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Gastric cancer (GC) remains a predominant form of malignant tumor globally, necessitating innovative non-surgical therapeutic approaches. This investigation aimed to delineate the expression landscape of macrophage-associated genes in GC and to evaluate their prognostic significance and influence on immunotherapeutic responsiveness. Utilizing the CellMarker2.0 database, we identified 69 immune cell markers with prognostic relevance in GC, including 12 macrophage-specific genes. A Weighted Gene Co-Expression Network Analysis (WGCNA) isolated 3,181 genes correlated with these macrophage markers. The Cancer Genome Atlas (TCGA-STAD) dataset was employed as the training set, while data from the GSE62254 served as the validation cohort. 13 genes were shortlisted through LASSO-Cox regression to formulate a prognostic model. Multivariable Cox regression substantiated that the calculated risk score serves as an imperative independent predictor of overall survival (OS). Distinct macrophage infiltration profiles, pathway associations, treatment susceptibilities, and drug sensitivities were observed between high- and low-risk groups. The preliminary validation of ANXA5 in predicting the survival rates of GC patients at 1 year, 3 years, and 5 years, as well as its expression levels were higher and role in promoting tumor angiogenesis in GC through immunohistochemistry and angiogenesis experiments. In summary, macrophage-related genes were potentially a novel crosstalk mechanism between macrophages and endothelial cells in the tumor microenvironment, and the interplay between inflammation and angiogenesis might have also offered new therapeutic targets, providing a new avenue for personalized treatment interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: This study clarified that in the tumor microenvironment, tumor cell-derived TGF-β1 induces the appearance of an IGFBP7+ CAFs subgroup, and its higher IGFBP7 extracellular secretion level accelerated the progression of tumors. Our work suggests that IGFBP7 is a novel predictive marker for clinical outcomes in gastric cancer patients. Patients with infiltrative-type gastric cancer (GC) (Ming's classification) have a poor prognosis due to more metastasis and recurrence. Cancer-associated fibroblasts (CAFs) in infiltrative-type extracellular matrix (ECM) have specific characteristics compared with those of expansive types with respect to metastasis, but the mechanism is still unclear. Based on our proteomics data, TCGA data analysis, and immunohistochemical staining results, significantly higher expression of IGFBP7 was observed in GC, especially in the infiltrative type, and was associated with a poor prognosis. Combining single-cell transcriptome data from GEO and multiple immunofluorescence staining on tissue showed that the differential expression of IGFBP7 mainly originated from myofibroblastic CAFs, the subgroup with higher expression of PDGFRB and α-SMA. After treating primary normal fibroblasts (NFs) with conditional medium or recombined protein, it was demonstrated that XGC-1-derived TGF-β1 upregulated the expression of IGFBP7 in the cells and its secretion via the P-Smad2/3 pathway and mediated its activation with higher FAP, PDGFRB, and α-SMA expression. Then, either conditional medium from CAFs with IGFBP7 overexpression or recombined IGFBP7 protein promoted the migration, invasion, colony formation, and sphere growth ability of XGC-1 and MGC-803, respectively. Moreover, IGFBP7 induced EMT in XGC-1. Therefore, our study clarified that in the tumor microenvironment, tumor-cell-derived TGF-β1 induces the appearance of the IGFBP7+ CAF subgroup, and its higher IGFBP7 extracellular secretion level accelerates the progression of tumors. [ABSTRACT FROM AUTHOR]

