HGF/c-Met Signalling in the Tumor Microenvironment

Zambelli, Alberto; Biamonti, Giuseppe; Amato, Antonella

doi:10.1007/978-3-030-47189-7_2

Cited by 20 publications

(9 citation statements)

References 101 publications

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“…We next explored how upregulation of B3GALT4 induced CXCL9/CXCL10 expression. The HGF/c-Met pathway in lipid rafts plays a significant role in the tumor microenvironment [ 38 , 39 ]. It has recently been reported that the clustering of GD2 activates c-Met [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

B3GALT4 remodels the tumor microenvironment through GD2-mediated lipid raft formation and the c-met/AKT/mTOR/IRF-1 axis in neuroblastoma

Sha

Liu

Yang

et al. 2022

J Exp Clin Cancer Res

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Background Beta-1,3-galactosyltransferase-4 (B3GALT4) plays a critical regulatory role in tumor biology. However, the role of B3GALT4 in modulating the tumor microenvironment (TME) of neuroblastoma (NB) remains unknown. Methods Public datasets and clinical NB samples were collected to evaluate the expression and clinical significance of GD2 and B3GALT4 in NB patients. CCK-8, colony formation, and transwell assays and experiments in tumor-bearing mouse models were conducted to investigate the function of B3GALT4. Flow cytometry, ELISA, immunohistochemistry, immunofluorescence, western blotting, and chemotaxis assays were conducted to ascertain the immunomodulatory mechanism of B3GALT4. The combined therapeutic effect of the lipid raft inhibitor MβCD and anti-GD2 mAb was validated in a murine model of NB. Results GD2 was overexpressed in NB tissues and high expression of GD2 was associated with poor prognosis in NB patients. B3GALT4 was downregulated in NB tissues, and low expression of B3GALT4 indicated poor prognosis in NB patients. Silencing B3GALT4 significantly enhanced tumor progression both in vitro and in vivo. Meanwhile, the overexpression of B3GALT4 increased the recruitment of CD8+ T lymphocytes via the chemokines CXCL9 and CXCL10. Additionally, B3GALT4 regulated NB-cell GD2 expression and lipid raft formation. Mechanistically, B3GALT4 regulated the expression of CXCL9 and CXCL10 via the c-Met signaling in the lipid rafts and the downstream AKT/mTOR/IRF-1 pathway. The lipid raft inhibitor, MβCD, attenuated B3GALT4 deficiency-induced tumor progression and immune evasion. Last, MβCD combined with anti-GD2 mAb treatment significantly enhanced the antitumor effect and the infiltration of CD8+ T cells. Conclusions Upregulation of B3GALT4 promotes the secretion of CXCL9 and CXCL10 to recruit CD8+ T lymphocytes via the GD2-mediated lipid rafts and the c-Met/AKT/mTOR/IRF-1 pathway. Moreover, lipid raft inhibitors may enhance the efficacy of anti-GD2 immunotherapy for NB.

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Section: Resultsmentioning

confidence: 99%

B3GALT4 remodels the tumor microenvironment through GD2-mediated lipid raft formation and the c-met/AKT/mTOR/IRF-1 axis in neuroblastoma

Sha

Liu

Yang

et al. 2022

J Exp Clin Cancer Res

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“…c-MET is a receptor tyrosine kinase abnormally activated in many cancer types, such as renal, liver, head and neck, gastroesophageal, breast, and lung cancer ( Reis et al, 2018 ), and activates several intracellular signaling pathways including RAS-MAPK, PI3K-AKT, RAC1, and PAK to promote the progression of cancers ( Graveel et al, 2013 ). Moreover, HGF/c-MET signaling is also involved in the regulation of tumor microenvironment, immune infiltration, and immune response ( Hartmann et al, 2016 ; Reis et al, 2018 ; Chen et al, 2019 ; Li et al, 2019 ; Zambelli et al, 2021 ). Thus, TMPRSS2- HGF/c-MET axis could be a potential mechanism that participated in the correlation of TMPRSS2 expression with immune infiltration and prognosis in LUAD and BRCA.…”

Section: Discussionmentioning

confidence: 99%

TMPRSS2 Serves as a Prognostic Biomarker and Correlated With Immune Infiltrates in Breast Invasive Cancer and Lung Adenocarcinoma

Xiao

Shan

Niu

et al. 2022

Front. Mol. Biosci.

