Expression of the Chemokine Receptor CXCR7 in CXCR4-Expressing Human 143B Osteosarcoma Cells Enhances Lung Metastasis of Intratibial Xenografts in SCID Mice

Patrick Brennecke,Carmen Campanile,Elisabetta Cameroni,Knut Husmann,Ana Gvozdenovic,Felix Ehrensperger,Marcus Thelen,Walter Born,Roman Muff,Bruno Fuchs,Nathalie Holzwarth,Matthias J E Arlt,Jeffrey K Harrison

doi:10.1371/journal.pone.0074045

Patrick Brennecke, Carmen Campanile + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0074045

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Journal: PloS one	Publication Date: Sep 10, 2013
Citations: 26	License type: CC BY 4.0

Affiliation: Universitätsklinik Balgrist, University of Zurich

Abstract

More effective treatment of metastasizing osteosarcoma with a current mean 5-year survival rate of less than 20% requires more detailed knowledge on mechanisms and key regulatory molecules of the complex metastatic process. CXCR4, the receptor of the chemokine CXCL12, has been reported to promote tumor progression and metastasis in osteosarcoma. CXCR7 is a recently deorphanized CXCL12-scavenging receptor with so far not well-defined functions in tumor biology. The present study focused on a potential malignancy enhancing function of CXCR7 in interaction with CXCR4 in osteosarcoma, which was investigated in an intratibial osteosarcoma model in SCID mice, making use of the human 143B osteosarcoma cell line that spontaneously metastasizes to the lung and expresses endogenous CXCR4. 143B osteosarcoma cells stably expressing LacZ (143B-LacZ cells) were retrovirally transduced with a gene encoding HA-tagged CXCR7 (143B-LacZ-X7-HA cells). 143B-LacZ-X7-HA cells co-expressing CXCR7 and CXCR4 exhibited CXCL12 scavenging and enhanced adhesion to IL-1β-activated HUVEC cells compared to 143B-LacZ cells expressing CXCR4 alone. SCID mice intratibially injected with 143B-LacZ-X7-HA cells had significantly (p<0.05) smaller primary tumors, but significantly (p<0.05) higher numbers of lung metastases than mice injected with 143B-LacZ cells. Unexpectedly, 143B-LacZ-X7-HA cells, unlike 143B-LacZ cells, also metastasized with high incidence to the auriculum cordis. In conclusion, expression of the CXCL12 scavenging receptor CXCR7 in the CXCR4-expressing human 143B osteosarcoma cell line enhances its metastatic activity in intratibial primary tumors in SCID mice that predominantly metastasize to the lung and thereby closely mimic the human disease. These findings point to CXCR7 as a target, complementary to previously proposed CXCR4, for more effective metastasis-suppressive treatment in osteosarcoma.

Highlights

Osteosarcoma (OS) is the most common primary bone tumor in young adolescents [1]
Time-dependent uptake of the three ligands was only observed in 143B-LacZ-HA-X7 cells, but not in 143BLacZ-EV cells lacking CXCR7 (Figure 2A, B and movie S1 “CXCL12 -Venus uptake in 143B cells transduced with CXCR7” and movie S2 “CXCL12-Venus uptake transduced with an empty vector construct”, supporting information)
All these parameters together result in CXCR7-mediated ligand internalisation that largely predominates that of CXCR4 under the experimental conditions used in this study

Summary

Introduction

Osteosarcoma (OS) is the most common primary bone tumor in young adolescents [1]. It occurs with an incidence of approximately 3 cases per million people per year. The survival of OS patients undergoing surgery and radiotherapy alone is poor [2]. Multi-agent chemotherapy increased the 5-year overall survival of patients with localized disease to between 60 and 70% [3]. The survival of patients with metastatic disease, remains poor with survival rates ranging from 11 to 20%. Metastasis is the major cause of death in OS [4,5]

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