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21 pages, 4874 KiB

Open AccessArticle

The Dysfunctional Immune System in Common Variable Immunodeficiency Increases the Susceptibility to Gastric Cancer

by Irene Gullo, Catarina Costa, Susana L. Silva, Cristina Ferreira, Adriana Motta, Sara P. Silva, Rúben Duarte Ferreira, Pedro Rosmaninho, Emília Faria, José Torres da Costa, Rita Câmara, Gilza Gonçalves, João Santos-Antunes, Carla Oliveira, José C. Machado, Fátima Carneiro and Ana E. Sousa

Cells 2020, 9(6), 1498; https://doi.org/10.3390/cells9061498 - 19 Jun 2020

Cited by 12 | Viewed by 4704

Abstract

Gastric carcinoma (GC) represents the most common cause of death in patients with common variable immunodeficiency (CVID). However, a limited number of cases have been characterised so far. In this study, we analysed the clinical features, bacterial/viral infections, detailed morphology and immune microenvironment [...] Read more.

Gastric carcinoma (GC) represents the most common cause of death in patients with common variable immunodeficiency (CVID). However, a limited number of cases have been characterised so far. In this study, we analysed the clinical features, bacterial/viral infections, detailed morphology and immune microenvironment of nine CVID patients with GC. The study of the immune microenvironment included automated digital counts of CD20+, CD4+, CD8+, FOXP3+, GATA3+ and CD138+ immune cells, as well as the evaluation of PD-L1 expression. Twenty-one GCs from non-CVID patients were used as a control group. GC in CVID patients was diagnosed mostly at early-stage (n = 6/9; 66.7%) and at younger age (median-age: 43y), when compared to non-CVID patients (p < 0.001). GC pathogenesis was closely related to Helicobacter pylori infection (n = 8/9; 88.9%), but not to Epstein-Barr virus (0.0%) or cytomegalovirus infection (0.0%). Non-neoplastic mucosa (non-NM) in CVID-patients displayed prominent lymphocytic gastritis (100%) and a dysfunctional immune microenvironment, characterised by higher rates of CD4+/CD8+/Foxp3+/GATA3+/PD-L1+ immune cells and the expected paucity of CD20+ B-lymphocytes and CD138+ plasma cells, when compared to non-CVID patients (p < 0.05). Changes in the immune microenvironment between non-NM and GC were not equivalent in CVID and non-CVID patients, reflecting the relevance of immune dysfunction for gastric carcinogenesis and GC progression in the CVID population. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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21 pages, 3887 KiB

Open AccessFeature PaperArticle

TAZ Controls Helicobacter pylori-Induced Epithelial–Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties

by Camille Tiffon, Julie Giraud, Silvia Elena Molina-Castro, Sara Peru, Lornella Seeneevassen, Elodie Sifré, Cathy Staedel, Emilie Bessède, Pierre Dubus, Francis Mégraud, Philippe Lehours, Océane C.B. Martin and Christine Varon

Cells 2020, 9(6), 1462; https://doi.org/10.3390/cells9061462 - 13 Jun 2020

Cited by 33 | Viewed by 4771

Abstract

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) [...] Read more.

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZ silencing reduced ZEB1 expression and EMT phenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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22 pages, 5185 KiB

Open AccessArticle

Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

by Marina Leite, Miguel S. Marques, Joana Melo, Marta T. Pinto, Bruno Cavadas, Miguel Aroso, Maria Gomez-Lazaro, Raquel Seruca and Ceu Figueiredo

Cells 2020, 9(2), 513; https://doi.org/10.3390/cells9020513 - 24 Feb 2020

Cited by 19 | Viewed by 5457

Abstract

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using [...] Read more.

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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18 pages, 5527 KiB

Open AccessArticle

High Levels of Class I Major Histocompatibility Complex mRNA Are Present in Epstein–Barr Virus-Associated Gastric Adenocarcinomas

by Farhad Ghasemi, Steven F. Gameiro, Tanner M. Tessier, Allison H. Maciver and Joe S. Mymryk

Cells 2020, 9(2), 499; https://doi.org/10.3390/cells9020499 - 21 Feb 2020

Cited by 20 | Viewed by 3401

Abstract

Epstein–Barr virus (EBV) is responsible for approximately 9% of stomach adenocarcinomas. EBV-encoded microRNAs have been reported as reducing the function of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus, which could allow infected cells to evade adaptive immune responses. Using data [...] Read more.

