RRC ID 62865
著者 Kodama T, Koma YI, Arai N, Kido A, Urakawa N, Nishio M, Shigeoka M, Yokozaki H.
タイトル CCL3-CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways.
ジャーナル Lab Invest
Abstract Tumor-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.
巻・号 100(9)
ページ 1140-1157
公開日 2020-9-1
DOI 10.1038/s41374-020-0441-4
PII 10.1038/s41374-020-0441-4
PMID 32457351
PMC PMC7438203
MeSH Aged Carcinoma, Squamous Cell / genetics* Carcinoma, Squamous Cell / metabolism Cell Line, Tumor Cell Movement / genetics Chemokine CCL3 / genetics* Chemokine CCL3 / metabolism Disease Progression Esophageal Neoplasms / genetics* Esophageal Neoplasms / metabolism Female Gene Expression Profiling / methods Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate MAP Kinase Signaling System / genetics* Macrophages / metabolism Macrophages / pathology Male Middle Aged Monocytes / metabolism Monocytes / pathology Neoplasm Invasiveness Proto-Oncogene Proteins c-akt / genetics* Proto-Oncogene Proteins c-akt / metabolism Receptors, CCR5 / genetics* Receptors, CCR5 / metabolism
IF 4.197
リソース情報
ヒト・動物細胞 TE-8(RCB2098) TE-9(RCB1988) TE-15(RCB1951)