Search Results (278)

Gastric adenocarcinoma is a malignant tumor that develops from the glandular cells of the inner wall of the stomach. The prevalence of this type of disease varies from 90 to 95% of all types of gastric cancer. The aim of our study was to investigate the differences in the content of cytokines and oxidative stress markers in patients with gastric adenocarcinoma associated with H. pylori infection depending on the stage. The study included 281 patients with gastric cancer. At stage I of the disease—75 people, stage II—70 people, stage III—69 people, and stage IV of the disease—67 people. The levels of TNF-α, IL-2, IL-8, IFNγ, TNF-β, IL-17A, IL-6, IL-10, and IL-4 in the blood serum of patients and healthy individuals were determined by enzyme immunoassay and plasma oxidative stress scores (MDA, SOD, CAT, GST, GPO, CP). The present study revealed that H. pylori-infected gastric adenocarcinoma at different stages is associated with different plasma levels of cytokines, lipid peroxidation products, and antioxidant defense factors. Further studies are needed to evaluate the effectiveness of therapeutic strategies combining cytokine regulation and oxidative stress to improve clinical outcomes in gastric cancer. Full article

Background: Short-chain fatty acids (SCFAs), microbial metabolites also known as postbiotics, are essential for maintaining gut health. However, their antiproliferative effects on gastric cancer cells and potential interactions with conventional therapies remain underexplored. This study aimed to investigate the effects of three SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—individually and in combination (APB), as well as in combination with dexamethasone (Dex), on AGS gastric adenocarcinoma cells. Methods: AGS cells were treated with PB, AP, AB, APB, Dex, and APB+Dex. Cell viability was assessed to determine antiproliferative effects, and the IC₅₀ of APB was calculated. Flow cytometry was used to evaluate apoptosis and necrosis. Reactive oxygen species (ROS) levels were measured to assess oxidative stress. Proteomic analysis via LC-MS was performed to identify differential protein expression and related pathways impacted by the treatments. Results: SCFA salts showed significant antiproliferative effects on AGS cells, with APB exhibiting a combined IC₅₀ of 568.33 μg/mL. The APB+Dex combination demonstrated strong synergy (combination index = 0.76) and significantly enhanced growth inhibition. Both APB and APB+Dex induced substantial apoptosis (p < 0.0001) with minimal necrosis. APB alone significantly increased ROS levels (p < 0.0001), while Dex moderated this effect in the combination group APB+Dex (p < 0.0001). Notably, the APB+Dex treatment synergistically targeted multiple tumour-promoting mechanisms, including the impairment of redox homeostasis through SLC7A11 suppression, and inhibition of the haemostasis, platelet activation network and NF-κB signalling pathway via downregulation of NFKB1 (−1.34), exemplified by increased expression of SERPINE1 (1.99) within the “Response to elevated platelet cytosolic Ca²⁺” pathway. Conclusions: These findings showed a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support in gastric cancer. Full article