Background: Real‐world safety and effectiveness data for trastuzumab plus chemotherapy treatment of patients with HER2‐positive metastatic gastric cancer (mGC) in China are lacking. Patients and Methods: EVIDENCE was a prospective, multicenter, noninterventional registry study evaluating the safety and effectiveness of trastuzumab in five cohorts of Chinese patients with gastric cancer, stratified by HER2 status and trastuzumab treatment. Effectiveness was analyzed for cohorts I (HER2‐positive, trastuzumab treated), II (HER2‐positive, trastuzumab untreated), and IV (HER2‐negative, trastuzumab untreated); trastuzumab‐related adverse events (AEs) were analyzed for cohort I. Results: Cohorts I, II, and IV included 174, 113, and 422 patients, respectively. Most patients received first‐line chemotherapy (87.6%). Median overall survival (OS1) for first‐line treatment was 22.3, 17.2, and 17.4 months in cohorts I, II, and IV, respectively. After excluding patients who had surgery, respective median OS1 was 19.9, 15.3, and 12.9 months. Respective first‐line progression‐free survival (PFS1) was 8.2, 6.9, and 6.2 months; and respective first‐line response rates (RR) were 51.7%, 18.4%, and 32.8%. Cohort I was significantly favored over cohort II for propensity score–matched first‐line median OS1 (hazard ratio [HR], 0.61), PFS1 (HR, 0.64), and RR (odds ratio, 4.93). Trastuzumab‐related AEs, grade 3–5 AEs, serious AEs, and AEs with a fatal outcome occurred in 23.6%, 3.4%, 2.3%, and 0.6% of cohort I patients, respectively. Conclusion: Safety profiles were consistent with those known for trastuzumab and chemotherapy; trastuzumab treatment improved outcomes. Our study provides real‐world data supporting first‐line trastuzumab plus chemotherapy in Chinese patients with HER2‐positive mGC. Implications for Practice: This prospective, noninterventional registry study aimed to provide safety and effectiveness data for the use of trastuzumab in combination with chemotherapy in Chinese patients with HER2‐positive metastatic gastric cancer (mGC) from the real‐world clinical setting. Trastuzumab plus first‐line chemotherapy was shown to be safe and to improve outcomes when compared with patients treated with chemotherapy alone. Trastuzumab was effective within a range of treatment regimens; subgroup analysis showed that trastuzumab paired most effectively with the XELOX regimen. This study provides real‐world clinical safety and effectiveness data supporting the use of trastuzumab in the treatment of Chinese patients with HER2‐positive mGC. This article reports the results of the EVIDENCE study, which evaluated the effectiveness and safety of trastuzumab in patients with HER2‐positive metastatic gastric cancer in a real‐world setting in China. [ABSTRACT FROM AUTHOR]

Background: The role of stress signals in regulating gastric cancer initiation and progression is not quite clear. It is known that stress signals modulate multiple processes such as immune function, cell migration and angiogenesis. However, few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis.Methods: Here, we used β2-adrenergic receptor (β2-AR) agonist isoprenaline to imitate a stress signal and demonstrated the molecular mechanism underlying stress's influence on tumor angiogenesis.Results: We found that isoprenaline stimulated vascular endothelial growth factor (VEGF) secretion in gastric cancer cells and plexin-A1 expression was induced by human recombinant VEGF165 in both gastric cancer cells and vascular endothelial cells. Furthermore, interfere with plexin-A1 expression in gastric cancer cells influence HUVEC tube formation, migration and tumor growth in vivo.Conclusions: These findings suggest that isoprenaline stimulate VGEF secretion and subsequently up-regulate the expression of plexin-A1 and VEGFR2 in gastric cancer cells, which form a positive impetus to promote tumor angiogenesis. This study reveals a novel molecular mechanism that a stress signal like isoprenaline may enhance angiogenesis via activating plexin-A1/VEGFR2 signaling pathway in gastric cancer, which may be a potential target in development of an anti-angiogenic therapy for gastric cancer. [ABSTRACT FROM AUTHOR]

In this study, chitosan/heparin immobilized delivery system was developed for the delivery of sorafenib in gastric cancers. The SRF NP was nanosized with spherical outfit and present in the amorphous form. The SRF NP exhibited a sustained release of drug at pH 7.4 conditions and enhanced drug released at pH 5.5 conditions. Flow cytometer analysis showed that cellular uptake of NP increased two-fold after 4 h of incubation compared to 1 h incubation. The SRF NP showed superior anticancer effect compared to that of free SRF in BGC-823 cancer cells. SRF NP induced a remarkable apoptosis of cancer cells consistent with the cytotoxicity assay. Approximately, ∼50% of cell fractions were observed in early apoptosis phase with ∼15% of cells in the late apoptosis stage. Consistently, SRF NP exhibited a strong band for caspase-3 and P-53 than compared to free SRF in MGC-823 cancer cells. Importantly, SRF NP showed superior anticancer effect in xenograft tumor model making it a promising delivery vehicle in the treatment of gastric cancers. [ABSTRACT FROM AUTHOR]