scholarly journals HOXC6 Promotes Metastasis of MSI-H CRC via Interacting with M2 Macrophages

2020 ◽  
Author(s):  
lina qi ◽  
biting zhou ◽  
jiani chen ◽  
kailun xu ◽  
kailai wang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Cells ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Mesenchymal Transition

Abstract Background: HOXC6 was the most significantly upregulated gene in right-sided colon cancer (RCC) compared to left-sided colon cancer (LCC) according to our previous study. It is known that RCC has a higher immunogenicity than LCC because much higher prevalence of MSI-H samples, however, the role of HOXC6 acted in MSI-H tumors remains poorly understood. Methods: Expression datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to analyze the differential expression and prognostic role of HOXC6 in CRC. ELISA and qRT-PCR were performed to examine the association of HOXC6 and CCL2. Immunohistochemistry and immunofluorescence were performed to evaluate the correlation of HOXC6 and M2 macrophage infiltration. CCK8 and Transwell were used to evaluate the proliferation and migration of tumor cells in vitro.Results: HOXC6 was overexpressed in MSI-H CRC and associated with poor prognosis. Upregulation of CCL2 by HOXC6 could attract more M2 macrophage infiltration. IL6 secreted by M2 macrophages could induce epithelial-mesenchymal transition (EMT) of tumor cells by upregulating HOXC6. Overexpression of HOXC6 promoted the migration and invasion of CRC cells in vitro. Finally, inhibition of IL6/JAK pathway using ruxolitinib downregulated HOXC6 and suppressed invasion of HCT116 cells.Conclusion: Our study revealed that overexpression of HOXC6 attracted more M2 macrophage infiltration and the positive crosstalk between M2 macrophages and HOXC6-highly expressed tumor led to EMT and enhanced the migration ability of CRC, which offered a promising therapic target for treatment of MSI-H CRC.

scholarly journals Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Patients With Colon Cancer and to Assist in Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Boyang Xu ◽  
Ziqi Peng ◽  
Guanyu Yan ◽  
Ningning Wang ◽  
Moye Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
High Morbidity ◽  
Consensus Clustering ◽  
M2 Macrophages ◽  
Hub Genes

BackgroundColon cancer is a malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divided it into different subtypes to facilitate individualized treatment. With the rise in the use of immunotherapy, its value in the field of tumor has begun to emerge. From the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored the same.MethodsCibersort algorithm was used to analyze the level of immune cell infiltration in patients with colon cancer in The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network analysis (WGCNA), Consensus Clustering analysis, Lasso analysis, and univariate Kaplan–Meier analysis were used to screen and verify the hub genes associated with M2 macrophages. Principal component analysis (PCA) was used to establish the M2 macrophage-related score (M2I Score). The correlation between M2I Score and somatic cell variation and microsatellite instability (MSI) were analyzed. Furthermore, the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored.ResultsM2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were identified as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in colon adenocarcinoma was determined based on four hub genes. The M2I Score was positively correlated with the tumor mutation load (TMB). The M2I Score of the group with high instability of microsatellites was higher than that of the group with low instability of microsatellites and microsatellite-stable group. Combined with the Cancer Immunome Atlas database, we concluded that patients with high M2I Scores were more sensitive to programmed cell death protein 1 (PD-1) inhibitors and PD-1 inhibitors combined with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors. The low-rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.ConclusionFour prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score. Patients were divided into two subgroups: high M2I Score group and low M2I Score group. TMB, MSI, and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

scholarly journals Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Chi-Shuan Fan ◽  
Li-Li Chen ◽  
Tsu-An Hsu ◽  
Chia-Chi Chen ◽  
Kee Voon Chua ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Underlying Mechanism ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Mesenchymal Transition

Abstract Background Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication. Methods Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor. Results A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth. Conclusions EndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

scholarly journals Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma

2018 ◽  
Vol 51 (5) ◽  
pp. 2065-2072 ◽  
Author(s):  
Wei Bian ◽  
Hongfei Zhang ◽  
Miao Tang ◽  
Shaojun Zhang ◽  
Lichao Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Reporter Assays

Background/Aims: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. Methods: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. Results: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3’-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. Conclusion: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.

scholarly journals Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Colon Cancer Patients and Assist Immunotherapy

2021 ◽  
Author(s):  
Boyang Xu ◽  
Ziqi Peng ◽  
Guanyu Yan ◽  
Ningning Wang ◽  
Moye Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Microsatellite Instability ◽  
Cancer Patients ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
High Morbidity ◽  
M2 Macrophages ◽  
Hub Genes