Background: Gastric cancer (GC) is a highly heterogeneous disease and remains one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including diffuse and intestinal GC that may differ in their incidence between Asian and non-Asian cohorts. The intestinal-subtype GC has declined over the past 50 years. In contrast to the intestinal-subtype adenocarcinoma, the incidence of diffuse-subtype GC, often associated with poor overall survival, has constantly increased in the USA and Europe. The aim of this study was to analyze the expression and clinical significance of steroid hormone receptors, two membrane-bound receptors (ERRγ and GPER), and several genes involved in epigenetic alterations. The findings may contribute to revealing events driving tumorigenesis and may aid prognosis. Methods: Using mRNA from diffuse and intestinal GC tumor samples, the expression level of 11 genes, including those coding for sex hormone receptors (estrogen receptors ERα and ERβ), progesterone receptor (PR) and androgen receptor (AR), and the putative relevant ERRγ and GPER receptor were determined by RT-qPCR. Results: In diffuse GC, the expression of ERα, ERβ, PR and AR differed from their expression in the intestinal subtype. The expression of ERα and ERβ was strongly increased in the diffuse subtype compared to the intestinal subtype (×1.90, p = 0.001 and ×2.68, p = 0.002, respectively). Overexpression of ERα and ERβ was observed in diffuse GC (15 and 42%, respectively). The expression levels of PR and AR were strongly decreased in the intestinal subtype as compared to diffuse GC (×0.48, p = 0.005 and ×0.25, p = 0.003, respectively; 37.5% and 56% underexpression). ERα, ERβ, PR and AR showed notable differences for clinicopathological correlation in the diffuse and intestinal GC. A significant decrease of ERα, ERβ, PR and AR in intestinal GC correlated with the absence of lymphatic invasion and lower TNM (I-II). In diffuse GC, among the hormone receptors, increases of ERs and PR mainly correlated with expression of growth factors and receptors (IGF1, FGF7 and FGFR1), and with genes involved in epithelial-mesenchymal transition (VIM and ZEB2) or cell migration (MMP2). Our results also report the strong decreased expression of ERRγ and GPER (two receptors that bind estrogen or xenoestrogens) in diffuse and intestinal subtypes. Conclusions: Our study identified new target genes, namely hormone receptors and membrane receptors (ERRγ and GPER), whose expression is associated with an aggressive phenotype of diffuse GC, and revealed the importance of epigenetic factors (EZH2, HOTAIR, H19 and DNMT1) in gastric cancers. Full article

Background/Objectives: In gastric cancer, only a subset of patients benefit clinically from neoadjuvant chemoimmunotherapy, underscoring the need for robust biomarkers that can predict treatment responses and guide personalized immunotherapy. This study aimed to characterize the immune microenvironment of gastric tumors and identify predictive markers associated with therapeutic efficacy. Methods: We prospectively enrolled 16 patients with histologically confirmed, PD-L1–positive (CPS ≥ 1) gastric adenocarcinoma (T_2–4N_0–1M₀). All patients received eight cycles of FLOT chemotherapy combined with pembrolizumab. Treatment response was assessed by Mandard tumor regression grading. Spatial transcriptomic profiling (10x Genomics Visium) and multiplex immunofluorescence were used to evaluate tumor-infiltrating immune cell subsets and PD-1 expression at baseline and after treatment. Results: Transcriptomic analysis differentiated the immune landscapes of responders from non-responders. Responders exhibited elevated expression of IL1B, CXCL5, HMGB1, and IFNGR2, indicative of an inflamed tumor microenvironment and type I/II interferon signaling. In contrast, non-responders demonstrated upregulation of immunosuppressive genes such as LGALS3, IDO1, and CD55, along with enrichment in oxidative phosphorylation and antigen presentation pathways. Multiplex immunofluorescence confirmed a higher density of FoxP3⁺ regulatory T cells in non-responders (median 5.36% vs. 2.41%; p = 0.0032). Notably, PD-1⁺ CD8⁺ T cell and PD-1⁺ FoxP3⁺ Treg frequencies were significantly elevated in non-responders, suggesting that PD-1 expression within cytotoxic and regulatory compartments may contribute to immune evasion. No substantial differences were observed in PD-L1 CPS or PD-1⁺ B cells and PD-1⁺ macrophages. Conclusions: Our findings identify PD-1⁺ CD8⁺ T cells and PD-1⁺ FoxP3⁺ Tregs as potential biomarkers of resistance to neoadjuvant chemoimmunotherapy in gastric cancer. Transcriptional programs centered on IL1B/CXCL5 and LGALS3/IDO1 define distinct immune phenotypes that may guide future combination strategies targeting both effector and suppressive arms of the tumor immune response. Full article

