CXCR7-mediated progression of osteosarcoma in the lungs

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. Despite significant improvements made over the past several decades in the therapeutic approach of OS, patients with metastases still have a very poor prognosis (less than 20% long-term survival). Osteosarcoma metastasises most commonly to the lungs, and pulmonary metastases are generally thought to be associated with a poor patient outcome (Aljubran et al, 2009). Of the many factors involved in tumorigenesis, the chemokine/chemokine-receptor system has a critical role in tumour initiation, promotion and progression. Many cancers have a complex chemokine network that influences the immune cells infiltration of a tumour, as well as growth, survival and migration of tumour cells, and angiogenesis (Johrer et al, 2008; O'Hayre et al, 2008). Many studies have shown that the chemokine CXCL12 and its receptor CXCR4 are critical components in the regulation of tumour spread and metastasis in several types of cancer (O'Hayre et al, 2008). CXCR4 expression was previously shown in OS, but the correlation between CXCR4 level and OS prognosis is still debated (Oda et al, 2006; Lin et al, 2011; Baumhoer et al, 2012). Nevertheless, human and murine OS cell lines have been reported to express CXCR4 and, using animal models of OS, it was demonstrated that the inhibition of this chemokine receptor reduces the tumour progression in the lungs (Perissinotto et al, 2005; Kim et al, 2008). Besides CXCR4, CXCL12 has been shown to exhibit a high affinity to the receptor CXCR7/RDC-1 (Balabanian et al, 2005; Burns et al, 2006). The expression of CXCR7 has been reported in a variety of tumour cell lines and human tumour samples (Burns et al, 2006; Miao et al, 2007; Meijer et al, 2008; Wang et al, 2008; Calatozzolo et al, 2010; Grymula et al, 2010; Hattermann et al, 2010; Kollmar et al, 2010; Luker et al, 2010; Miekus et al, 2010; Sun et al, 2010; Zheng et al, 2010; Guillemot et al, 2012). Moreover, tumour growth and aggressiveness are often correlated with the alteration of the receptor expression (Bennani-Baiti et al, 2010; D'Alterio et al, 2010; Grymula et al, 2010). A number of these studies have reported the critical role of CXCR7 in tumour vascular formation, angiogenesis and growth promotion of various cancers in vivo (Burns et al, 2006; Miao et al, 2007; Meijer et al, 2008; Wang et al, 2008; Kollmar et al, 2010; Guillemot et al, 2012). However, the role of CXCR7 in OS has not yet been clearly evaluated. The present study was carried out to assess the contribution of CXCR7 receptor in the pulmonary expansion of OS. First, we investigated whether CXCR7 was expressed in OS cells and tissues of human and murine origins. Then, we explored whether the interactions between CXCR7 and its ligands are critical components for OS progression in the lungs. To test this hypothesis, experimental lung tumours of OS as well as specific synthetic CXCR7 ligands were used. Our results indicate that CXCR7 mainly expressed on tumour-associated vessels can regulate OS progression in the lungs, where are expressed CXCR7 ligands, and thus could have a critical role in the metastatic process of OS.