Abstract Background: Colon cancer is a kind of malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divide it into different subtypes in order to achieve individualized treatment. With the rise of immunotherapy, its value in the field of tumor has initially emerged. Based on the above background, from the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored it.Methods: Cibersort was used to analyze the level of immune cell infiltration in colon cancer patients in the TCGA database. WGCNA, Consensus Clustering analysis, Lasso analysis, and univariate KM analysis were used to screen and verify the hub genes associated with M2 macrophages. PCA was used to establish the M2 macrophage-related score—M2I Score. The correlation between M2I Score and somatic cell variation and microsatellite instability were analysed. Furthermore the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored. Results: M2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were selected as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in COAD was constructed based on four hub genes. M2I Score was positively correlated with tumor mutation load (TMB). The M2I Score of MSI-H group was higher than that of MSI-L group and MSS group. Combine with the TCIA database, we concluded that patients with a high M2I Score were more sensitive to PD-1 inhibitors and PD-1 inhibitors combined with CTLA-4 inhibitors. The low rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.Conclusion: Four prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score and divided the patients into two subgroups: high M2I Score group and low M2I Score group. TMB, microsatellite instability and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

scholarly journals New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1676
Author(s):  
Monserrat Olea-Flores ◽  
Juan C. Juárez-Cruz ◽  
Miriam D. Zuñiga-Eulogio ◽  
Erika Acosta ◽  
Eduardo García-Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Patients With Cancer

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.

scholarly journals RACK1 Acts as a Potential Tumor Promoter in Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Xue-Yang Li ◽  
Yi Hu ◽  
Nian-Shuang Li ◽  
Jian-Hua Wan ◽  
Yin Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
The Cancer Genome Atlas ◽  
Biological Role ◽  
Tumor Promoter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Normal Tissues ◽  
Geo Dataset

Background. The receptor of activated protein kinase C 1 (RACK1) promotes the progression and invasion of several cancers. However, the role of RACK1 in the pathogenesis of colorectal cancer (CRC) has not been clearly defined. Herein, we aimed to investigate the biological role of RACK1 in CRC. Materials and Methods. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset were searched, and the expression of RACK1 in CRC tissues and adjacent normal tissues was evaluated. Immunohistochemical staining was performed to detect the expression of RACK1 in human CRC, adenoma, and normal tissues. Western blotting was used to detect the expression of RACK1 in human CRC cell lines. Functional assays, such as BrdU, colony formation, and wound healing and transwell invasion assays, were used to explore the biological role of RACK1 in CRC. Results. RACK1 was upregulated in CRC tissues compared with its expression in adjacent normal tissues in TCGA and the GEO dataset (P<0.05). Moreover, RACK1 was significantly overexpressed in CRC and adenoma tissues compared with its expression in normal tissues (P<0.05). Loss-of-function experiments showed that RACK1 promoted cell proliferation, migration, and invasion in vitro. Conclusions. Our data indicated that RACK1, as an oncogene, markedly promoted the progression of CRC, which suggested that RACK1 is a potential therapeutic target for CRC management.

scholarly journals Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial–mesenchymal transition

Oncogene ◽  
2015 ◽  
Vol 35 (24) ◽  
pp. 3151-3162 ◽  
Author(s):  
Q Zhang ◽  
T Wei ◽  
K Shim ◽  
K Wright ◽  
K Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Abstract Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241–5253). We investigated the mechanisms by which SPRY regulates epithelial–mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3′ untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1 −/− and Spry2 −/− double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis.

scholarly journals Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice

2017 ◽  
Vol 114 (43) ◽  
pp. 11494-11499 ◽  
Author(s):  
Yixiang Xu ◽  
Dong-Kee Lee ◽  
Zhen Feng ◽  
Yan Xu ◽  
Wen Bu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Lung Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Migration And Invasion ◽  
Small Subset ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Twist1 is an epithelial–mesenchymal transition (EMT)-inducing transcription factor (TF) that promotes cell migration and invasion. To determine the intrinsic role of Twist1 in EMT and breast cancer initiation, growth, and metastasis, we developed mouse models with an oncogene-induced mammary tumor containing wild-type (WT) Twist1 or tumor cell-specific Twist1 knockout (Twist1TKO). Twist1 knockout showed no effects on tumor initiation and growth. In both models with early-stage tumor cells, Twist1, and mesenchymal markers were not expressed, and lung metastasis was absent. Twist1 expression was detected in ∼6% of the advanced WT tumor cells. Most of these Twist1+ cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ERα and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin+/vimentin+). In advanced Twist1TKO tumor cells, Twist1 knockout largely diminished the expression of the aforementioned EMT-inducing TFs and basal and mesenchymal markers, but maintained the expression of the luminal markers. Circulating tumor cells (CTCs) were commonly detected in mice with advanced WT tumors, but not in mice with advanced Twist1TKO tumors. Nearly all WT CTCs coexpressed Twist1 with other EMT-inducing TFs and both epithelial and mesenchymal markers. Mice with advanced WT tumors developed extensive lung metastasis consisting of luminal tumor cells with silenced Twist1 and mesenchymal marker expression. Mice with advanced Twist1TKO tumors developed very little lung metastasis. Therefore, Twist1 is required for the expression of other EMT-inducing TFs in a small subset of tumor cells. Together, they induce partial EMT, basal-like tumor progression, intravasation, and metastasis.

scholarly journals Intrahepatic cholangiocarcinoma induced M2-polarized tumor-associated macrophages facilitate tumor growth and invasiveness

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hui Yuan ◽  
Zelong Lin ◽  
Yingjun Liu ◽  
Yuchuan Jiang ◽  
Ke Liu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Intrahepatic Cholangiocarcinoma ◽  
Normal Liver ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Murine Models ◽  
Tumor Associated Macrophages ◽  
Stat3 Signaling

Abstract Background M2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism. Methods Two progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system. Results We found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p < 0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial–mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC. Conclusion Our results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.

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