Abstract
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.
Highlights
The tumor microenvironment has important roles in tumor progression [1]
The C-X-C chemokine ligand 8 (CXCL8) mRNA expression was significantly up-regulated by TECM (TE-8, TE-9 and TE-15) compared to PBModerived macrophages and peripheral blood monocytes (PBMo)-derived macrophages stimulated by Het-1A CM (Figure 1A)
Immunofluorescence demonstrated that CXCL8 was strongly expressed in the cytoplasm of Tumor-associated macrophages (TAMs)-like PBModerived macrophages (TE-8, TE-9 and TE-15) compared to the PBMo-derived macrophages and PBMo-derived macrophages stimulated by Het-1A CM (Figure 1B)
Summary
The tumor microenvironment has important roles in tumor progression [1]. Macrophages are the main cellular component of the tumor microenvironment. Macrophages have two different functions; i.e., as tumor suppressive (M1) or tumor supportive (M2) cells. M2 macrophages, which express high interleukin (IL)-10 and low IL-12, play roles in the wound healing process, allergies, and pro-tumoral activity. They display the www.impactjournals.com/oncotarget specific receptors known as hemoglobin scavenger receptor (CD163), macrophage scavenger receptor I (CD204), and mannose receptor (CD206) [2, 3]. Tumorassociated macrophages (TAMs) polarize into the M2-like phenotype and are involved in tumor growth, invasion, angiogenesis and metastasis formation [4]. A high level of TAMs infiltrating into the tumor site is associated with poor prognosis [5,6,7,8]
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