Gastric Phenotype Research Articles

Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease

Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3SA/SA mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3SA/SA mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3SA/SA mice, which was associated with reduced proliferative potential of infected Stat3SA/SA gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3SA/SA mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.

Diagnostic algorithm of magnifying endoscopy with crystal violet staining for non-ampullary duodenal epithelial tumors.

Little is known about the usefulness of magnifying endoscopy with crystal violet staining (ME-CV) for the diagnosis of duodenal tumors. We assessed the ability of ME-CV to distinguish Vienna classification (VCL) category 4/5 (C4/5) from category 3 (C3) non-ampullary duodenal epithelial tumors (NADETs). A total of 76 NADETs were studied. We retrospectively analyzed the diagnostic values of the white light endoscopy (WLE) scoring system and the ME-CV algorithm with receiver operating characteristic (ROC) curves, and three endoscopists calculated the sensitivity, specificity, accuracy, and the area under the curve (AUC) of each. The diagnostic values were tested among NADETs overall and among subgroups of tumors with gastric, gastrointestinal or intestinal mucin phenotypes. Inter-observer agreement of the diagnostic results was also calculated. According to the VCL, 54 lesions (71.1%) were regarded as C3 and 22 lesions (28.9%) as C4/5. The sensitivity, specificity, accuracy and AUC of ME-CV were higher than those of the WLE scoring system (63.6 vs 54.5, 85.2 vs 75.9, 78.9 vs 69.7, 0.744 vs 0.652, respectively). Inter-observer agreements of the WLE scoring system and ME-CV were both moderate (kappa 0.45 and 0.41). ME-CV had higher sensitivity, specificity, accuracy and AUC than those of the WLE scoring system among the gastric and intestinal phenotypes of NADETs. ME-CV is appropriate for the diagnosis of C4/5 and C3 NADETs.

Annexin A10 is involved in the induction of pancreatic duodenal homeobox‑1 in gastric cancer tissue, cells and organoids.

Gastric cancer (GC) is the third most common cause of cancer‑related death in the world. Annexin A10 (ANXA10), a member of the Annexin family, is a calcium‑/phospholipid‑binding protein; however, little is known concerning its functions. It is still unclear what molecule is involved in the induction of ANXA10. In the present study, we performed immunohistochemistry to evaluate the expression of ANXA10, pancreatic and duodenal homeobox‑1 (PDX1) and mucin phenotype markers in 130GC samples. ANXA10 was detected in 63(48%) of the 130GC cases and loss of ANXA10 was significantly correlated with disease progression and poor clinical outcomes in GC. PDX1 was significantly correlated with ANXA10 in GC cases and cell lines. Although PDX1 was not significantly correlated with the GC cases with any of the mucin phenotypes, ANXA10 was preferentially detected in the GC cases with the gastric mucin phenotype. As a further investigation, we generated organoids derived from human GC and identified the duplication of the mucin phenotypes of GC by immunohistochemistry. The repression effect on cell growth that was observed in the ANXA10‑knockdown cell lines was also clearly observed in the human gastric organoids. We demonstrated that the expression of ANXA10 was correlated with the gastric mucin phenotype and ANXA10 was involved in the induction of PDX1 expression in GC. We also provided evidence that GC organoids represent a powerful tool for scrutinizing the biology of GC, especially with regard to the mucin phenotype.

