Context Of Gastric Cancer Research Articles

Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer

The epigenetic regulation of N6-methyladenosine (m6A) has attracted considerable interest in tumor research, but the potential roles of m6A regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m6A regulators (including novel anti-readers) was employed to identify m6A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m6A regulator-related patterns were identified through the unsupervised clustering of 56 m6A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m6A-related scoring system was developed to quantify the m6A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m6A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m6A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.

Granzyme B Promotes Proliferation, Migration and EMT Process in Gastric Cancer.

Granzyme B (GZMB), a critical member of the Gr gene family, is known to play an essential role in diverse physiological and pathological processes such as inflammation, acute and chronic inflammatory diseases, and cancer progression. In this study, we delve deeper into the role of GZMB within the context of gastric cancer (GC) to examine its expression patterns and functional implications. To accomplish this, we applied a combination of quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry techniques. These methodologies allowed us to accurately gauge GZMB expression levels in GC tissues and investigate their correlation with various clinical-pathological variables. Our secondary focus was to discern the regulatory influence of GZMB on GC cell biology. We used an array of assays including cell counting kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine, and migration assays. The effect of GZMB on gastric cancer progression was further validated through a subcutaneous xenograft mouse model. Our findings underscored that GZMB mRNA and protein levels were upregulated in GC tissues, a feature that showed a significant correlation with GC staging. We also discovered that a decrease in GZMB expression via knockdown experiments suppressed the proliferation and migration capabilities of GC cells. This effect was manifested through diminished expression levels of epithelial-mesenchymal transition (EMT) markers. In stark contrast, the overexpression of GZMB through plasmid transfection appeared to enhance the proliferation and migration abilities of GC cells. This was coupled with an upregulation in EMT expression. Our study concludes by emphasizing that GZMB promotes the growth, migration, and EMT processes in gastric cancer. In vitro, cell-based experiments and in vivo xenograft mouse models confirm this. Our findings provide a more comprehensive understanding of GZMB's role in gastric cancer pathogenesis, potentially opening doors for novel therapeutic strategies targeting this molecular pathway.

Double-Regulated Oncolytic Adenovirus-Mediated Interleukin-24 Overexpression Exhibits Potent Antitumor Activity on Gastric Adenocarcinoma

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), identified by subtraction hybridization in the mid-1990s, is a potent gene therapeutic for cancer. Using a replication-deficient adenovirus as vector, it provokes apoptosis in diverse cancer cells without harming normal cells or tissues. To exploit the anticancer capability of IL-24 to the best, in this study, we generated a novel gene-virotherapy agent MUD55-IL-24, utilizing a replication-competent oncolytic adenovirus MUD55 as the gene delivery vector. It was documented that MUD55-IL-24 exhibited much stronger antitumor activity on gastric carcinoma both in vitro and in vivo, and its safety was comparable to the replication-deficient adenovirus Ad-IL-24. The unique properties of IL-24, including apoptosis induction, antiangiogenesis, and antimigration, were all significantly enhanced in MUD55-IL-24. After looking into the underlying mechanism, we found that intracellular ROS (Reactive Oxygen Species) generation may have caused the induction of apoptosis, mitochondrial dysfunction, and the activation of caspases in MUD55-IL-24-infected SG-7901 cells. Taken together, these results suggest that MUD55-IL-24 may be able to provide a potential strategy for future treatment of human gastric carcinoma.

299. Increasing Gene Transfer and Oncolytic Potency of Adenoviruses in Orthotopic Models of Gastric Cancer

Background: Gene therapy with adenoviral (Ad) vectors is a promising modality for treatment of cancer. The primary limiting factor for Ad vectors is their dependence on the coxsackie and adenovirus receptor (CAR), which is down-regulated in many cancers. However, this has not been studied in the context of gastric cancer, the fifth most common cause of cancer mortality worldwide. Native Ad5 tropism can be modified to circumvent CAR deficiency. For instance, Ad5/3luc1 with serotype 3 fiber knob binds to a receptor distinct from CAR. The fiber of Ad5lucRGD is modified with an integrin-targeted arginine-glycine-aspartic acid motif. Polylysine motifs pK7 and pK21 bind to heparan sulphates. The oncolytic potency of replicating agents is partly determined by their capability for infecting cells. Conditionally replicating adenoviruses (CRAds) are replication competent in tumor but not in non-cycling normal cells. |[Delta]|24 based CRAds with a 24 bp deletion in E1A region take advantage of tumor specific changes in the Rb pathway. Our hypothesis was, that capsid modified adenoviruses possess enhanced ability for transduction of gastric cancer cells and primary tumor tissues, and that this targeting would also benefit the oncolytic potency of CRAds.