title: CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice.
abstract: Current combined surgical and neo-adjuvant chemotherapy of primary metastatic osteosarcoma (OS) is ineffective, reflected by a 5-year survival rate of affected patients of less than 20 %. Studies in experimental OS metastasis models pointed to the CXCR4/CXCL12 homing axis as a novel target for OS metastasis-suppressive treatment. The present study investigated for the first time the CXCR4-blocking principle in a spontaneously metastasizing human 143B OS cell line-derived orthotopic xenograft mouse model. The highly metastatic 143B cells, unlike the parental non-metastatic HOS cells, express functional CXCR4 receptors at the cell surface, as revealed in this study by RT/PCR of gene transcripts, by FACS analysis with the monoclonal anti CXCR4 antibody 12G5 (mAb 12G5) and by CXCL12 time- and dose-dependent stimulation of AKT and ERK phosphorylation. A significantly (p < 0.05) higher CXCL12 dose-dependent chemotactic response of 143B compared to HOS cells in a Boyden chamber trans-well migration assay suggested a crucial role of the CXCL12/CXCR4 homing axis in 143B cell lung metastasis. Repetitive treatment of mice with 143B cell-derived intratibial tumors given intravenous bolus injections of mAb12G5 indeed inhibited significantly (p < 0.01) the number of X-gal-stainable lung micrometastases of lacZ-transduced 143B cells. Antibody treatment had also a mild inhibitory effect on primary tumor growth associated with remarkably less osteolysis, but it did not affect the number of developing lung macrometastases. In conclusion, these results demonstrate considerable potential of high-affinity CXCR4-blocking agents for OS tumor cell homing suppressive treatment in metastasizing OS complementary to current (neo)-adjuvant chemotherapy.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, 8008, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brennecke
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Carmen
authors.initials: C
authors.lastname: Campanile
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.forename: Ana
authors.initials: A
authors.lastname: Gvozdenovic
authors.forename: Tiziana
authors.initials: T
authors.lastname: Apuzzo
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D019718:Receptors, CXCR4 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4