title: Functional Interference in the Bone Marrow Microenvironment by Disseminated Breast Cancer Cells.
abstract: Skeletal metastasis of breast cancer is associated with a poor prognosis and significant morbidity. Investigations in other solid tumors have revealed an impairment in hematopoietic function upon bone marrow invasion. However, the interaction between disseminated breast cancer cells and the bone marrow microenvironment which harbors them has not been addressed comprehensively. Employing advanced co-culture assays, proteomic studies, organotypic models as well as in vivo xenotransplant models, we define the consequences of this interaction on the stromal compartment of bone marrow, affected molecular pathways and subsequent effects on the hematopoietic stem and progenitor cells (HSPCs). The results showed a basic fibroblast growth factor (bFGF)-mediated, synergistic increase in proliferation of breast cancer cells and mesenchymal stromal cells (MSCs) in co-culture. The stromal induction was associated with elevated phosphoinositide-3 kinase (PI3K) signaling in the stroma, which coupled with elevated bFGF levels resulted in increased migration of breast cancer cells towards the MSCs. The perturbed cytokine profile in the stroma led to reduction in the osteogenic differentiation of MSCs via downregulation of platelet-derived growth factor-BB (PDGF-BB). Long term co-cultures of breast cancer cells, HSPCs, MSCs and in vivo studies in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice showed a reduced support for HSPCs in the altered niche. The resultant non- conducive phenotype of the niche for HSPC support emphasizes the importance of the affected molecular pathways in the stroma as clinical targets. These findings can be a platform for further development of therapeutic strategies aiming at the blockade of bone marrow support to disseminated breast cancer cells. Stem Cells 2016;34:2224-2235.
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: 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.
authors.forename: Malte
authors.initials: M
authors.lastname: von Bonin
authors.affiliation: Institute of Biofunctional Polymer Materials, Leibniz Institute for Polymer Research, Max Bergmann Center of Biomaterials, Dresden, Germany.|Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bray
authors.affiliation: Institute of Biofunctional Polymer Materials, Leibniz Institute for Polymer Research, Max Bergmann Center of Biomaterials, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Freudenberg
authors.affiliation: German Consortium for Translational Cancer Research (DKTK), partner site, Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Elham
authors.initials: E
authors.lastname: Pishali 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: German Consortium for Translational Cancer Research (DKTK), partner site, Dresden, Germany.|Department of Internal Medicine III, University Clinic, Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
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 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; D001853:Bone Marrow / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010012:Osteogenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D016222:Fibroblast Growth Factor 2; D019869:Phosphatidylinositol 3-Kinases
keywords: Basic fibroblast growth factor; Breast cancer; HSPC engraftment; Hematopoietic stem and progenitor cells; Mesenchymal stromal cells; Platelet derived growth factor