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Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.

ABSTRACT: Cholangiocarcinoma (CCA) is an aggressive and multifactorial malignancy of the biliary tract. The carcinogenesis of CCA is associated with genomic and epigenetic abnormalities, as well as environmental effects. However, early clinical diagnosis and reliable treatment strategies of CCA remain unsatisfactory. Multiple compartments of the tumor microenvironment significantly affect the progression of CCA. Tumor-associated macrophages (TAMs) are a type of plastic immune cells that are recruited and activated in the CCA microenvironment, especially at the tumor invasive front and perivascular sites. TAMs create a favorable environment that benefits CCA growth by closely interacting with CCA cells and other stromal cells via releasing multiple protumor factors. In addition, TAMs exert immunosuppressive and antichemotherapeutic effects, thus intensifying the malignancy. Targeting TAMs may provide an improved understanding of, and novel therapeutic approaches for, CCA. This review focuses on revealing the interplay between TAMs and CCA.

SUBMITTER: Zhou M

PROVIDER: S-EPMC8134032 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.

Zhou Menghua M Wang Chaoqun C Lu Shounan S Xu Yanan Y Li Zihao Z Jiang Hongchi H Ma Yong Y

EBioMedicine 20210513

Cholangiocarcinoma (CCA) is an aggressive and multifactorial malignancy of the biliary tract. The carcinogenesis of CCA is associated with genomic and epigenetic abnormalities, as well as environmental effects. However, early clinical diagnosis and reliable treatment strategies of CCA remain unsatisfactory. Multiple compartments of the tumor microenvironment significantly affect the progression of CCA. Tumor-associated macrophages (TAMs) are a type of plastic immune cells that are recruited and ...[more]

PMID: 33993051

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Project description:BackgroundPatients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) have limited treatment options and poor prognosis. Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment and promote tumor stemness, proliferation, invasion and metastasis. Evidence suggested that transthyretin (TTR) influenced the prolifetation and invasion functions of different tumors and play an essential role in the tumor microenvironment.AimsTo investigate the involvement of TTR in TAMs affecting the invasion of cHCC-CCA.Methods and resultsData sets obtained from the Gene Expression Omnibus database were integrated. Differentially expressed genes (DEGs) were obtained using R software, and modules associated with cHCC-CCA were screened by weighted gene co-expression network analysis (WGCNA). Human THP-1 cells were induced to differentiate into macrophages and then co-cultured with HCCC9810 cells and tumor necrosis factor-α (TNF-α) to simulate the inflammatory microenvironment of cHCC-CAA. In addition, small interfering RNA against TTR was transfected into HCCC9810 cells, and recombinant TTR and ERK and AKT-specific inhibitors were added to HCCC9810 cells, respectively; after that, the levels of NF-κB protein and phosphorylated ERK and AKT were measured. The invasive abilities of HCCC9810 cells were also tested. One hundred forty-five DEGs were associated with cHCC-CCA, of which TTR was up-regulated. Turquoise modules containing TTR in WGCNA were most significantly associated with cHCC-CCA. TTR was highly expressed in HCCC9810 compared to Huh-28. HCCC9810 showed enhanced invasive capacity after co-culture with TNF-α + macrophages (p < .05). After interfering with TTR, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB, p-ERK1/2, and p-AKT (p < .05). After treating HCCC9810 with ERK and AKT-specific inhibitors, the invasive ability of HCCC9810 was diminished, accompanied by decreased expression of NF-κB and TTR (p < .05).ConclusionTTR can promote the invasive ability of cHCC-CCA by regulating AKT/NF-κB and ERK pathways with the assistance of TAMs.

Dataset Information

Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.

Publications

Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.

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