Identification and Validation of a Tumour Microenvironment-Based Immune Molecular Subgroups for Gastric Cancer: Immunotherapeutic Implications

AbstractExosomes are a subpopulation of the tumour microenvironment (TME) that transmit various biological molecules to promote intercellular communication. Exosomes are derived from nearly all types of cells and exist in all body fluids. Noncoding RNAs (ncRNAs) are among the most abundant contents in exosomes, and some ncRNAs with biological functions are specifically packaged into exosomes. Recent studies have revealed that exosome-derived ncRNAs play crucial roles in the tumorigenesis, progression and drug resistance of gastric cancer (GC). In addition, regulating the expression levels of exosomal ncRNAs can promote or suppress GC progression. Moreover, the membrane structures of exosomes protect ncRNAs from degradation by enzymes and other chemical substances, significantly increasing the stability of exosomal ncRNAs. Specific hallmarks within exosomes that can be used for exosome identification, and specific contents can be used to determine their origin. Therefore, exosomal ncRNAs are suitable for use as diagnostic and prognostic biomarkers or therapeutic targets. Regulating the biogenesis of exosomes and the expression levels of exosomal ncRNAs may represent a new way to block or eradicate GC. In this review, we summarized the origins and characteristics of exosomes and analysed the association between exosomal ncRNAs and GC development.

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The role of tumour microenvironment in gastric cancer angiogenesis

Gastroenterology Review ◽

10.5114/pg.2014.47894 ◽

2014 ◽

Vol 6 ◽

pp. 325-328 ◽

Cited By ~ 1

Author(s):

Marlena Brzozowa ◽

Marek Michalski ◽

Marzena Harabin-Słowińska ◽

Romuald Wojnicz

Keyword(s):

Gastric Cancer ◽

Tumour Microenvironment

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H.Pylori Infection Induces CXCL8 Expression and Promotes Gastric Cancer Progress Through Downregulating KLF4

10.21203/rs.3.rs-21028/v1 ◽

2020 ◽

Author(s):

zhengxia liu ◽

Xiao Wu ◽

Yuanyuan Tian ◽

wanchun zhang ◽

siyuan qiao ◽

...

Keyword(s):

Gastric Cancer ◽

Suppressor Cells ◽

Tumour Microenvironment ◽

Transcriptional Level ◽

Downstream Target ◽

Klf4 Expression ◽

Two Factors ◽

Downstream Target Gene ◽

Immunosuppressive Microenvironment ◽

Biological Methods

Abstract Background Tumour-derived CXCL8 facilitates the movement of myeloid-derived suppressor cells (MDSCs), which have the capacity to restrain antitumour immune responses, into the tumour microenvironment. Kruppel-like factor 4 (KLF4) is a potential tumour suppressor in gastric cancer (GC). However, little is known about the correlation between KLF4 and CXCL8 in gastric carcinoma.Methods In this study, we used cellular and molecular biological methods to assess whether these two factors interact in GC.Results We found that the expression levels of CXCL8 and KLF4 were altered in human GC tissues compared to normal gastric tissues in opposite ways. In addition, we found that CagA gene transduction or Helicobacter pylori infection resulted in the upregulation of CXCL8 expression. Knockdown of KLF4 expression increased CXCL8 expression at the protein and RNA levels, whereas overexpression of KLF4 had the opposite effect. Further mechanistic research revealed that KLF4 binds the CXCL8 promoter and negatively regulates CXCL8 at the transcriptional level. Moreover, CXCL8 factor stimulation reduced KLF4 expression, and the CXCL8-mediated increase in GC cell migration and proliferation was reversed by the upregulation of KLF4 expression, eventually promoting neoplasm growth in vivo.Conclusions Taken together, our findings demonstrate that CXCL8 is a decisive downstream target gene of KLF4 in gastric carcinoma. Targeted KLF4 activation could improve the immunosuppressive microenvironment through direct, negative regulation of CXCL8, providing a new potential target to strengthen the efficacy of immunotherapy in patients with GC.

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Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

Journal of Clinical Medicine ◽

10.3390/jcm9092967 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2967

Author(s):

Anne M. Macpherson ◽

Simon C. Barry ◽

Carmela Ricciardelli ◽

Martin K. Oehler

Keyword(s):

Ovarian Cancer ◽

Immune System ◽

Epithelial Ovarian Cancer ◽

Current Knowledge ◽

Tumour Microenvironment ◽

Tumour Immunology ◽

The Us ◽

Cancer Types ◽

Cancer Immunotherapeutic ◽

Cancer Immunotherapies

Recent advances in the understanding of immune function and the interactions with tumour cells have led to the development of various cancer immunotherapies and strategies for specific cancer types. However, despite some stunning successes with some malignancies such as melanomas and lung cancer, most patients receive little or no benefit from immunotherapy, which has been attributed to the tumour microenvironment and immune evasion. Although the US Food and Drug Administration have approved immunotherapies for some cancers, to date, only the anti-angiogenic antibody bevacizumab is approved for the treatment of epithelial ovarian cancer. Immunotherapeutic strategies for ovarian cancer are still under development and being tested in numerous clinical trials. A detailed understanding of the interactions between cancer and the immune system is vital for optimisation of immunotherapies either alone or when combined with chemotherapy and other therapies. This article, in two main parts, provides an overview of: (1) components of the normal immune system and current knowledge regarding tumour immunology, biology and their interactions; (2) strategies, and targets, together with challenges and potential innovative approaches for cancer immunotherapy, with attention given to epithelial ovarian cancer.