Background: The glucocorticoid receptor (GR) regulates the transcription of thousands of genes. In cancer, both oncogenic and tumor suppressive roles of GR have been proposed. Methods: A tissue microarray containing 18,527 samples from 147 tumor (sub-)types and 608 samples from 76 normal tissue types was analyzed for GR expression by immunohistochemistry. Results: GR positivity was found in 76.4% of 14,349 interpretable cancers, including 18.5% with weak, 19.6% with moderate, and 38.3% with strong positivity. GR positivity appeared in all 147 tumor types, with at least one strongly positive tumor in 136 types. Of out tumor entities, 77 of the 147 showed GR positivity in 100% of the cases analyzed. Only six tumor types had less than 50% GR-positive cases, including adenomas with low-/high-grade dysplasia (32.5%/21.7%), adenocarcinomas (17%) and neuroendocrine carcinomas (45.5%) of the colorectum, endometrial carcinomas (25.6%), and rhabdoid tumors (25%). Reduced GR staining was associated with grade progression in pTa (p < 0.0001) and with nodal metastasis in pT2-4 (p = 0.0051) urothelial bladder carcinoma, advanced pT stage (p = 0.0006) in breast carcinomas of no special type (NST), and high grade (p = 0.0066), advanced pT stage (p < 0.0001), and distant metastasis (p = 0.0081) in clear cell renal cell carcinoma. GR expression was unrelated to clinico-pathological parameters in gastric, pancreatic, and colorectal adenocarcinoma, and in serous high-grade carcinoma of the ovary. Conclusions: GR expression is frequent across all cancer types. Associations between reduced GR expression and unfavorable tumor features in certain cancers suggest that the functional importance of GR-regulated genes in cancer progression depends on the cell of tumor origin. Full article

Background/Objectives: TTF-1 and Napsin A are immunohistochemical markers that are widely used for the diagnosis of lung adenocarcinomas or thyroid carcinomas, as well as the characterization of metastases. However, several publications have reported the aberrant expression of one or both markers in extrathoracic malignancies, including gastrointestinal adenocarcinomas. The goal of our study was to determine the frequency of TTF-1- and Napsin A-positive neoplasms in cohorts consisting of esophageal, gastric and colorectal adenocarcinomas. Methods: Buffered formalin-fixed paraffin-embedded tumor tissues from 854 patients with primary resected gastrointestinal and esophageal carcinomas were placed in tissue microarrays (TMAs) for investigation. Between two and six tumor cores were analyzed for each case. For immunohistochemical staining, we used TTF-1 (SPT24 clone) and Napsin A (IP64 clone). Tumors were considered positive if at least 5% of their tumor cells showed weak nuclear (TTF-1) or cytoplasmic (Napsin A) staining. Results: In total, 16 cases showed positive staining for TTF-1, alongside 7 cases for Napsin A. The greatest proportion of TTF-1- and/or Napsin A-positive tumors was found among esophageal adenocarcinomas (5/125 cases; 4%). Co-expression of TTF-1 and Napsin A was found in five cases, including three esophageal and two gastric adenocarcinomas. In colorectal carcinomas, co-expression of these markers was not detected. Conclusions: TTF-1 and Napsin A are useful immunohistochemical makers for establishing the diagnosis of pulmonary adenocarcinoma. Additionally, knowing that a proportion of gastrointestinal neoplasms express these markers can help to avoid diagnostic misinterpretations. Full article

Background/Objectives: TIGD1 (Trigger Transposable Element Derived 1) is a recently identified oncogene with largely unexplored biological functions. Emerging evidence suggests its involvement in multiple cellular processes across cancer types. This study aimed to perform a comprehensive pan-cancer analysis of TIGD1 to evaluate its expression patterns, diagnostic utility, prognostic value, and association with immunotherapy response and drug resistance. Methods: Transcriptomic and clinical data from TCGA and GTEx were analyzed using various bioinformatic tools. Expression profiling, survival analysis, immune correlation studies, gene set enrichment, single-cell sequencing, and drug sensitivity assessments were performed. Results: TIGD1 was found to be significantly upregulated in various tumor types, with notably high expression in colon adenocarcinoma. Elevated TIGD1 expression was associated with poor prognosis in several cancers. TIGD1 levels correlated with key features of the tumor immune microenvironment, including immune checkpoint gene expression, TMB, and MSI, suggesting a role in modulating anti-tumor immunity. GSEA and single-cell analyses implicated TIGD1 in oncogenic signaling pathways. Furthermore, high TIGD1 expression was linked to resistance to several therapeutic agents, including Zoledronate, Dasatinib, and BLU-667. Conclusions: TIGD1 may serve as a promising diagnostic and prognostic biomarker, particularly in colon, gastric, liver, and lung cancers. Its strong associations with immune modulation and therapy resistance highlight its potential as a novel target for precision oncology and immunotherapeutic intervention. Full article

