title: Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib.
abstract: Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor-initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met(+) tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB.
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Aleksandrowicz
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Fan
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schönsiegel
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Experimental Orthopedics, Orthopedic University Hospital, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Sähr
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Gladkich
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Mattern
authors.affiliation: Department of Experimental Orthopedics, Orthopedic University Hospital, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Depeweg
authors.affiliation: Department of Experimental Orthopedics, Orthopedic University Hospital, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Lehner
authors.affiliation: Department of Experimental Orthopedics, Orthopedic University Hospital, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Fellenberg
authors.affiliation: Department of Molecular OncoSurgery, General, Visceral and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Herr
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D005260:Female; D005306:Fertilization; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010063:Ovum / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D014408:Biomarkers, Tumor; D011725:Pyridines; C558660:cabozantinib; D019859:Proto-Oncogene Proteins c-met