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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 3/2014

Open Access 01-03-2014 | Research Paper

CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice

Authors: Patrick Brennecke, Matthias J. E. Arlt, Carmen Campanile, Knut Husmann, Ana Gvozdenovic, Tiziana Apuzzo, Marcus Thelen, Walter Born, Bruno Fuchs

Published in: Clinical & Experimental Metastasis | Issue 3/2014

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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.
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Metadata
Title
CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice
Authors
Patrick Brennecke
Matthias J. E. Arlt
Carmen Campanile
Knut Husmann
Ana Gvozdenovic
Tiziana Apuzzo
Marcus Thelen
Walter Born
Bruno Fuchs
Publication date
01-03-2014
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 3/2014
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-013-9632-3

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