1207 Differences of Gastric Cancer Characteristics Between With and Without Helicobacter pylori Eradication

INTRODUCTION: Although the rate of gastric cancer (GC) after Helicobacter pylori (H. pylori) eradication has gradually increased over time, the features of GC following eradication remain to be examined. In this study, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. METHODS: 50 subjects with GC following eradication [HP(-) group] and 151 patients with GC with H. pylori infection [HP(+) group] were enrolled in this study. Clinicopathological features, such as age, gender, endoscopic atrophy, tumor form, location, depth of invasion, histology, were assessed. The manifestation of GC was further evaluated using immunohistochemistry of Ki-67, CDX22, p53, claudin18, E-cadherin, c-myc and In situ hybridization for detecting Epstein-Barr virus (EBV). RESULTS: Macroscopic analysis revealed a significantly higher ratio of depressed type/elevated type in HP(-) group compared with HP(+) group (30/19 vs. 61/77, P = 0.041). Tumor size was significantly greater in HP(-) group compared with the HP(+) group (13.02 ± 7.10 vs. 16.53 ± 11.12, P = 0.0019). The gastric mucin phenotype was more predominant in HP(-) group compared with HP(+) group, and the proportion of CDX2-positive cases was lower in HP(-) group (8 out of 18; 44.4%) compared with HP(+) group (18 out of 19; 94.7%) (P = 0.00082). Ki-67 labeling index was significantly lower in HP(-) group (32.03 ± 22.15) compared with the HP(+) group (79.20 ± 14.87, P < 0.0001). No patient in HP(-) group showed significant expression of EBV infection. CONCLUSION: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in morphology, mucin phenotype, and proliferation rate. It is necessary to be careful about these differences in GC screening.

Different phenotypes of gastric fundic gland polyposis and cancer in patients with familial adenomatous polyposis depending on Helicobacter pylori infection

A 37-year-old male with tarry stool presented to our hospital. Esophagogastroduodenoscopy revealed advanced gastric cancer, fundic gland polyposis (FGPsis), and negativity for Helicobacter pylori (HP) infection. Computed tomography exhibited multiple liver tumors. Total colonoscopy (TCS) demonstrated 139 tubular adenomas. He was diagnosed as having unresectable gastric cancer and received systemic chemotherapy. His sister and mother had colorectal adenomatous polyposis as revealed by TCS. His sister had FGPsis and was negative for HP infection, whereas his mother had early gastric cancer with HP infection but not FGPsis. Genetic analysis revealed a novel mutation in exon 15 of the APC gene (NM_000038.5: c.7647_7648_delTG) for the patient, his mother, and his sister, whereas no mutation was found for his father who had no gastrointestinal polyps. Therefore, the pedigree was diagnosed as an FAP family with a novel APC germline mutation which had different gastric phenotypes depending on the status of HP infection.

Gastric foveolar-type adenomas endoscopically showing a raspberry-like appearance in the Helicobacter pylori -uninfected stomach.

Background and study aims Foveolar-type adenoma is described as a very rare tumor that occurs in individuals without Helicobacter pylori (HP) infection and diagnosed as adenocarcinoma in the Japanese Classification of Gastric Carcinoma (JCGC). However, we have frequently encountered patients with foveolar-type adenoma that endoscopically resembles a hyperplastic polyp, suggesting that it has just been overlooked to date. Here, we analyzed clinicopathological characteristics of a special subtype of foveolar-type adenoma showing specific endoscopic findings. Patients and methods From a total of 212 patients with gastric cancer resected during a 22-month period, we enrolled 14 (6.6 %) diagnosed with foveolar-type adenoma (adenocarcinoma in JCGC). HP infection status was determined by eradication history, HP serum IgG antibody level, urea breath test, and endoscopic and histological findings. All lesions were observed using white-light endoscopy and narrow-band imaging with magnification endoscopy (NBIME). Endoscopically resected lesions were histologically examined. Results None of 14 patients had a current or past history of HP infection. All lesions were visualized on non-atrophic gastric mucosa as small reddish protrusions with fine granular surface, showing a raspberry-like appearance. NBIME showed papillary or gyrus-like microstructures with irregular capillary. Lesions were histologically diagnosed as foveolar-type adenoma showing MUC5AC-positive gastric mucin phenotype. Ki-67 was overexpressed (median labeling index 69.9 %, range 28.4 – 92.1 %), though all lesions were an intraepithelial tumor without stromal invasion. p53 over-staining was not seen in any. Conclusions Raspberry-like lesions on non-atrophic gastric mucosa in HP-uninfected individuals should be evaluated for the possibility of a special subtype of foveolar-type adenoma.

Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells.

Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.

Endoscopic and clinicopathological features of intramucosal, histologically mixed-type, low-grade, well-differentiated gastric tubular adenocarcinoma with the potential for late-onset lymph node metastasis

BackgroundIntramucosal, histologically mixed-type, low-grade (LG), well-differentiated gastric tubular adenocarcinomas (tub1s; LG-tub1s) have larger mean diameters and exhibit a higher frequency of the gastric mucin phenotype (G-phenotype) than pure LG-tub1s. In proportion to their increases in diameter, G-phenotype differentiated-type early gastric cancer (EGC) tumours reportedly grow to eventually contain (an) undifferentiated-type component(s) and LG-tub1s, which are included in differentiated-type EGCs, reportedly exhibit changes in their glandular architectural and cytological atypia grades from LG to high-grade (HG) and can grow to contain a moderately differentiated tubular adenocarcinoma (tub2) component and undifferentiated components. Because they generally show a higher frequency of malignancy relative to tumours with a higher atypia grade and lower differentiation degree, it is suggested that, among mixed-type LG-tub1s, G-phenotype LG-tub1s containing an HG-tub2 component (LG-tub1s > HG-tub2) with undifferentiated components might lead to late-onset metastasis to lymph nodes even after a successful endoscopic submucosal dissection (ESD). We aimed to clarify the endoscopic and clinicopathological features of these G-phenotype LG-tub1s > HG-tub2.MethodsOf the 13,217 oesophagogastroduodenoscopies performed at our institutions between September 2008 and March 2016, 185 EGC lesions were evaluated in this retrospective observational study. Among these EGC lesions, 60 intramucosal LG-tub1s were divided into 53 tub1 (44 pure LG-tub1s and nine LG-tub1s containing HG-tub1) lesions and seven LG-tub1 > tub2 (LG-tub1 containing LG- and HG-tub2) lesions.ResultsThe frequencies of the superficial depressed type (P = 0.026), reddish colour (P = 0.006), HG of contained tub2s (P = 0.006), and G-phenotype (P = 0.028) were significantly higher in the LG-tub1 > tub2 group than those in the tub1 group. However, the largest lesion of the LG-tub1 > tub2 group had a superficial flat appearance, an isochromatic colour, an HG-tub2 and an undifferentiated component, and a large diameter greater than 30 mm, and it exhibited a G-phenotype.ConclusionsIntramucosal G-phenotype LG-tub1s > HG-tub2 are potential premalignant stomach neoplasms that may have specific endoscopic and clinicopathological features. However, G-phenotype LG-tub1s > HG-tub2 with undifferentiated component, which potentially show higher malignancy than those without undifferentiated components might change from a reddish to isochromatic colour. Accurately diagnosing, treating, and following-up G-phenotype LG-tub1s > HG-tub2 might decrease the number of patients who experience late-onset metastasis after ESD.

EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma.

Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.

MYC aberrations in AC and PDA

Introduction: The aim of our study was investigation of the presence of MYC amplification in PDA and carcinoma of the vater. Method: 74 cases of PDA, 15 cases of cancer of the vater and seven cases of control pancreatic tissue were included in the study. We examined the expression of MUC1, 2 and 5AC types by immunohistochemical analyses in PDA and carcinoma of the vater. Dual-color interphase fluorescent in situ hybridization (FISH) was performed on 4-μm thick sections of formalin-fixed paraffin-embedded (FFPE) tumors. Results: Most of the PDA have been reported as - MUC1 + / MUC5AC + and accounted for 42% (31/74), the smallest was a group with the intestinal mucin phenotype (MUC2 +) and only 7% (5/74). The group with the gastric phenotype (MUC5AC +) was - 15% (11/74). Carcinoma of the vater in most cases have been reported as MUC2 + and accounted for 80% (12/15), 20% (3/15) of cases the tumor presented as MUC1 + /MUC5AC +. In normal ducts of all 7 control cases the tested loci had balanced (diploid) profile. FISH analysis of PDA revealed of MYC gene copy number in 21/74 (28%) cases. Eight of the 74 pancreatic tumors (10,8%) revealed MYC gain in association with an increased chromosome 8 copy number. Conclusion: MYC gene amplification should be considered as a marker of a more aggressive behavior in cancers biliary pancreaticduodenal region. Diploid profile MYC gene in carcinomas of the vater indicates a more favorable prognosis compared with ductal adenocarcinomas of the pancreas.