Background/Aims: Gastric dysplasia is a critical precursor to gastric cancer (GC), and accurate diagnosis and grading of these lesions are essential for effective surveillance and intervention. However, current diagnostic methods such as forceps biopsy have notable limitations, underscoring the need for reliable biomarkers. This study aimed to evaluate the diagnostic and grading utility of endocan, a soluble proteoglycan secreted by activated endothelial cells, in gastric dysplastic lesions. Methods: A total of 72 patients with gastric dysplasia, 80 with gastric adenocarcinoma, and 55 healthy controls were prospectively enrolled. Endocan expression in gastric tissue samples was assessed via immunohistochemistry and semi-quantitatively graded. Statistical comparisons were made between control, dysplastic (low-grade and high-grade), and malignant groups. Results: Endocan was negatively expressed in all control subjects and positively expressed in 65.3% of the dysplasia group and 100% of the gastric cancer group (p < 0.001). Notably, all high-grade dysplasia cases were endocan-positive, whereas 75.8% of low-grade dysplasia cases were endocan-negative (p < 0.001). Conclusions: This is the first study to demonstrate that endocan is overexpressed in gastric dysplastic lesions. Tissue endocan expression may serve as a practical and robust marker for the diagnosis and grading of gastric dysplasia, potentially enhancing early detection and risk stratification in gastric carcinogenesis. Full article

The gut microbiota significantly impacts the development and progression of upper gastrointestinal (GI) cancers, including esophageal and gastric cancers. Microbial dysbiosis contributes to carcinogenesis through mechanisms such as inflammation, immune modulation, and direct DNA damage. Techniques for sampling oral, esophageal, and gastric microbiota vary, with standardization being essential for reliable results. Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) are associated with an enrichment of Gram-negative bacteria, promoting inflammation and cancer progression. Esophageal squamous cell carcinoma (ESCC) also shows distinct microbial patterns, with reduced diversity and increased harmful bacteria like Porphyromonas gingivalis and Fusobacterium nucleatum. In gastric cancer (GC), Helicobacter pylori (HP) and non-HP gastric microbiota play significant roles, with diverse microbial communities contributing to cancer development through nitrate reduction, immune modulation, and inflammation. Emerging evidence highlights the role of non-HP bacteria in promoting carcinogenesis, with specific taxa like Fusobacterium nucleatum and Lactobacillus influencing tumor growth and immune evasion. Further research is needed to elucidate the complex interactions between gut microbiota and upper GI cancers, paving the way for novel diagnostic and therapeutic approaches. Understanding these microbial dynamics offers potential for microbiota-based interventions, improving the early detection, prognosis, and treatment of upper GI cancers. This comprehensive review summarizes the available evidence on the role of microbiota in upper GI oncology and the need for continued exploration in this field. Full article

Objectives: The objective of this study was to assess the relationship of VEGF-C and LVD with pathoclinical factors of potential prognostic value and with the survival time of gastric cancer patients. Materials and methods: A total of 103 radically operated patients for gastric cancer who did not undergo neoadjuvant therapy were included in this study. The minimum follow-up period after surgery was 61 months. VEGF-C and lymphatic vessels were immunohistochemically determined using antibodies, including VEGF-C (c-20) sc 1881-Goat Polyclonal IgG (Santa Cruz Biotechnology) and Podoplanin D2-40 Mouse Monoclonal Antibody (ROCHE). The relationship between VEGF-C expression in gastric adenocarcinoma cells and the density of lymphatic vessels at the periphery of the primary tumor was assessed, along with the relationships of VEGF-C and LVD with selected pathoclinical parameters of gastric cancer and prognosis. Results: VEGF-C overexpression was associated with increased LVD (Mann–Whitney U test, p = 0.03) and the Lauren intestinal type of cancer (Pearson’s chi-square test, p < 0.001). Increased LVD was more often associated with cancers located beyond the cardia (Mann–Whitney U test, p = 0.04). We did not demonstrate an association of VEGF-C or LVD with OS or with prognostic features, such as pT, pN, or pTNM staging. However, in the Lauren intestinal type of cancer, VEGF-C overexpression correlated with shorter OS (log-rank, p = 0.01) and, at the level of p = 0.05 in multivariate analysis, it had an independent negative prognostic value. Conclusions: Peritumoral overexpression of VEGF-C in primary gastric cancer tumors is associated with increased LVD. The Lauren intestinal type of cancer is associated with VEGF-C overexpression. The overexpression of VEGF-C in intestinal-type gastric cancer is associated with worse prognosis. Full article

