Abstract
Osteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvβ3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells through its interaction with its specific receptor, C-C chemokine receptor type 5 (CCR5). Analysis of mRNA expression in human osteosarcoma tissue identified upregulated levels of CCL4, integrin αv and β3 expression. Similarly, an analysis of records from the Gene Expression Omnibus (GEO) dataset showed that CCL4 was upregulated in human osteosarcoma tissue. Importantly, the expression of both CCL4 and integrin αvβ3 correlated positively with osteosarcoma clinical stages and lung metastasis. Analysis of osteosarcoma cell lines identified that CCL4 promotes integrin αvβ3 expression and cell migration by activating the focal adhesion kinase (FAK), protein kinase B (AKT), and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling pathways, which can downregulate microRNA-3927-3p expression. Pharmacological inhibition of CCR5 by maraviroc (MVC) prevented increases in integrin αvβ3 expression and cell migration. This study is the first to implicate CCL4 as a potential target in the treatment of metastatic osteosarcoma.
Highlights
Levels of C-C motif ligand 4 (CCL4) expression were higher in osteosarcoma tissue than in normal bone tissue (Figure 1A–C), and significant associations were observed with clinical disease stages (Figure 1A,B)
Analysis of Gene Expression Omnibus (GEO) Dataset osteosarcoma tissue samples revealed increased levels of CCL4 compared with levels in primary osteoblasts (Figure 1D), especially in lung metastatic osteosarcoma tissue (Figure 1E)
These findings suggest that CCL4 is overexpressed in osteosarcoma and is associated with lung metastasis
Summary
Osteosarcoma, the most common primary bone malignancy, is renowned for its high propensity for metastasis [1]. As many as 20% of patients present with lung metastases at their initial diagnosis; around 40% of patients develop metastases after their initial presentation despite the best available treatment [2]. Whereas 5-year overall survival is around 50–80% in patients with localized osteosarcoma [1], only 27% of patients with metastatic disease survive longer than 5 years [3]. No agents exist that can successfully cure metastatic osteosarcoma, so it is essential that such treatment is developed [4]
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