Global Gene Expression Profiling of Human Osteosarcomas Reveals Metastasis-Associated Chemokine Pattern

Abstract

Global gene expression analysis was performed on a panel of 23 osteosarcoma samples of primary and metastatic origin using the Applied Biosystems Gene Expression Array System. When comparing the primary tumours with the metastases, we found a significantly increased expression of genes involved in immunological processes, for example coding for cytokines and chemokines, in the metastatic samples. In addition, a comparison of the gene expression in primary samples from patients with or without metastases demonstrated that patients who later developed metastases had high expression of the chemokine (C-X-C motif) receptor 4 (CXCR4), similar to the metastatic samples, suggesting that these signal molecules play an important role in promoting metastasis. Increased knowledge of mechanisms and interactions between specified molecular signalling pathways in osteosarcomas could lead to a more rational strategy for development of targeted therapy.

Altered CXCL12 expression reveals a dual role of CXCR4 in osteosarcoma primary tumor growth and metastasis

“…These results showed that the percentage of CXCR4-expressing tumor cells in lung metastases, amounting to over 80 % independent of the expressed transgenes, was significantly higher than that observed in the primary tumors. These findings are in line with the results obtained from analyses of human OS primary tumor tissue and lung metastases that also showed higher expression of CXCR4 in lung metastases than in primary tumors (Oda et al 2006;Namlos et al 2012). These observations suggest that the expression of CXCR4 in OS cells settling in the lung is likely induced by regulatory molecules released from the lung microenvironment as recently proposed in studies of colon (Zeelenberg et al 2003) and lung cancers (Bertolini et al 2015).…”

“…In OS, however, the role of CXCR4 is contradictorily discussed. Several studies demonstrated upregulated expression of CXCR4 in lung metastases compared to primary tumors of OS patients and found CXCR4 expression associated with metastatic activity (Oda et al 2006;Lin et al 2011;Namlos et al 2012). Other studies, however, did not find evidence for a correlation between CXCR4 expression in primary tumor tissue and metastatic activity (Ma et al 2012) or patient survival (Baumhoer et al 2012).…”

Stress-Induced CXCR4 Promotes Migration and Invasion of Ewing Sarcoma

“…Chemokine (C-X-C motif) receptor 4 (CXCR4) is the most commonly expressed chemokine receptor in human cancer, and increased expression of the CXCR4-encoding transcript was recently found to be associated with metastatic disease in Ewing sarcoma-derived cell lines and tumors [4]. Significantly, high CXCR4 expression has also been associated with metastatic disease and poor outcome in many other human cancers of both epithelial and non-epithelial origin [3, 5], including breast cancer [6], pancreatic cancer [7], leukemia [8], rhabdomyosarcoma [9–11] and osteosarcoma [12–14]. Interestingly, the ligand for CXCR4, CXCL12 (SDF-1α), is highly expressed in common sites of Ewing sarcoma metastasis including lung, bone, and bone marrow, further implicating the potential role of this axis in mediating the distant spread of primary tumor cells.…”

Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization

“…Furthermore, Naml¿s et al report that infiltrating stroma (macrophages) could be the major source of chemokine expression in osteosarcoma [36]. ECFCs are found to be recruited into tumour environment as they are actively involved in tumour vascularization [17,18].…”