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. 2013 Sep 17;109(6):1579-85.
doi: 10.1038/bjc.2013.482. Epub 2013 Sep 3.

CXCR7-mediated progression of osteosarcoma in the lungs

E Goguet-Surmenian  1 , P Richard-Fiardo, E Guillemot, M Benchetrit, A Gomez-Brouchet, P Buzzo, B Karimdjee-Soilihi, P Alemanno, J-F Michiels, A Schmid-Alliana, H Schmid-Antomarchi
Affiliations

CXCR7-mediated progression of osteosarcoma in the lungs

E Goguet-Surmenian et al. Br J Cancer. .

Abstract

Background: Osteosarcoma (OS) is the most frequent primary malignant bone tumour in children and adolescents with a high propensity for lung metastasis. Chemokines and chemokine receptors have been described to have an important role in many malignancies including OS. The aim of this study was to investigate the expression of CXCR7 receptor in OS tissues and its role in the progression of the disease in the lungs.

Methods: Immunohistochemistry was used to study CXCR7 expression in primary tumours and metastatic tissues from patients with OS. Its contribution to tumour expansion in the lungs has been also assessed using animal models and synthetic-specific CXCR7 ligands.

Results: CXCR7 was expressed on human primary bone tumours and on lung metastases. Its expression was predominantly located on tumour-associated blood vessels. Mice challenged with OS cells and systematically treated with synthetic CXCR7 ligands presented a significant reduction of lung nodules compared with untreated mice.

Conclusion: This study shows that CXCR7 has a critical role in OS progression in the lungs, where are expressed CXCR7 ligands, especially CXCL12. Moreover, we highlight that synthetic CXCR7 ligands could represent a powerful therapeutic tool to impede lung OS progression.

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Figures

Figure 1
Figure 1
Expression of CXCR7 and its ligands in murine and human tissues. (A, B) Immunohistochemical analysis of CXCR7 expression on human biopsies of primary skeletal OS (A) and lung metastatic lesions (B). The filled arrows show CXCR7-stained tumour-associated vessels, whereas the open arrow signals CXCR7-stained OS cells. Magnifications × 400. (C) Flow cytometry investigation of surface CXCR7 expression on K7M2 and SaOS-LM7 cells. Grey histograms represent cells stained with the isotype-matched control antibody. Black histograms show cells stained with an anti-CXCR7 antibody. Panels are representative of two independent experiments. (D) CXCR7 immunostaining of lung sections from SaOS-LM7-bearing mice (upper panel). Spleen sections from nude mouse are used as CXCR7-positive tissue control (lower panel). Positive staining is depicted as brown. Magnification × 200. (E) Quantitative real-time PCR for the analysis of CXCR7 ligands expression in mouse healthy lungs. The relative expression levels of genes were calculated using 18S as a normalising gene and expressed as 1/ΔCT. The mean±s.e.m. of duplicate per condition is shown. Representative of three independent experiments.
Figure 2
Figure 2
Effects of CXCR7-targeted treatment in the prevention of OS lung development. (A) Schematic representation of the preventive CXCR7-targeted treatment. K7M2 cells were injected into the tail vein of mice pretreated with vehicle or CCX754 compound, as described in the Materials and Methods section. Fifteen days later, mice were killed for lung examination (n=10–14 mice per group). (B) Representative crude photographs of India ink-stained lungs harvested from vehicle-and CCX754-treated mice. (C) Extent of tumour development by recording the number of pulmonary nodules (left panel) and by measuring the cumulative tumour volume (right panel) in the lungs. Each dot represents the number or the cumulative volume of nodules for one mouse and the middle line represents the median values of each group of mice.
Figure 3
Figure 3
Effects of CXCR7-targeted treatment on pre-established K7M2 lung tumours. (A) Schematic representation of the curative CXCR7-targeted treatment. Mice were injected with K7M2 cells into the tail vein before receiving intraperitoneal injections of CCX771 or vehicle, as described in the Materials and Methods section. Fifteen days after injection of the K7M2 cells, mice were killed for lung examination (n=9–11 mice per group). (B) Representative crude photographs of the lungs of vehicle-treated and CCX771-treated tumour-bearing mice. (C) Extent of tumour development by recording the number of pulmonary nodules (left panel) and by measuring the cumulative tumour volume (right panel) in the lungs. Each dot represents the number or the cumulative volume of nodules for one mouse and the middle line represents the median values of each group of mice. (D) Representative haematoxylin/eosin staining of lungs from vehicle-treated and CCX771-treated tumour-bearing mice. Arrows show metastases. Magnifications × 40.
Figure 4
Figure 4
Effects of CXCR7-targeted treatment on pre-established SaOS-LM7 lung tumours. (A) Schematic representation of the curative CXCR7-targeted treatment. Mice were injected with SaOS-LM7 cells into the tail vein before receiving intraperitoneal injections of CCX771 or vehicle, as described in the Materials and Methods section. Ten weeks after injection of the SaOS-LM7 cells, mice were killed for lung examination (n=14 mice per group). (B) Representative crude photographs of the lungs of vehicle-treated and CCX771-treated tumour-bearing mice. (C) Extent of tumour development by recording the number of pulmonary nodules (left panel) and by measuring the cumulative tumour volume (right panel) in the lungs. Each dot represents the number or the cumulative volume of nodules for one mouse and the middle line represents the median values of each group of mice. (D) Representative haematoxylin/eosin staining of lungs from vehicle-treated and CCX771-treated tumour-bearing mice. Deep purple areas show metastases. Magnifications × 40.
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