CXCL8 derived from tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression by promoting migration and invasion of cancer cells
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Masayoshi Hosono1,2, Yu-Ichiro Koma1, Nobuhisa Takase1,2, Naoki Urakawa1,2, Nobuhide Higashino1,2, Kazuki Suemune1, Himiko Kodaira1, Mari Nishio1, Manabu Shigeoka1, Yoshihiro Kakeji2 and Hiroshi Yokozaki1
1Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan
2Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan
Hiroshi Yokozaki, email: [email protected]
Keywords: CXCL8; esophageal squamous cell carcinoma; tumor-associated macrophage; tumor progression; tumor microenvironment
Received: July 19, 2017 Accepted: October 28, 2017 Published: November 20, 2017
Tumor-associated macrophages (TAMs) are involved in tumor progression and poor prognosis in several malignancies. We previously demonstrated the interaction between high numbers of infiltrating TAMs and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To investigate the significance of TAMs in ESCC, we conducted a cDNA microarray analysis of peripheral blood monocytes (PBMo)-derived macrophages and PBMo-derived macrophages stimulated with conditioned media of TE-series ESCC cell lines (TAM-like PBMo-derived macrophages). C-X-C motif chemokine ligand 8 (CXCL8) was up-regulated in the TAM-like PBMo-derived macrophages. Here we confirmed a high expression level of CXCL8 in TAM-like PBMo-derived macrophages and the expression of CXCR1/2, known as CXCL8 receptors, in TE-series ESCC cell lines. Recombinant human CXCL8 induced the ESCC cell lines’ migration and invasion by the phosphorylation of Akt and Erk1/2. In indirect co-cultures, not only signal pathway inhibitors but also neutralizing antibodies against CXCL8, CXCR1 and CXCR2 suppressed these phenotypes induced by TAM-like PBMo-derived macrophages. Immunohistochemical analysis of 70 resected ESCC samples showed that high expression levels of CXCL8 in ESCC tissues were significantly associated with lymph node metastasis and poor prognosis. These results suggest that CXCL8 up-regulated in the microenvironment may contribute to ESCC progression by promoting cancer cells’ migration and invasion.
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