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Integrated Analysis of Helicobacter Pylori-Related Prognostic Gene Modification Patterns in the Tumour Microenvironment of Gastric Cancer

10.21203/rs.3.rs-1082270/v1 ◽

2021 ◽

Author(s):

Ye Wang ◽

kaitian Zheng ◽

Jiancheng Wang ◽

congjun Wang ◽

Junqiang Chen

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Immune Cell ◽

External Validation ◽

Principal Component ◽

Tumour Microenvironment ◽

Cell Infiltration ◽

Integrated Analysis ◽

Gene Markers ◽

Immunological Surveillance

Abstract Background Helicobacter pylori (HP) infection is one of the leading causes of gastric cancer (GC). However, the interaction between HP and the TME, and its carcinogenic mechanism remains unknown. Methods We screened 28 HP-related prognostic genes based on HP infection-related gene markers and HP infection sample datasets (GSE6143 and GSE60662). We then constructed an HPscore system by using the principal component analysis algorithm and successfully quantified the HP modification characteristics of a single GC sample. In addition, we comprehensively analysed the relationship between the HPscore and the clinical characteristics of patients with GC, the immune cell infiltration characteristics of the TME and stemness. Results We successfully identified 28 HP-related prognostic genes that accurately classified the GC population. There are significant differences in survival between different subgroups(high-, low-risk and cluster_1,2). Thereafter, we constructed the HPscore system to systematically evaluate the modification characteristics of the 28 HP-related prognostic genes, and the internal and external validation of the HPscore system suggested similar results: the overall survival rate in the high -HPscore group was poor, and immunological surveillance was reduced, whereas the low-HPscore group had a survival advantage, and was related to the inflammatory response. HPscore was also strongly correlated with the tumour stage, TME cell infiltration and stemness. Conclusions HP-modified characteristics play a crucial role in the TME and tumourigenesis. HPscore evaluation of a single tumour sample can help identify the TME characteristics and the carcinogenic mechanism of GC patients infected with HP, based on which personalised treatment can be administered.

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Molecular alterations of cancer cell and tumour microenvironment in metastatic gastric cancer

Oncogene ◽

10.1038/s41388-018-0341-x ◽

2018 ◽

Vol 37 (36) ◽

pp. 4903-4920 ◽

Cited By ~ 16

Author(s):

Weilin Li ◽

Jennifer Mun-Kar Ng ◽

Chi Chun Wong ◽

Enders Kwok Wai Ng ◽

Jun Yu

Keyword(s):

Gastric Cancer ◽

Cancer Cell ◽

Metastatic Gastric Cancer ◽

Tumour Microenvironment ◽

Molecular Alterations

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Hypothesis‐free deep survival learning applied to the tumour microenvironment in gastric cancer

The Journal of Pathology Clinical Research ◽

10.1002/cjp2.170 ◽

2020 ◽

Vol 6 (4) ◽

pp. 273-282

Author(s):

Armin Meier ◽

Katharina Nekolla ◽

Lindsay C Hewitt ◽

Sophie Earle ◽

Takaki Yoshikawa ◽

...

Keyword(s):

Gastric Cancer ◽

Tumour Microenvironment

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The role and application of small extracellular vesicles in gastric cancer

Molecular Cancer ◽

10.1186/s12943-021-01365-z ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Hao Wu ◽

Mengdi Fu ◽

Jin Liu ◽

Wei Chong ◽

Zhen Fang ◽

...

Keyword(s):

Gastric Cancer ◽

Extracellular Vesicles ◽

Poor Prognosis ◽

Cell Communication ◽

Drug Carriers ◽

Tumour Microenvironment ◽

Bioactive Molecules ◽

Long Distance ◽

Distance Effects ◽

Application Prospects

AbstractGastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.

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LncRNA MALAT1 promotes gastric cancer progression via inhibiting autophagic flux and inducing fibroblast activation

Cell Death and Disease ◽

10.1038/s41419-021-03645-4 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Zhenqiang Wang ◽

Xinjing Wang ◽

Tianqi Zhang ◽

Liping Su ◽

Bingya Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Rna Binding ◽

Tumour Microenvironment ◽

Autophagic Flux ◽

Intercellular Interaction ◽

Pten Mrna ◽

Autophagy Inhibition

AbstractAutophagy defection contributes to inflammation dysregulation, which plays an important role in gastric cancer (GC) progression. Various studies have demonstrated that long noncoding RNA could function as novel regulators of autophagy. Previously, long noncoding RNA MALAT1 was reported upregulated in GC cells and could positively regulate autophagy in various cancers. Here, we for the first time found that MALAT1 could promote interleukin-6 (IL-6) secretion in GC cells by blocking autophagic flux. Moreover, IL-6 induced by MALAT1 could activate normal to cancer-associated fibroblast conversion. The interaction between GC cells and cancer-associated fibroblasts in the tumour microenvironment could facilitate cancer progression. Mechanistically, MALAT1 overexpression destabilized the PTEN mRNA in GC cells by competitively interacting with the RNA-binding protein ELAVL1 to activate the AKT/mTOR pathway for impairing autophagic flux. As a consequence of autophagy inhibition, SQSTM1 accumulation promotes NF-κB translocation to elevate IL-6 expression. Overall, these results demonstrated that intercellular interaction between GC cells and fibroblasts was mediated by autophagy inhibition caused by increased MALAT1 that promotes GC progression, providing novel prevention and therapeutic strategies for GC.

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