title: Breast cancer cells compete with hematopoietic stem and progenitor cells for intercellular adhesion molecule 1-mediated binding to the bone marrow microenvironment.
abstract: Adhesion-based cellular interactions involved in breast cancer metastasis to the bone marrow remain elusive. We identified that breast cancer cells directly compete with hematopoietic stem and progenitor cells (HSPCs) for retention in the bone marrow microenvironment. To this end, we established two models of competitive cell adhesion-simultaneous and sequential-to study a potential competition for homing to the niche and displacement of the endogenous HSPCs upon invasion by tumor cells. In both models, breast cancer cells but not non-tumorigenic cells competitively reduced adhesion of HSPCs to bone marrow-derived mesenchymal stromal cells (MSCs) in a tumor cell number-dependent manner. Higher adhesive force between breast cancer cells and MSCs, as compared with HSPCs, assessed by quantitative atomic force microscopy-based single-cell force spectroscopy could partially account for tumor cell mediated reduction in HSPC adhesion to MSCs. Genetic inactivation and blockade studies revealed that homophilic interactions between intercellular adhesion molecule 1 (ICAM-1) expressed on tumor cells and MSCs, respectively, regulate the competition between tumor cells and HSPCs for binding to MSCs. Moreover, tumor cell-secreted soluble ICAM-1(sICAM-1) also impaired HSPC adhesion via blocking CD18-ICAM-1 binding between HSPCs and MSCs. Xenotransplantation studies in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice revealed reduction of human HSPCs in the bone marrow via metastatic breast cancer cells. These findings point to a direct competitive interaction between disseminated breast cancer cells and HSPCs within the bone marrow micro environment. This interaction might also have implications on niche-based tumor support. Therefore, targeting this cross talk may represent a novel therapeutic strategy.
authors.affiliation: Department of Hematology/Oncology, Medical Clinic and Policlinic I, University Hospital, Dresden, Germany.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Dhawan
authors.affiliation: Institute of Biofunctional Polymer Materials, Leibniz Institute for Polymer Research, Max Bergmann Center of Biomaterials, Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Friedrichs
authors.affiliation: Department of Hematology/Oncology, Medical Clinic and Policlinic I, University Hospital, Dresden, Germany.|German Consortium for Translational Cancer Research (DKTK), Partner Site, Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany and.
authors.forename: Malte von
authors.initials: MV
authors.lastname: Bonin
authors.affiliation: German Consortium for Translational Cancer Research (DKTK), Partner Site, Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany and.
authors.forename: Elham Peshali
authors.initials: EP
authors.lastname: Bejestani
authors.affiliation: Institute of Biofunctional Polymer Materials, Leibniz Institute for Polymer Research, Max Bergmann Center of Biomaterials, Dresden, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Werner
authors.affiliation: Department of Hematology/Oncology, Medical Clinic and Policlinic I, University Hospital, Dresden, Germany.
authors.forename: Manja
authors.initials: M
authors.lastname: Wobus
authors.affiliation: Department of Clinical Pathobiochemistry, University Clinic, Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Department of Hematology/Oncology, Medical Clinic and Policlinic I, University Hospital, Dresden, Germany.|German Consortium for Translational Cancer Research (DKTK), Partner Site, Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
mesh_terms: D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018821:CD18 Antigens / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells; D051379:Mice; D009362:Neoplasm Metastasis; D011485:Protein Binding; D059016:Tumor Microenvironment / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D018821:CD18 Antigens; C573420:ICAM1 protein, human; D018799:Intercellular Adhesion Molecule-1