Epstein–Barr virus (EBV) is responsible for approximately 9% of stomach adenocarcinomas. EBV-encoded microRNAs have been reported as reducing the function of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus, which could allow infected cells to evade adaptive immune responses. Using data from nearly 400 human gastric carcinomas (GCs), we assessed the impact of EBV on MHC-I heavy and light chain mRNA levels, as well as multiple other components essential for antigen processing and presentation. Unexpectedly, mRNA levels of these genes were as high, or higher, in EBV-associated gastric carcinomas (EBVaGCs) compared to normal control tissues or other GC subtypes. This coordinated upregulation could have been a consequence of the higher intratumoral levels of interferon γ in EBVaGCs, which correlated with signatures of increased infiltration by T and natural killer (NK) cells. These results indicate that EBV-encoded products do not effectively reduce mRNA levels of the MHC-I antigen presentation apparatus in human GCs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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14 pages, 3747 KiB

Open AccessFeature PaperArticle

Impact of Truncated O-glycans in Gastric-Cancer-Associated CD44v9 Detection

by Inês B. Moreira, Filipe Pinto, Catarina Gomes, Diana Campos and Celso A. Reis

Cells 2020, 9(2), 264; https://doi.org/10.3390/cells9020264 - 21 Jan 2020

Cited by 9 | Viewed by 4069

Abstract

CD44 variant isoforms are often upregulated in cancer and associated with increased aggressive tumor phenotypes. The CD44v9 is one of the major protein splice variant isoforms expressed in human gastrointestinal cancer cells. Immunodetection of CD44 isoforms like CD44v9 in tumor tissue is almost [...] Read more.

CD44 variant isoforms are often upregulated in cancer and associated with increased aggressive tumor phenotypes. The CD44v9 is one of the major protein splice variant isoforms expressed in human gastrointestinal cancer cells. Immunodetection of CD44 isoforms like CD44v9 in tumor tissue is almost exclusively performed by using specific monoclonal antibodies. However, the structural variability conferred by both the alternative splicing and CD44 protein glycosylation is disregarded. In the present work, we have evaluated the role of O-glycosylation using glycoengineered gastric cancer models in the detection of CD44v9 by monoclonal antibodies. We demonstrated, using different technical approaches, that the presence of immature O-glycan structures, such as Tn and STn, enhance CD44v9 protein detection. These findings can have significant implications in clinical applications mainly at the detection and targeting of this cancer-related CD44v9 isoform and highlight the utmost importance of considering glycan structures in cancer biomarker detection and in therapy targeting. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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17 pages, 2367 KiB

Open AccessArticle

Comprehensive Multi-Omics Analysis Reveals Aberrant Metabolism of Epstein–Barr-Virus-Associated Gastric Carcinoma

by Sang Jun Yoon, Jun Yeob Kim, Nguyen Phuoc Long, Jung Eun Min, Hyung Min Kim, Jae Hee Yoon, Nguyen Hoang Anh, Myung Chan Park, Sung Won Kwon and Suk Kyeong Lee

Cells 2019, 8(10), 1220; https://doi.org/10.3390/cells8101220 - 8 Oct 2019

Cited by 26 | Viewed by 5362

Abstract

The metabolic landscape of Epstein–Barr-virus-associated gastric cancer (EBVaGC) remains to be elucidated. In this study, we used transcriptomics, metabolomics, and lipidomics to comprehensively investigate aberrant metabolism in EBVaGC. Specifically, we conducted gene expression analyses using microarray-based data from gastric adenocarcinoma epithelial cell lines [...] Read more.

