumor tropism will further enable development of novel cellular therapies for cancers.
authors.affiliation: Lungs for Living Research Centre, Division of Medicine, University College London, London WC1E 6JF, United Kingdom; s.janes@ucl.ac.uk.
authors.forename: Sofia
authors.initials: S
authors.lastname: Lourenco
authors.affiliation: Lungs for Living Research Centre, Division of Medicine, University College London, London WC1E 6JF, United Kingdom;
authors.forename: Vitor H
authors.initials: VH
authors.lastname: Teixeira
authors.affiliation: Lungs for Living Research Centre, Division of Medicine, University College London, London WC1E 6JF, United Kingdom; University College London Centre of Advanced Biomedical Imaging, University College London, London WC1E 6DD, United Kingdom;
authors.forename: Tammy
authors.initials: T
authors.lastname: Kalber
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College London, London WC1E 6JF, United Kingdom; and.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Jose
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, CB2 0XY, United Kingdom.
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
authors.affiliation: Lungs for Living Research Centre, Division of Medicine, University College London, London WC1E 6JF, United Kingdom;
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D017077:Culture Media, Conditioned; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; C045084:invariant chain; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2