Introduction: Bronchopulmonary Neuroendocrine Neoplasms (NEN) occur in 2–7% of patients with multiple endocrine neoplasia type 1 (MEN1). Precursor lesions have been identified for MEN1-related pancreatic, duodenal, and gastric NEN. The aim of the current study using a MEN1 mouse model was to define the precursor lesions of bronchopulmonary NEN and evaluate the potential prophylactic antitumor effects of somatostatin analogues in a transgenic MEN1 mouse model. Methods: Fifteen mice, germline heterozygous for Men1(+/T), were treated with subcutaneous injections of lanreotide autogel (Somatuline Autogel^®, IPSEN Pharma), while 15 mice were treated with subcutaneous injections of physiologic sodium chloride as the control group. Five mice from each group were euthanized after 12, 15, and 18 months, respectively. The complete lungs were resected and evaluated after hematoxylin and eosin staining and immunohistochemistry for synaptophysin and chromogranin A. Results: In the lungs of the 30 evaluated mice, whether treated or placebo treated, no bronchopulmonary neuroendocrine cell hyperplasia nor neuroendocrine neoplasia was detected through histopathology. However, pulmonary adenocarcinoma developed in 2 (13%) of the 15 untreated mice and in 1 (7%) of the 15 lanreotide-treated mice. Conclusions: Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary NEN or precursor lesions, but pulmonary adenocarcinoma. This surprising result needs to be investigated in more detail. Full article

Background: The survival rate among stomach adenocarcinoma patients is exceedingly low. NGAL (neutrophil gelatinase-associated lipocalin) has pivotal roles in cell proliferation, immunity, and tumorigenesis. KIM-1 (Kidney Injury Molecule-1), also referred to as TIM-1 and HAVcr-1, is a transmembrane glycoprotein located in healthy immune cells and epithelial cells, and its upregulated form is generally found in several human cancers. Aim: The aim of this study was to investigate the prognostic significance of the expression of KIM-1 and NGAL in stomach cancers and identify NGAL-positive inflammatory cells in the tumor microenvironment. Materials and Methods: We immunohistochemically evaluated the expression of NGAL and KIM1 in 172 cases of stomach adenocarcinomas. Result: The mean age of the patients was 64.07 ± 12.35 years, and the mean and median follow-up period were 25.5 and 20.3 months, respectively. The expression rates of KIM-1 and NGAL in tumor cells were identical at 31.4% (n = 54). In 27 of these cases, both proteins were present. Among the deceased patients, the rate of simultaneous KIM-1 and NGAL positivity was relatively higher (p = 0.041). NGAL-positive inflammatory cells were observed in 13.4% of cases, with no significant correlation between these cells and survival times (p = 0.497). However, there was a negative correlation between survival times and KIM-1 (p = 0.037) and NGAL (p = 0.016) expressions in tumor cells. Conclusions: The present study has shown that KIM-1- and NGAL-positive tumor cells are influential in gastric tumorigenesis. Given the progress in anti-KIM-1 therapy, the presence of KIM-1 expression could contribute to the development of new treatment options for aggressive gastric cancer. However, these discoveries need to be validated in larger-scale studies. Full article

