Abstract
AbstractTumor-associated macrophages (TAMs) contribute to the progression and mortality of various malignancies. We reported that high numbers of infiltrating TAMs were significantly associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma (ESCC). In our previous investigation of TAMs' actions in ESCC, we compared gene expression profiles between peripheral blood monocyte (PBMo)-derived macrophages and TAM-like macrophages stimulated with conditioned media of ESCC cell lines. Among the upregulated genes in the TAM-like macrophages, we focused on CC chemokine ligand 3 (CCL3), which was reported to contribute to tumor progression in several malignancies. Herein, we observed that not only TAMs but also ESCC cell lines expressed CCL3. A CCL3 receptor, CC chemokine receptor 5 (CCR5) was expressed in the ESCC cell lines. Treating the ESCC cell lines with recombinant human (rh)CCL3 induced the phosphorylations of Akt and ERK, which were suppressed by CCR5 knockdown. Migration and invasion of ESCC cells were promoted by treatment with rhCCL3 and co-culture with TAMs. TAMs/rhCCL3-promoted cell migration and invasion were suppressed by inhibition of the CCL3–CCR5 axis, PI3K/Akt, and MEK/ERK pathways. Treatment with rhCCL3 upregulated MMP2 and VEGFA expressions in ESCC cell lines. Our immunohistochemical analysis of 68 resected ESCC cases showed that high expression of CCL3 and/or CCR5 in ESCC tissues was associated with poor prognosis. High CCR5 expression was associated with deeper invasion, presence of vascular invasion, higher pathological stage, higher numbers of infiltrating CD204+ TAMs, and higher microvascular density. High expression of both CCL3 and CCR5 was an independent prognostic factor for disease-free survival. These results suggest that CCL3 derived from both TAMs and cancer cells contributes to the progression and poor prognosis of ESCC by promoting cell migration and invasion via the binding of CCR5 and the phosphorylations of Akt and ERK. The CCL3–CCR5 axis could become the target of new therapies against ESCC.The authors. show that CCL3 derived from both tumor-associated macrophages and esophageal squamous cell carcinoma (ESCC) cells promotes cell migration and invasion of ESCC cells via binding CCR5. High expression of CCL3 and/or CCR5 associates with poor prognosis in ESCC patients. CCL3–CCR5 axis could be a specific target of anti-cancer therapy.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, JapanDivision of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, JapanWorldwide, esophageal cancer was the seventh most common cancer and the sixth leading cause of cancer-related deaths, with an estimated 572,000 new cases (3% of all cancers) and 509,000 deaths (5% of all cancers) in 2018 [1]
Compared with the CC chemokine ligand 3 (CCL3) mRNA expression level in the peripheral blood monocyte (PBMo)-derived Tumor-associated macrophages (TAMs)-like macrophages (1.0 ± 0.0-folds), the expression levels were significantly higher in the PBMo-derived TAM-like macrophages polarized by TE-8CM (TAM8 cells, 1.7 ± 0.1fold, p = 0.002), TE-9CM (TAM9 cells, 1.6 ± 0.1-fold, p = 0.018), and TE-15CM (TAM15 cells, 2.5 ± 0.2-fold, p = 0.002) (Fig. 1a)
The Enzyme-linked immunosorbent assay (ELISA) results showed that the CCL3 concentrations of the conditioned medium of TAM8 cells (451.0 ± 29.1 pg/ml, p < 0.001), TAM9 cells (873.0 ± 31.2 pg/ml, p < 0.001), and TAM15 cells (131.5 ± 17.3 pg/ml, p = 0.016) were significantly higher than that of the PBModerived macrophages (52.7 ± 11.3 pg/ml) (Fig. 1b)
Summary
Among the upregulated molecules in the TAM-like macrophages, we observed that growth differentiation factor 15, neural cell adhesion molecule, and CXC chemokine ligand 8 (CXCL8, known as IL-8) contribute to the tumor cell migration, progression, and poor prognosis of ESCC [13,14,15]. CCR5 expressed in neoplastic cells contributes to cell migration, invasion and tumor progression via the CCL3–CCR5 axis [20, 21, 23, 27], and via the CCL5–CCR5 axis in breast cancer, pancreatic cancer, salivary adenoid cystic carcinoma, Hodgkin lymphoma, and ESCC [31,32,33,34,35,36,37,38].
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