| RRC ID |
83362
|
| 著者 |
Ishihara N, Koma YI, Omori M, Komatsu S, Torigoe R, Yokoo H, Nakanishi T, Yamanaka K, Azumi Y, Tsukamoto S, Kodama T, Nishio M, Shigeoka M, Yokozaki H, Fukumoto T.
|
| タイトル |
Chemokine (C-C Motif) Ligand 2/CCR2/Extracellular Signal-Regulated Kinase Signal Induced through Cancer Cell-Macrophage Interaction Contributes to Hepatocellular Carcinoma Progression.
|
| ジャーナル |
Am J Pathol
|
| Abstract |
Tumor-infiltrating macrophages, known as tumor-associated macrophages, play a crucial role in the tumor microenvironment. Herein, immunohistochemistry revealed that intratumoral CD68-positive macrophages are associated with poor prognosis and clinicopathologic factors in patients with hepatocellular carcinoma (HCC). Subsequently, an indirect co-culture system involving HCC cells and peripheral blood-derived macrophages was developed. cDNA microarray analysis revealed that chemokine (C-C motif) ligand 2 (CCL2) was highly expressed in HCC cells co-cultured with macrophages. CCL2 neutralization suppressed proliferation, migration, and phosphorylation of extracellular signal-regulated kinase (Erk) in HCC cells and macrophages enhanced through co-culture. In contrast, recombinant human CCL2 (rhCCL2) addition facilitated these malignant phenotypes and increased Erk phosphorylation levels in HCC cells and macrophages. The primary CCL2 receptor, CCR2, was expressed in HCC cells and macrophages and was up-regulated in co-cultured HCC cells. CCR2 inhibition suppressed malignant phenotypes and reduced phosphorylated levels of Erk enhanced by rhCCL2. Additionally, the inhibition of Erk signal suppressed rhCCL2-enhanced malignant phenotypes. Moreover, serum CCL2 levels were higher in patients with HCC than those in healthy donors. On the basis of immunohistochemistry, CCL2-positive cases with high CCR2 expression and phosphorylated Erk-positive cases exhibited poor survival outcomes. Therefore, CCL2 up-regulation through interactions between HCC cells and macrophages contributed to HCC progression, making the CCL2/CCR2/Erk signal a potential target for HCC treatment.
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| 巻・号 |
195(3)
|
| ページ |
589-608
|
| 公開日 |
2025-3-1
|
| DOI |
10.1016/j.ajpath.2024.12.007
|
| PII |
S0002-9440(24)00480-2
|
| PMID |
39756577
|
| PMC |
PMC12179538
|
| MeSH |
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / pathology
Cell Communication
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chemokine CCL2* / metabolism
Coculture Techniques
Disease Progression
Extracellular Signal-Regulated MAP Kinases* / metabolism
Female
Humans
Liver Neoplasms* / metabolism
Liver Neoplasms* / pathology
MAP Kinase Signaling System
Macrophages* / metabolism
Macrophages* / pathology
Male
Middle Aged
Receptors, CCR2* / metabolism
Signal Transduction
Tumor Microenvironment
Tumor-Associated Macrophages* / metabolism
Tumor-Associated Macrophages* / pathology
|
| IF |
3.491
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2
HuH-7 |