A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk

BackgroundHelicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.ResultsWe performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.ConclusionThere are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.

Variables affecting penetrance of gastric and duodenal phenotype in familial adenomatous polyposis patients

BackgroundPatients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk-reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance.MethodsIndividuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number.ResultsThe distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype.ConclusionsMost FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location.Trial registrationNCT 01187901 registered August 24, 2010, prospective to enrollment.

Abstract 2475: Long noncoding RNA NNT-AS1 sponges miR-424 to promote the progression and metastasis of gastric cancer

Abstract Background: Long noncoding RNAs (lncRNAs) have been illustrated to function as important regulator in carcinogenesis and cancer progression. However, the roles of lncRNA NNT-AS1 in gastric cancer remain unclear. In present study, we investigate the expression level of NNT-AS1 in gastric cancer tissue and the role on gastric cancer cells tumorigenesis. Methods: NNT-AS1 expression level was measured using RT-PCR. The prognosis and survival rate of gastric cancer patients with high/low expression of NNT-AS1 was tracked and analyzed. Cellular experiments were performed to test the role of NNT-AS1 on gastric cancer phenotype, including proliferation analysis, transwell assay, EMT-related marker blots and xenograft mice assay. Bioinformatics online program and luciferase assay were performed to predict and verify the potential miRNAs targeting NNT-AS1. Results: NNT-AS1 expression level was significantly upregulated in 55 cases of gastric cancer tissue samples compared with adjacent normal tissue. Besides, the aberrantly enhanced NNT-AS1 expression predicted poor prognosis and lower survival rate. In vitro, NNT-AS1 knockdown suppressed the gastric cancer cells proliferation, invasion and EMT-related marker (N-cadherin and vimentin) expression. In vivo, lentivirus mediated NNT-AS1 silencing decreased the tumor growth. MiR-503 was verified to be the target miRNA of NNT-AS1 using bioinformatics online program and luciferase assay. Furthermore, miR-424 could reverse the role of NNT-AS1 on gastric cancer cells. Conclusion: In conclusion, our study indicates that NNT-AS1 sponges miR-424 to facilitate gastric cancer cells invasion and metastasis, revealing the oncogenic role of NNT-AS1 on gastric cancer cells. Citation Format: Beibei Chen, Qingfang Zhao, Lulu Guan, Huifang Lv, Liangyu Bie, Jinxi Huang, Jitian Li, Jianying Zhang, Xiaobing Chen. Long noncoding RNA NNT-AS1 sponges miR-424 to promote the progression and metastasis of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2475.

Capillary morphogenesis gene 2 maintains gastric cancer stem-like cell phenotype by activating a Wnt/\u03b2-catenin pathway

A growing body of evidence shows that the development and progression of gastric cancer (GC) is mainly associated to the presence of gastric cancer stem-like cells (GCSLCs). However, it is unclear how GCSLC population is maintained. This study aimed to explore the role of capillary morphogenesis gene 2 (CMG2) in GCSLC maintenance and the relevance to GC progression. We found that CMG2 was highly expressed in GC tissues and the expression levels were associated with the invasion depth and lymph node metastasis of GC, and inversely correlated with the survival of GC patients. Sorted CMG2High GC cells preferentially clustered in CD44High stem-like cell population, which expressed high levels of stemness-related genes with increased capabilities of self-renewal and tumorigenicity. Depletion of CMG2 gene resulted in reduction of GCSLC population with attenuated stemness and decrease of invasive and metastatic capabilities with subdued epithelial–mesenchymal transition phenotype in GC cells. Mechanistically, CMG2 interacted with LRP6 in GCSLCs to activate a Wnt/β-catenin pathway. Thus, our results demonstrate that CMG2 promotes GC progression by maintaining GCSLCs and can serve as a new prognostic indicator and a target for human GC therapy.

Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice.

The molecular mechanisms underlying the pathogenesis of diffuse-type gastric cancer (DGC) have not been adequately explored due to a scarcity of appropriate animal models. A recently developed tool well suited for this line of investigation is the Pdx-1-Cre;Cdh1F/+ ;Trp53F/F ;Smad4F/F (pChe PS) mouse model that spontaneously develops metastatic DGC showing nearly complete E-cadherin loss. Here, we performed a proteogenomic analysis to uncover the molecular changes induced by the concurrent targeting of E-cadherin, p53, and Smad4 loss. The gene expression profiles of mouse DGCs and in vivo gastric phenotypes from various combinations of gene knockout demonstrated that these mutations collaborate to activate cancer-associated pathways to generate aggressive DGC. Of note, WNT-mediated epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM)-cytokine receptor interactions were prominently featured. In particular, the WNT target gene osteopontin (OPN) that functions as an ECM cytokine is highly upregulated. In validation experiments, OPN contributed to DGC stemness by promoting cancer stem cell (CSC) survival and chemoresistance. It was further found that Bcl-xL acts as a targetable downstream effector of OPN in DGC CSC survival. In addition, Zeb2 and thymosin-β4 (Tβ4) were identified as prime candidates as suppressors of E-cadherin expression from the remaining Cdh1 allele during DGC development. Specifically, Tβ4 suppressed E-cadherin expression and anoikis while promoting cancer cell growth and migration. Collectively, these proteogenomic analyses broaden and deepen our understanding of the contribution of key driver mutations in the stepwise carcinogenesis of DGC through novel effectors, namely OPN and Tβ4.

Endoscopic and Immunohistochemical Characteristics of Gastric Cancer with versus without Helicobacter Pylori Eradication

Background/Aims: The rate of gastric cancer (GC) after Helicobacter pylori eradication has gradually increased; therefore, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. Methods: This study included 50 subjects with GC after eradication (GCE) and 151 patients with GC with H. pylori infection (GCI). Clinicopathological factors were assessed. The manifestation of GC was further evaluated using immunohistochemical analysis and in situ hybridization. Results: Macroscopic analysis revealed a significantly higher ratio of depressed type /elevated type in the GCE compared with the GCI (30/19 vs. 61/77, p = 0.041). The gastric phenotype was more common in the GCE compared with the GCI, and the proportion of CDX2-positive cases was lower in the GCE (8 out of 18; 44.4%) compared with the GCI (18 out of 19; 94.7%; p = 0.00082). Ki-67 labeling index was significantly lower in the GCE (32.03 ± 22.15) compared with the GCI (79.20 ± 14.87, p < 0.0001). No patient in the GCE showed evidence of Epstein-Barr virus infection. Conclusion: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in terms of morphology, mucin phenotype, and proliferation rate.

Oesophago-gastric cancer: One disease or separate entities?: Translating molecular subtyping into clinical practice