Advanced gastric adenocarcinoma (GAC) carries a poor prognosis. Targeted therapy in GAC has traditionally been limited to anti-human epidermal growth factor receptor-2 and anti-vascular endothelial growth factor agents. Recent years have brought immune checkpoint therapy to the GAC treatment landscape. However, continued discovery of targeted therapy in GAC is needed. Claudins, transmembrane proteins located in tight junctions of epithelial and endothelial cells, help regulate cellular polarity. Claudin dysregulation has been linked to cancers and other diseases. Claudin 18.2 specifically has become a new novel and exciting biomarker for GAC. Many agents are in the investigative pipeline, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric T-cell therapy. Recently, zolbetuximab, an anti-claudin 18.2 monoclonal antibody, was the first of these agents to get FDA approval. Here, we review zolbetuximab’s place in therapy along with other agents being explored. Full article

Background: Gastric adenocarcinoma is a highly lethal neoplasm with a short survival especially when metastatic. Few effective treatments are available for the control of the disease and palliation of patients with metastatic gastric cancer. Although progress has been made in the elucidation of molecular pathways invoked in gastric carcinogenesis, this knowledge has not yet led to major breakthroughs, in contrast to several other types of cancer. The role of stem cell transcription factors SOX2 and CDX2 is of particular interest in the pathogenesis of gastric cancer. Methods: The cohort of gastric adenocarcinomas from The Cancer Genome Atlas (TCGA) was interrogated and two groups of gastric cancers, with CDX2 induction and SOX2 suppression on the one hand and with CDX2 induction and SOX2 maintained expression on the other hand were retained. The induction of expression of the two transcription factors was defined as a mRNA expression z score compared with normal samples above zero. The two groups were compared for clinical-pathologic and genomic differences. Results: Among gastric cancers with up-regulated CDX2 mRNA, cancers with suppressed SOX2 mRNA were slightly more numerous (55.9%) than those with a maintained SOX2 expression. The SOX2 suppressed group had a higher prevalence of MSI high cancers (30.9% versus 10%) and of cases with high tumor mutation burden (35% versus 12.4%) than cancers with a SOX2 maintained expression, which presented more frequently high Chromosomal Instability (CIN). The group with SOX2 suppression had higher rates of mutations in many gastric cancer-associated genes such as epigenetic modifiers ARID1A, KMT2D, KMT2C, and KMT2B, as well as higher rates of mutations in genes encoding for receptor tyrosine kinases ERBB4 and FGFR1. On the other hand, TP53 mutations and amplifications in MYC, ERBB2, and CCNE1 were more common in the group with a maintained expression of SOX2, approaching significance for MYC. Conclusions: Notable differences are present in the genomic landscape of CDX2-induced gastric cancer depending on the level of expression of SOX2 mRNA. Despite this, SOX2 mRNA expression levels were not prognostic. Full article

Background: Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) of the esophago-gastric junction (EGJ) are rare aggressive malignant neoplasms, with, currently, limited evidence regarding the appropriate therapeutic approach. Methods: Herein, we report multimodal treatment management of a patient with oligometastatic MiNEN of EGJ (Siewert III), discuss the lessons learnt, and provide a review of the literature. Results: A 69-year-old female was diagnosed with a locally advanced EGJ tumor and three liver metastases (cT4, cN+, M1). Although the initial histology from biopsy revealed adenocarcinoma, the histopathology of a lymph node biopsy from staging laparoscopy revealed infiltration of neuroendocrine carcinoma cells. Thus, the diagnosis of a mixed neuroendocrine adenocarcinoma was set, and systemic chemotherapy with etoposide and cisplatin was initiated. A major clinical response led to conversion surgical resection of the primary tumor and metastases, followed by adjuvant therapy with immunotherapy. The patient is free of disease at the 3-year follow-up. A review of the literature on similar cases of EGJ or gastric MiNENs revealed a limited number of cases. Out of the 39 patients, 20 of them (51.3%) suffered from advanced-stage disease. The MiNEN diagnosis typically occurred after surgical resection. Systemic chemotherapy against the neuroendocrine component demonstrated significant response rates, while in cases in which conversion surgery was offered, prolongation of survival was demonstrated. Conclusions: Our case and the existing literature on MiNENs of EGJ underline the need for a personalized treatment approach following thorough interpretation of comprehensive pretherapeutic staging. Conversion radical surgery with curative intent could be considered in cases of major or complete clinical response to induction chemotherapy with potentially favorable outcomes. Full article