RRC ID 63629
著者 Fujikawa M, Koma YI, Hosono M, Urakawa N, Tanigawa K, Shimizu M, Kodama T, Sakamoto H, Nishio M, Shigeoka M, Kakeji Y, Yokozaki H.
タイトル Chemokine (C-C Motif) Ligand 1 Derived from Tumor-Associated Macrophages Contributes to Esophageal Squamous Cell Carcinoma Progression via CCR8-Mediated Akt/Proline-Rich Akt Substrate of 40 kDa/Mammalian Target of Rapamycin Pathway.
ジャーナル Am J Pathol
Abstract Tumor-associated macrophages (TAMs) promote tumor progression. The number of infiltrating TAMs is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) patients; however, the mechanism underlying this phenomenon is unclear. Our previous cDNA microarray analysis had revealed that the expression of chemokine (C-C motif) ligand 1 (CCL1) is up-regulated in peripheral blood monocyte-derived macrophages stimulated using conditioned media from ESCC cells (TAM-like macrophages). In this study, we evaluated the role of CCL1 in ESCC progression. We confirmed that CCL1 is overexpressed in TAM-like macrophages, and that CCR8, a CCL1 receptor, is expressed on ESCC cell surface. TAM-like macrophages significantly enhanced the motility of ESCC cells, and neutralizing antibodies against CCL1 or CCR8 suppressed this increased motility. Recombinant human CCL1 promoted ESCC cell motility via the Akt/proline-rich Akt substrate of 40 kDa/mammalian target of rapamycin pathway. Phosphatidylinositol 3-kinase or Akt inhibitors, CCR8 silencing, and neutralizing antibody against CCR8 could significantly suppress these effects. The overexpression of CCL1 in stromal cells or CCR8 in ESCC cells was significantly associated with poor overall survival (P = 0.002 or P = 0.009, respectively) and disease-free survival (P = 0.009 or P = 0.047, respectively) in ESCC patients. These results indicated that the interaction between stromal CCL1 and CCR8 on cancer cells promotes ESCC progression via the Akt/proline-rich Akt substrate of 40 kDa/mammalian target of rapamycin pathway, providing novel therapeutic targets.
巻・号 191(4)
ページ 686-703
公開日 2021-4-1
DOI 10.1016/j.ajpath.2021.01.004
PII S0002-9440(21)00005-5
PMID 33460563
MeSH Carcinoma, Squamous Cell / pathology Cell Movement / physiology Esophageal Neoplasms / metabolism* Esophageal Neoplasms / pathology Esophageal Squamous Cell Carcinoma / metabolism* Esophageal Squamous Cell Carcinoma / pathology Humans Ligands Macrophages / metabolism Proto-Oncogene Proteins c-akt / metabolism* Receptors, CCR8 / metabolism* Sirolimus / metabolism* Sirolimus / pharmacology TOR Serine-Threonine Kinases / metabolism Tumor-Associated Macrophages / metabolism Tumor-Associated Macrophages / pathology
IF 3.491
リソース情報
ヒト・動物細胞 TE-8(RCB2098) TE-9(RCB1988) TE-15(RCB1951)