The comprehensive molecular analysis of esophageal adenocarcinomas (EAC), gastroesophageal junction (GEJ) carcinomas and gastric adenocarcinomas showed several resemblances and a continuum of molecular profile can be described (1). EAC are molecularly closer to gastric cancer than to esophageal squamous cell carcinoma (ESCC), which are in turn close to head and neck cell carcinoma. Among the 4 four described molecular groups of gastric cancer (Epstein-Barr virus (EBV) infection, microsatellite instability (MSI), chromosomal instability (CIN) and genomic stability (GS), EAC and gastric cancer group with a CIN phenotype form a distinct group from the others 3 gastric cancer groups. For the GEJ clearly derived for esophagus the only phenotype was the CIN. On the contrary, the MSI phenotype and the phenotype linked to EBV was observed only in GEJ for which the origin is uncertain or gastric. These results suggest that there is no specific anatomic entity but rather molecular entities with a large predominance of gastric CIN phenotype in the GEJ carcinomas, the others phenotypes show be considered as gastric cancers. Nevertheless, among the EAC and GEJ with CIN phenotype there is an inverse gradient of methylation from the esophagus to the stomach. Four clusters (C1 to C4) can be identified based on the abundance of CpG methylation. Several genes are specifically methylated according to the cluster of methylation and could explain a difference of sensitivity regarding alkylating agents. Several other differences in the CIN subgroup can be reported in terms of frequency of somatic genetic alteration in APC, SMARC4 or CDKN2A accordingly to the tumor location.

Neoplastic Lesions of Gastric Adenocarcinoma and Proximal Polyposis Syndrome (GAPPS) Are Gastric Phenotype.

(1) the spectrum of gastric pathology associated with GAPPS is wider than previously reported, (2) the earliest microscopic clue is the finding of hyperproliferative aberrant pits, and (3) the dysplasia is gastric phenotype and the subsequent adenocarcinoma may follow the gastric pathway of carcinogenesis.

CD44v6 increases gastric cancer malignant phenotype by modulating adipose stromal cell-mediated ECM remodeling.

CD44, an abundantly expressed adhesion molecule, and its alternative splice variants have been associated with tumorigenesis and metastasis. In the context of gastric cancer (GC), de novo expression of CD44 variant 6 (CD44v6) is found in more than 60% of GCs, but its role in the pathogenesis and progression of this type of cancer remains unclear. Using a combination of media conditioning experiments and decellularized extracellular matrices (ECMs), this study investigates the hypothesis that CD44v6 overexpression enhances tumor cell malignant behavior by modulating stromal cell-mediated ECM remodeling. Our findings indicate that soluble factors secreted by CD44v6 expressing GC cells particularly increase proliferation and myofibroblastic differentiation of adipose stromal cells (ASCs). These changes in ASC phenotype mediate the deposition of fibrotic/desmoplastic ECM that, in turn, stimulates GC proliferation and inhibits GC clustering. Pharmacological inhibition of matrix metalloproteinase (MMP) activity in tumor cells abrogated matrix-induced changes in tumor cell malignant behavior. Additionally, studies in mice confirmed the pathological relevance of CD44v6 expression and consequential changes in ECM remodeling to gastric tumorigenesis in vivo. Collectively, these results indicate a direct link between CD44v6, ECM remodeling, and GC malignant behavior opening new insights into potential CD44v6-targeted therapies.

Activation of Signal Transduction and Activator of Transcription 3 Signaling Contributes to Helicobacter-Associated Gastric Epithelial Proliferation and Inflammation.

Background/Aim Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter-associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter-induced gastric phenotypes. Methods To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3-knockout (Stat3Δgec) mice. Mice were infected with Helicobacter felis and euthanized at 18 months postinfection. Mouse gastric organoids were treated with recombinant IL-6 (rIL-6) or rIL-11 and a JAK inhibitor (JAKi) to assess the role of IL-6/STAT3 signaling in vitro. Results Inflammation and mucous metaplasia were more severe in WT mice than in Stat3Δgec mice. The epithelial cell proliferation rate and STAT3 activation were increased in WT mice. Application of rIL-6 and rIL-11 induced expression of intestinal metaplasia-associated genes, such as Tff2; this induction was suppressed by JAKi administration. Conclusions Loss of STAT3 signaling in the gastric mucosa leads to decreased epithelial cell proliferation, atrophy, and metaplasia in the setting of Helicobacter infection. Therefore, activation of STAT3 signaling may play a key role in Helicobacter-associated gastric carcinogenesis.