Progression Of Gastric Carcinogenesis Research Articles

Helicobacter pylori-associated Chronic Atrophic Gastritis and Progression of Gastric Carcinogenesis.

Chronic inflammation due to a Helicobacter pylori (H. pylori) infection is a representative cause of gastric cancer that can promote gastric carcinogenesis by abnormally activating immune cells and increasing the inflammatory cytokines levels. H. pylori infections directly cause DNA double-strand breaks in gastric epithelial cells and genetic damage by increasing the enzymatic activity of cytidine deaminase. Eventually, gastric cancer is induced through dysplasia. Hypermethylation of tumor suppressor genes is an important cause of gastric cancer because of a H. pylori infection. In addition, the changes in gastric microbiota and the mucosal inflammatory changes associated with a co-infection with the Epstein-Barr virus are associated with gastric cancer development. DNA damage induced by H. pylori and the subsequent responses of gastric stem cells have implications for gastric carcinogenesis. Although the pathogenesis of H. pylori has been established, many uncertainties remain, requiring more study.

Meta-analysis reveals Helicobacter pylori mutual exclusivity and reproducible gastric microbiome alterations during gastric carcinoma progression

ABSTRACT Accumulating evidence shows that the gastric bacterial community may contribute to the development of gastric cancer (GC). However, the reported alterations of gastric microbiota were not always consistent among the literature. To assess reproducible signals in gastric microbiota during the progression of GC across studies, we performed a meta-analysis of nine publicly available 16S datasets with standard tools of the state-of-the-art. Despite study-specific batch effect, significant changes in the composition of the gastric microbiome were found during the progression of gastric carcinogenesis, especially when the Helicobacter pylori (HP) reads were removed from analyses to mitigate its compositional effect as they accounted for extremely large proportions of sequencing depths in many gastric samples. Differential microbes, including Fusobacterium, Leptotrichia, and several lactic acid bacteria such as Bifidobacterium, Lactobacillus, and Streptococcus anginosus, which were frequently and significantly enriched in GC patients compared with gastritis across studies, had good discriminatory capacity to distinguish GC samples from gastritis. Oral microbes were significantly enriched in GC compared to precancerous stages. Intriguingly, we observed mutual exclusivity of different HP species across studies. In addition, the comparison between gastric fluid and mucosal microbiome suggested their convergent dysbiosis during gastric disease progression. Taken together, our systematic analysis identified novel and consistent microbial patterns in gastric carcinogenesis.

Is intestinal metaplasia the point of no return in the progression of gastric carcinogenesis?

Is intestinal metaplasia the point of no return in the progression of gastric carcinogenesis?

Inhibition or Reversal of the Epithelial-Mesenchymal Transition in Gastric Cancer: Pharmacological Approaches.

Epithelial-mesenchymal transition (EMT) constitutes one of the hallmarks of carcinogenesis consisting in the re-differentiation of the epithelial cells into mesenchymal ones changing the cellular phenotype into a malignant one. EMT has been shown to play a role in the malignant transformation and while occurring in the tumor microenvironment, it significantly affects the aggressiveness of gastric cancer, among others. Importantly, after EMT occurs, gastric cancer patients are more susceptible to the induction of resistance to various therapeutic agents, worsening the clinical outcome of patients. Therefore, there is an urgent need to search for the newest pharmacological agents targeting EMT to prevent further progression of gastric carcinogenesis and potential metastases. Therapies targeted at EMT might be combined with other currently available treatment modalities, which seems to be an effective strategy to treat gastric cancer patients. In this review, we have summarized recent advances in gastric cancer treatment in terms of targeting EMT specifically, such as the administration of polyphenols, resveratrol, tangeretin, luteolin, genistein, proton pump inhibitors, terpenes, other plant extracts, or inorganic compounds.

Nuclear magnetic resonance-based tissue metabolomic analysis clarifies molecular mechanisms of gastric carcinogenesis.

Gastric cancer (GC) is one of the deadliest cancers worldwide, and the progression of gastric carcinogenesis (GCG) covers multiple complicated pathological stages. Molecular mechanisms of GCG are still unclear. Here, we undertook NMR‐based metabolomic analysis of aqueous metabolites extracted from gastric tissues in an established rat model of GCG. We showed that the metabolic profiles were clearly distinguished among 5 histologically classified groups: control, gastritis, low‐grade gastric dysplasia, high‐grade gastric dysplasia (HGD), and GC. Furthermore, we carried out metabolic pathway analysis based on identified significant metabolites and revealed significantly disturbed metabolic pathways closely associated with the 4 pathological stages, including oxidation stress, choline phosphorylation, amino acid metabolism, Krebs cycle, and glycolysis. Three metabolic pathways were continually disturbed during the progression of GCG, including taurine and hypotaurine metabolism, glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism. Both the Krebs cycle and glycine, serine, and threonine metabolism were profoundly impaired in both the HGD and GC stages, potentially due to abnormal energy supply for tumor cell proliferation and growth. Furthermore, valine, leucine, and isoleucine biosynthesis and glycolysis were significantly disturbed in the GC stage for higher energy requirement of the rapid growth of tumor cells. Additionally, we identified potential gastric tissue biomarkers for metabolically discriminating the 4 pathological stages, which also showed good discriminant capabilities for their serum counterparts. This work sheds light on the molecular mechanisms of GCG and is of benefit to the exploration of potential biomarkers for clinically diagnosing and monitoring the progression of GCG.

Association of increased B7 protein expression by infiltrating immune cells with progression of gastric carcinogenesis.

