Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages

Marigo, Ilaria; Trovato, Rosalinda; Hofer, Francesca; Ingangi, Vincenzo; Desantis, Giacomo; Leone, Kevin; Sanctis, Francesco De; Ugel, Stefano; Canè, Stefania; Simonelli, Anna; Lamolinara, Alessia; Iezzi, Manuela; Fassan, Matteo; Rugge, Massimo; Boschi, Federico; Borile, Giulia; Eisenhaure, Thomas; Sarkizova, Siranush; Lieb, David; Hacohen, Nir; Azzolin, Luca; Piccolo, Stefano; Lawlor, Rita T.; Scarpa, Aldo; Carbognin, Luisa; Bria, Emilio; Bicciato, Silvio; Murray, Peter J.; Bronte, Vincenzo

doi:10.1158/2159-8290.cd-20-0036

Cited by 50 publications

(37 citation statements)

References 48 publications

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“…Emerging evidence suggests that tumor development, progression, and metastasis are influenced by dynamic changes in macrophage polarization. The defined subpopulations of macrophages are responsible for tumor-promoting activities [ 22 , 23 , 24 , 25 ]. Hence, targeting TAMs as novel immunotherapeutic strategies to stop tumor progression and metastasis has attracted increasing attention in recent years.…”

Section: Introductionmentioning

confidence: 99%

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Wang

Yung

Ngan

et al. 2021

IJMS

151

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Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

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Section: Introductionmentioning

confidence: 99%

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Wang

Yung

Ngan

et al. 2021

IJMS

151

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“…However, Chao et al suggested that upregulation of DAB2 could promote EMT by inhibiting E-cadherin while stimulating vimentin and phospho-FAK, indicating the significance of DAB2 in EMT ( Chao et al, 2012 ). In human gastric carcinomas, DAB2 + tumor-associated macrophages correlated with a poor clinical outcome ( Marigo et al, 2020 ). SERPINE1, an inhibitor of tissue plasminogen activator and urokinase, is a fibrinolytic inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Identification of an EMT-Related Gene Signature for Predicting Overall Survival in Gastric Cancer

et al. 2021

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BackgroundIt has been widely reported that epithelial-mesenchymal transition (EMT) is associated with malignant progression in gastric cancer (GC). Integration of the molecules related to EMT for predicting overall survival (OS) is meaningful for understanding the role of EMT in GC. Here, we aimed to establish an EMT-related gene signature in GC.MethodsTranscriptional profiles and clinical data of GC were downloaded from The Cancer Genome Atlas (TCGA). We constructed EMT-related gene signature for predicting OS by using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. Time-dependent receiver operating characteristic (ROC), Kaplan-Meier analysis were performed to assess its predictive value. A nomogram combining the prognostic signature with clinical characteristics for OS prediction was established. And its predictive power was estimated by concordance index (C-index), time-dependent ROC curve, calibration curve and decision curve analysis (DCA). GSE62254 dataset from Gene Expression Omnibus (GEO) was used for external validation. Quantitative real-time PCR (qRT-PCR) was used to detected the mRNA expression of the five EMT-related genes in human normal gastric mucosal and GC cell lines. To further understand the potential mechanisms of the signature, Gene Set Enrichment Analysis (GSEA), pathway enrichment analysis, predictions of transcription factors (TFs)/miRNAs were performed.ResultsA novel EMT-related gene signature (including ITGAV, DAB2, SERPINE1, MATN3, PLOD2) was constructed for OS prediction of GC. With external validation, ROC curves indicated the signature’s good performance. Patients stratified into high- and low-risk groups based on the signature yielded significantly different prognosis. Univariate and multivariate Cox regression suggested that the signature was an independent prognostic variable. Nomogram for prognostication including the signature presented better predictive accuracy and clinical usefulness than the similar model without risk score to some extent with external validation. The qRT-PCR assays suggested that high expression of the five EMT-related genes could be found in human GC cell lines compared with normal gastric mucosal cell line. GSEA and pathway enrichment analysis revealed that focal adhesion and ECM-receptor interaction might be the two important pathways to the signature.ConclusionOur EMT-related gene signature may have practical application as an independent prognostic factor in GC.

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“…Disabled homolog 2 (DAB2), as a member of the disable gene family, has been proven to function as a tumor suppressor that plays an crucial role in the occurrence and progression of various tumors ( Albertsen et al, 1996 ), including colorectal cancer ( Kleeff et al, 2002 ) and epithelial ovarian cancer ( Mok et al, 1998 ). Besides, DAB2 is highly expressed in tumor-infiltrating tumor-associated macrophages ( Marigo et al, 2020 ). DAB2 may attenuate the miR-106b promotion effect on HCC cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Identifying Dendritic Cell–Related Genes Through a Co-Expression Network to Construct a 12-Gene Risk-Scoring Model for Predicting Hepatocellular Carcinoma Prognosis

Huang

Jiang

Huang

et al. 2021

Front. Mol. Biosci.

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The prognostic prediction of hepatocellular carcinoma (HCC) is still challenging. Immune cells play a crucial role in tumor initiation, progression, and drug resistance. However, prognostic value of immune-related genes in HCC remains to be further clarified. In this study, the mRNA expression profiles and corresponding clinical information of HCC patients were downloaded from public databases. Then, we estimated the abundance of immune cells and identified the differentially infiltrated and prognostic immune cells. The weighted gene co-expression network analysis (WGCNA) was performed to identify immune-related genes in TCGA cohort and GEO cohort. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to establish a risk-scoring model in the TCGA cohort. HCC patients from the GSE14520 datasets were utilized for risk model validation. Our results found that high level of dendritic cell (DC) infiltration was associated with poor prognosis. Over half of the DC-related genes (58.2%) were robustly differentially expressed between HCC and normal specimens in the TCGA cohort. 17 differentially expressed genes (DEGs) were found to be significantly associated with overall survival (OS) by univariate Cox regression analysis. A 12-gene risk-scoring model was established to evaluate the prognosis of HCC. The high-risk group exhibits significantly lower OS rate of HCC patients than the low-risk group. The risk-scoring model shows benign predictive capacity in both GEO dataset and TCGA dataset. The 12-gene risk-scoring model may independently perform prognostic value for HCC patients. Receiver operating characteristic (ROC) curve analysis of the risk-scoring model in GEO cohort and TCGA cohort performed well in predicting OS. Taken together, the 12-gene risk-scoring model could provide prognostic and potentially predictive information for HCC. SDC3, NCF2, BTN3A3, and WARS were noticed as a novel prognostic factor for HCC.

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Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages

Cited by 50 publications

References 48 publications

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Identification of an EMT-Related Gene Signature for Predicting Overall Survival in Gastric Cancer

Identifying Dendritic Cell–Related Genes Through a Co-Expression Network to Construct a 12-Gene Risk-Scoring Model for Predicting Hepatocellular Carcinoma Prognosis

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