Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase.

Malignant ascites (MA) is a common manifestation of advanced gastric cancer (GC) with peritoneal metastasis (PM), which usually indicates a poor prognosis. The present study aimed to explore the effects of MA, a unique microenvironment of PM, on the proliferation of cancer cells and investigate the underlying mechanisms. Ex vivo experiments demonstrated that GC cells treated with MA exhibited enhanced proliferation. RNA sequencing indicated that asparagine synthetase (ASNS) was one of the differentially expressed genes in GC cells following incubation with MAs. Furthermore, the present study suggested that MA induced an upregulation of ASNS expression and the stimulatory effect of MA on cancer cell proliferation was alleviated upon ASNS downregulation. Activating transcription factor 4 (ATF4), a pivotal transcription factor regulating ASNS, was upregulated when cells were treated with MA supernatant. After ATF4 knockdown, the proliferation of MA-treated GC cells and the expression of ASNS decreased. In addition, the decline in the proliferation of the ATF4-downregulated AGS GC cell line was rescued by ASNS upregulation. The findings indicated that MA could promote the proliferation of GC cells via activation of the ATF4-ASNS axis. Hence, it may be a potential target for treating GC with PM and MA.

Liquid tumor microenvironment enhances WNT signaling pathway of peritoneal metastasis of gastric cancer.

Gastric cancer remains one of the most prevalent tumors worldwide and peritoneal metastasis is responsible for approximately 60% of death in advanced gastric cancer patients. However, the underlying mechanism of peritoneal metastasis is poorly understood. We have established organoids derived from malignant ascites (MA) of gastric cancer patients and noticed that MA supernatant could strongly increase the colony formation of organoids. Thus, we realized the interaction between exfoliated cancer cells (ECCs) and liquid tumor microenvironment contributes to peritoneal metastasis. Further, we designed a medium component control test which proved that exosomes derived from MA could not enhance the growth of organoids. Using Immunofluorescence and confocal imaging as well as dual-luciferase reporter assay, our data showed WNT signaling pathway was upregulated by high concentrations of WNT ligands (wnt3a and wnt5a), which was verified by ELISA. Besides, suppressing WNT signaling pathway diminished the growth promoting function of MA supernatant. This result implicated WNT signaling pathway as a potential therapeutic target for peritoneal metastasis of gastric cancer.

Bioinformatics Analysis Reveals the Vital Role of AKR1B1 in Immune Infiltration and Clinical Outcomes of Gastric Cancer.

Infiltrated immune cells are an important constitute of tumor microenvironment, which exert complex effects on gastric cancer (GC) pathogenesis and progression. By using weighted gene co-expression network analysis, integrating the data from The Cancer Genome Atlas-stomach adenocarcinoma and GSE62254, we identify Aldo-Keto Reductase Family 1 Member B (AKR1B1) as a hub gene for immune regulation in GC. Notably, AKR1B1 is associated with higher immune infiltration and worse histologic grade of GC. In addition, AKR1B1 is an independent factor for predicting the survival rate of GC patients. In vitro experiments further demonstrated that AKR1B1-overexpressed THP-1-derived macrophages promoted the proliferation and migration of GC cells. Taken together, AKR1B1 plays an important role in GC progression by regulating immune microenvironment, which could be a biomarker for predicting GC prognosis as well as a potential therapeutic target for GC treatment.

The effect of neoadjuvant chemotherapy on the tumor immune microenvironment in gastrointestinal tumors.

In recent years, numerous studies have demonstrated that the tumor immune microenvironment (TIME) is capable of regulating the growth of tumors, and tumor-infiltrating immune cells in the TIME can affect the prognosis and treatment responses of patients. Consequently, therapies targeting these immune cells have emerged as important antitumor treatments. As a crucial componet of the perioperative treatment of malignant tumors, neoadjuvant chemotherapy (NACT) can improve the surgical resection rate and prognosis of patients and is a suitable clinical model to evaluate the effect of chemotherapy on the TIME. To provide a rationale for developing valid combinational therapies, this review summarizes the impact of NACT on the TIME, the relationship between tumor-infiltrating immune cells and treatment responses of patients, and the prognostic value of these infiltrating immune cells.