The metabolic landscape of Epstein–Barr-virus-associated gastric cancer (EBVaGC) remains to be elucidated. In this study, we used transcriptomics, metabolomics, and lipidomics to comprehensively investigate aberrant metabolism in EBVaGC. Specifically, we conducted gene expression analyses using microarray-based data from gastric adenocarcinoma epithelial cell lines and tissue samples from patients with clinically advanced gastric carcinoma. We also conducted complementary metabolomics and lipidomics using various mass spectrometry platforms. We found a significant downregulation of genes related to metabolic pathways, especially the metabolism of amino acids, lipids, and carbohydrates. The effect of dysregulated metabolic genes was confirmed in a survival analysis of 3951 gastric cancer patients. We found 57 upregulated metabolites and 31 metabolites that were downregulated in EBVaGC compared with EBV-negative gastric cancer. Sixty-nine lipids, mainly ether-linked phospholipids and triacylglycerols, were downregulated, whereas 45 lipids, mainly phospholipids, were upregulated. In total, 15 metabolisms related to polar metabolites and 15 lipid-associated pathways were involved in alteration of metabolites by EBV in gastric cancer. In this work, we have described the metabolic landscape of EBVaGC at the multi-omics level. These findings could help elucidate the mechanism of EBVaGC oncogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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13 pages, 2248 KiB

Open AccessArticle

ARID1A Mutations Are Associated with Increased Immune Activity in Gastrointestinal Cancer

by Lin Li, Mengyuan Li, Zehang Jiang and Xiaosheng Wang

Cells 2019, 8(7), 678; https://doi.org/10.3390/cells8070678 - 4 Jul 2019

Cited by 86 | Viewed by 6539

Abstract

Because traditional treatment strategies for advanced gastrointestinal (GI) cancers often have a limited therapeutic effect, immunotherapy could be a viable approach for the therapy of advanced GI cancers, considering the recent success of immunotherapy in treating various refractory malignancies, including the DNA mismatch [...] Read more.

Because traditional treatment strategies for advanced gastrointestinal (GI) cancers often have a limited therapeutic effect, immunotherapy could be a viable approach for the therapy of advanced GI cancers, considering the recent success of immunotherapy in treating various refractory malignancies, including the DNA mismatch repair-deficient GI cancers. However, only a subset of cancer patients currently respond to immunotherapy. Thus, it is important to identify useful biomarkers for predicting cancer immunotherapy response. The tumor suppressor gene ARID1A has a high mutation rate in GI cancers and its deficiency is correlated with the microsatellite instability (MSI) genomic feature of cancer. We investigated the correlation between ARID1A mutations and tumor immunity using three GI cancer genomics datasets by the bioinformatic approach, and found that diverse antitumor immune signatures were more highly enriched in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers. The elevated immune activity in ARID1A-mutated GI cancers was associated with the higher tumor mutation burden and lower tumor aneuploidy level, as well as a higher proportion of MSI cancers in this GI cancer subtype. Moreover, we found that ARID1A-mutated GI cancers more highly expressed PD-L1 than ARID1A-wildtype GI cancers. The elevated antitumor immune signatures and PD-L1 expression could contribute to the more active immunotherapeutic responsiveness and better survival prognosis in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers in the immunotherapy setting, as evidenced in three cancer cohorts receiving immunotherapy. Thus, the ARID1A mutation could be a useful biomarker for identifying GI cancer patients responsive to immunotherapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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Review

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23 pages, 1178 KiB

Open AccessReview

The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression

by Ana Margarida Moreira, Joana Pereira, Soraia Melo, Maria Sofia Fernandes, Patrícia Carneiro, Raquel Seruca and Joana Figueiredo

Cells 2020, 9(2), 394; https://doi.org/10.3390/cells9020394 - 8 Feb 2020

Cited by 69 | Viewed by 11065

Abstract

The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though [...] Read more.

The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though the detailed mechanisms underlying cell-ECM crosstalk are yet to unravel, it is well established that ECM deregulation accompanies the development of many pathological conditions, such as gastric cancer. Notably, gastric cancer remains a worldwide concern, representing the third most frequent cause of cancer-associated deaths. Despite increased surveillance protocols, patients are usually diagnosed at advanced disease stages, urging the identification of novel diagnostic biomarkers and efficient therapeutic strategies. In this review, we provide a comprehensive overview regarding expression patterns of ECM components and cognate receptors described in normal gastric epithelium, pre-malignant lesions, and gastric carcinomas. Important insights are also discussed for the use of ECM-associated molecules as predictive biomarkers of the disease or as potential targets in gastric cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)

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