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TMPRSS2 is a transmembrane serine protease and plays a pivotal role in coronavirus disease 2019 (COVID-19). However, the correlation of TMPRSS2 with prognosis and immune infiltration in tumors has not yet been explored. Here, we analyzed the expression of TMPRSS2 in Oncomine and TIMER databases, the correlation between TMPRSS2 and overall survival in the PrognoScan, Kaplan-Meier plotter, and GEPIA databases. The association between TMPRSS2 and immune infiltration levels was investigated in the TIMER database. In addition, the prognosis of TMPRSS2 related to immune cells in cancers was analyzed. Quantitative real-time PCR (qRT-PCR) confirmed that TMPRSS2 was upregulated in lung adenocarcinoma (LUAD) and downregulated in breast invasive carcinoma (BRCA). We demonstrated that high TMPRSS2 expression was associated with favorable prognosis in LUAD, but it was associated with poor prognosis in BRCA. Interestingly, we found that TMPRSS2 expression was significantly correlated with immune infiltration of B cells, CD4+ T cells, macrophages, and dendritic cells in LUAD, and it was positively correlated with the infiltrating levels of CD8+ T cells, CD4+ T cells, neutrophils, and dendric cells in BRCA. Consistent with the prognosis of TMPRSS2 in LUAD and BRCA, the high expression level of TMPRSS2 has a favorable prognosis in enriched immune cells such as B cells, macrophages, and CD4+ T cells in LUAD, and it has a poor prognosis in CD4+ T cells and CD8+ T cells in BRCA. In conclusion, our results indicate that the prognosis of TMPRSS2 in LUAD and BRCA is significantly correlated with immune cells infiltration. Our study comprehensively revealed the relationship between the prognosis of TMPRSS2 in pan-cancers and tumor immunity.

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“…The results showed that hGF and PTX3 expression was downregulated and S100P expression was upregulated in LUAD, and that the expression of all the three was correlated with immune cell infiltration, suggesting that all the three gene could promote tumor progression. HGF, which is a cytokine produced by mesenchymal fibroblasts ( 29 ), could stimulate the migration, proliferation, migration, cell survival, morphogenesis, and angiogenesis of epithelial cells ( 30 ). It has been found that the HGF/c-Met signaling pathway may influence multiple aspects of tumor development by activating specific pathways that induce interactions between cancer cells and the tumor microenvironment in which they reside ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…HGF, which is a cytokine produced by mesenchymal fibroblasts ( 29 ), could stimulate the migration, proliferation, migration, cell survival, morphogenesis, and angiogenesis of epithelial cells ( 30 ). It has been found that the HGF/c-Met signaling pathway may influence multiple aspects of tumor development by activating specific pathways that induce interactions between cancer cells and the tumor microenvironment in which they reside ( 29 ). For example, in EGFR-mutant lung cancer, HGF may be involved in endogenous and acquired resistance to acid kinase inhibitors ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Three-Gene Signature Based on Epithelial-Mesenchymal Transition of Lung Adenocarcinoma Through Construction and Validation of a Risk-Prediction Model

et al. 2021

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Epithelial-mesenchymal transition (EMT) process, which is regulated by genes of inducible factors and transcription factor family of signaling pathways, transforms epithelial cells into mesenchymal cells and is involved in tumor invasion and progression and increases tumor tolerance to clinical interventions. This study constructed a multigene marker for lung predicting the prognosis of lung adenocarcinoma (LUAD) patients by bioinformatic analysis based on EMT-related genes. Gene sets associated with EMT were downloaded from the EMT-gene database, and RNA-seq of LUAD and clinical information of patients were downloaded from the TCGA database. Differentially expressed genes were screened by difference analysis. Survival analysis was performed to identify genes associated with LUAD prognosis, and overlapping genes were taken for all the three. Prognosis-related genes were further determined by combining LASSO regression analysis for establishing a prediction signature, and the risk score equation for the prognostic model was established using multifactorial COX regression analysis to construct a survival prognostic model. The model accuracy was evaluated using subject working characteristic curves. According to the median value of risk score, samples were divided into a high-risk group and low-risk group to observe the correlation with the clinicopathological characteristics of patients. Combined with the results of one-way COX regression analysis, HGF, PTX3, and S100P were considered as independent predictors of LUAD prognosis. In lung cancer tissues, HGF and PTX3 expression was downregulated and S100P expression was upregulated. Kaplan-Meier, COX regression analysis showed that HGF, PTX3, and S100P were prognostic independent predictors of LUAD, and high expressions of all the three were all significantly associated with immune cell infiltration. The present study provided potential prognostic predictive biological markers for LUAD patients, and confirmed EMT as a key mechanism in LUAD progression.

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HGF/c-Met Signalling in the Tumor Microenvironment

Cited by 20 publications

References 101 publications

B3GALT4 remodels the tumor microenvironment through GD2-mediated lipid raft formation and the c-met/AKT/mTOR/IRF-1 axis in neuroblastoma

B3GALT4 remodels the tumor microenvironment through GD2-mediated lipid raft formation and the c-met/AKT/mTOR/IRF-1 axis in neuroblastoma

TMPRSS2 Serves as a Prognostic Biomarker and Correlated With Immune Infiltrates in Breast Invasive Cancer and Lung Adenocarcinoma

Identification of a Three-Gene Signature Based on Epithelial-Mesenchymal Transition of Lung Adenocarcinoma Through Construction and Validation of a Risk-Prediction Model

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