Identification of N7-methylguanosine related subtypes and construction of prognostic model in gastric cancer.

Background: N7-methylguanosine (m7G), one of the most common post-transcriptional modifications, can be present in tRNA, mRNA, and miRNA to mediate the progression of various tumors. However, the possible role of m7G in gastric cancer (GC) is still unknown. Materials and Methods: In this study, SNVs (single nucleotide variations), CNVs (copy number variations), and methylation of m7G-related genes (m7GRGs) were analyzed. The relationship between them and the expression of m7GRGs and prognosis of GC patients was explored. Based on 13 prognostic-related m7GRGs, 567 GC samples were classified into three subtypes using the ConsensusClusterPlus package. we compared survival status, clinical traits, immune cell infiltration, immune checkpoints, tumor microenvironment (TME), tumor immune dysfunction and exclusion (TIDE), and potential biological pathways among the three subtypes. Then, patients were again grouped into different genetic subtypes based on the DEGs among the three subtypes. In addition, a prognostic m7GRG_Score was constructed using five risk genes applicable to patients of any age, gender and stage. We also assessed tumor mutational burden (TMB), microsatellite instability (MSI), cancer stem cell (CSC) index, sensitivity of antineoplastic drugs, efficacy of anti-PD-1 and anti-CTLA4 immunotherapy between high and low m7GRG_Score groups. Finally, we established a nomogram based on m7GRG_Score and tumor stage to enhance the clinical application of the model. miRNAs and lncRNAs that could regulate expression of risk genes were searched. Results: SNVs, CNVs, and methylation of m7GRGs were associated with m7GRGs expression. However, they did not significantly affect the survival of GC patients. Our results also confirmed that patients in subtypes B and C and low m7GRG_Score groups had longer survival time, better clinical stage, more immune cell infiltration, fewer immune escape and dysfunction compared to subtype A and high m7GRG_Score groups. A low m7GRG_score was featured with increased microsatellite instability-high (MSI-H), TMB, and efficacy of immunotherapy. Conclusion: The m7GRG_Score model may become a beneficial tool for predicting prognosis and guiding personalized treatment in GC patients. These findings will improve our knowledge of m7G in GC and provide new methods for more effective treatment strategies.

Application of natural killer cells in pancreatic cancer.

Pancreatic cancer, a highly malignant disease, is characterized by rapid progression and early metastasis. Although the integrative treatment of pancreatic cancer has made great progress, the prognosis of patients with advanced pancreatic cancer remains extremely poor. In recent years, with the advancements in tumor immunology, immunotherapy has become a promising remedy for pancreatic cancer. Natural killer (NK) cells are the key lymphocytes in the innate immune system. NK cell function does not require antigen pre-sensitization and is not major histocompatibility complex restricted. By targeting tumors or virus-infected cells, the cells play a key role in immune surveillance. Although several questions about NK cells in pancreatic cancer still need to be further studied, there are extensive theories supporting the clinical application prospects of NK cell immunotherapy in pancreatic cancer. Since very few studies have evaluated the role of NK cells in pancreatic cancer, this review provides a comprehensive update of the role of NK cells in pancreatic cancer immunotherapy.

The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways.

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in brain ischemia. To further study the roles of JNK activation in hippocampal CA1 neurons in a rat model of transient global ischemia, we assessed the effect of JNK inhibition by SP600125 on the degree of brain injury. Our results demonstrated that SP600125 significantly increased the number of surviving cells in hippocampal CA1 subfield and decreased the activation of p-JNK1/2 and p-JNK3 at 30 min and 3 days after brain ischemia. Moreover, SP600125 significantly diminished the increased levels of phosphorylated-c-Jun (Ser63/73) and phosphorylated-Bcl-2 (Ser87) at 3 h after brain ischemia. These results indicate that SP600125, a new inhibitor of JNK, protected transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region at least via suppressing the activation of nuclear substrate (c-Jun) and inactivating non-nuclear substrate (Bcl-2) induced by ischemic insult. Thus, inhibiting JNK activity by SP600125 may represent a new and effective strategy to treat ischemic stoke.