Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

• Published in: Cellular & molecular immunology Vol. 10; no. 2; pp. 176 - 182
• Main Authors: Sun, Jintang, Feng, Alei, Chen, Songyu, Zhang, Yun, Xie, Qi, Yang, Meixiang, Shao, Qianqian, Liu, Jia, Yang, Qifeng, Kong, Beihua, Qu, Xun
• Format: Journal Article
• Language: English
• Published: China Nature Publishing Group 01.03.2013
• Subjects: Alternative splicing; Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; CD163 antigen; Cell activation; Cell differentiation; Cell Line, Tumor; Chemokine CCL2 - physiology; Expression vectors; Gene Expression Regulation, Neoplastic - immunology; Genetic Variation - immunology; Histocompatibility antigen HLA; Humans; IL-10; Immune Evasion - genetics; Interleukin 10; MCP-1; Mice; Mice, Nude; Monocyte chemoattractant protein 1; Monocytes; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; Osteopontin; Osteopontin - biosynthesis; Osteopontin - genetics; RNA Splicing - genetics; RNA Splicing - immunology; TNF-α; Transforming Growth Factor beta1 - physiology; Transforming growth factor-b1; Tumor cells; Tumor necrosis factor-α; Tumors; 乳腺肿瘤; 单核细胞; 变体; 细胞活化; 骨桥蛋白
• DOI: 10.1038/cmi.2012.67
• ISSN: 1672-7681

Osteopontin （OPN）, a multifunctional glycoprotein, has three transcripts that have distinct roles in tumors in vitro. Whether OPN transcripts have different functions in tumor processes in vivo is unclear. It has been reported that immune cell-derived OPN can promote tumor formation. We propose a hypothesis that tumor-derived OPN may facilitate tumor immune escape by affecting immune cell differentiation and function. In this study, we constructed lentiviral expression vectors of OPN transcripts and transfected them into the MCF-7 cell line. MCF-7 cells transfected with OPN transcripts were injected into the armpit of nude mice, and tumor growth was monitored. The results showed that all OPN transcripts promoted local tumor formation, but that there was no significant difference among transcripts. We also investigated the effect of the OPN expressed by tumor cells on monocyte differentiation by coculturing monocytes with tumor supernatant. We found OPN-c upregulated CD163 levels compared with OPN-a and OPN-b; however, none of the transcripts affected HLA-DR and CD206 levels. All OPN transcripts significantly inhibited TNF-α and enhanced IL-10 production by monocytes. Furthermore, we found that the overexpression of OPN transcripts significantly upregulated TGF-β1 and MCP-1 production by tumor cells. Using neutralizing antibody and recombinant cytokines, we found that OPN overexpressed by tumor cells regulates the production of TNF-α and IL-10 by monocytes partly via MCP-1 and TGF-β1, respectively. Collectively, our results show that OPN transcripts have no distinct role in breast cancer formation in vivo. We also demonstrate that OPN regulates the alternative activation of monocytes via TGF-β1 and MCP-1, which may represent an additional mechanism for tumor immune escape.