B7 negative costimulatory molecules are a group of molecules associated with the occurrence, development, and therapy of cancers. Here, we aimed to determine the clinical significance of PD-L1, B7-H3, and B7-H4 and their expression in CD8 and CD68 positive cells at different stages of gastric carcinogenesis.We detected PD-L1, B7-H3, B7-H4, CD8, and CD68 expression in samples by immunohistochemical staining of 62 chronic superficial gastritis (CSG) samples, 72 chronic atrophic gastritis (CAG) samples, 68 low-grade intraepithelial neoplasia (LIN) samples, 65 high-grade intraepithelial neoplasia (HIN) samples obtained from gastroscopic biopsies and 50 gastric adenocarcinoma (GA) samples obtained from surgical resections. Then we statistically analyzed the expression differences and correlations.Our results indicated that B7 and CD68 expression on infiltrating immune cells was associated with disease progression. However, infiltration of CD8+ cells decreased with disease progression. B7-H3 expression was markedly enhanced at neoplasia and GA stages. B7-H3 in tumor cells was negatively correlated with CD8-expressing cells. Conversely, B7-H3 expression in tumor-infiltrating immune cells was positively correlated with CD68-expressing cells. B7-H4 expression was found in the cell membrane at the stages of gastritis and low-grade neoplasia and was gradually expressed in the cytoplasm at high-grade neoplasia and GA stages. High B7-H4 expression in infiltrating immune cells was also significantly associated with lower CD8-positive and higher CD68-positive cell densities.Increased B7 protein expression by infiltrating immune cells was associated with disease progression, and specifically, the level of B7-H3 expression and localization of B7-H4 expression differed significantly among different stages of gastric carcinogenesis.

1077 - Helicobacter Pylori Cag+ Strains Induce Alterations in the In Vivo Epithelial Proteome that are Associated with Progression of Gastric Carcinogenesis

1077 - Helicobacter Pylori Cag+ Strains Induce Alterations in the In Vivo Epithelial Proteome that are Associated with Progression of Gastric Carcinogenesis

Combined Detection of Plasma ZIC1, HOXD10 and RUNX3 Methylation is a Promising Strategy for Early Detection of Gastric Cancer and Precancerous Lesions.

We try to explore the value of aberrant DNA methylation of several cancer-related genes in plasma as non-invasive biomarkers for gastric cancer (GC) and precancerous lesions. By using methylation-specific polymerase chain reaction assay we determined the methylation status of three selected genes ZIC1, HOXD10 and RUNX3 in blood samples from patients with GC and precancerous lesions. We discovered that the methylation rate of ZIC1, HOXD10 and RUNX3 increased significantly in the progression of gastric carcinogenesis. Methylation of ZIC1 was associated with positive serum CA19-9, while that of HOXD10 was related to H. pylori status, serum CA19-9 and CEA levels and tumor invasion depth. The Odds ratios (ORs) of ZIC1, HOXD10 and RUNX3 methylation for predicting GC were 4.285 (95%CI: 2.435-7.542), 3.133 (95%CI: 1.700-5.775) and 2.674 (95%CI: 1.441-4.960), while for predicting “gastric cancer and intraepithelial neoplasia” (GnI), the ORs were 12.011 (95%CI: 0.050-28.564), 9.174 (95%CI: 3.220-26.135) and 12.794 (95%CI: 4.115-39.778), respectively. In terms of combined detection of these three genes, the sensitivity was 91.6% for GC and 89.8% for GnI, with the highest Youden index in both GC and GnI determination. Conclusively, combined detection of ZIC1, HOXD10 and RUNX3 promoter hypermethylation might be a promising strategy for early detection of GC and precancerous lesions.

Metabolomic analysis reveals altered metabolic pathways in a rat model of gastric carcinogenesis.

Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression.

JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression.

Helicobacter pylori (H. pylori) infection is the strongest risk factor for the initiation and progression of gastric cancer. However, the mechanism of H. pylori-induced pathogenesis remains unclear. In this study, we investigate the role of H. pylori infection in JMJD2B upregulation and the mechanism underlying gastric carcinogenesis. We find that JMJD2B can be induced by H. pylori infection via β-catenin pathway. β-catenin directly binds to JMJD2B promoter and stimulates JMJD2B expression following H. pylori infection. Increased JMJD2B, together with NF-κB, binds to COX-2 promoter to enhance its transcription by demethylating H3K9me3 locally. JMJD2B and COX-2 expression is upregulated in H. pylori infected mice in vivo. Furthermore, JMJD2B and COX-2 expression is gradually increased in human gastric tissues from gastritis to gastric cancer. The level of JMJD2B and COX-2 in H. pylori-positive gastritis tissues is significantly higher than that in H. pylori-negative tissues. Moreover, a positive correlation between JMJD2B and COX-2 expression is found in both gastritis and gastric cancer tissues. Therefore, JMJD2B is a crucial factor in triggering H. pylori-induced chronic inflammation and progression of gastric carcinogenesis and it may serve as a novel target for the intervention of gastric cancer.

Inverse Relation between Expression of Gastric Tumor Suppressor RUNX3 and Helicobacter pylori Cag A status in Gastric Epithelial Dysplasia: 2011 ACG Presidential Poster

Purpose: RUNX3 is a novel tumor suppressor gene and necessary for the suppression of cell proliferation of the gastric epithelium. Immunohistochemically, RUNX3 protein is expressed in normal mucosa, but not in cancer cells. The aim of this study was to evaluate the expression of RUNX3 in the category 3 and 4 gastric epithelial dysplasia (GED) according to the revised Vienna classification. We explored the role of RUNX3 in early gastric carcinogenesis. Methods: All tissue samples were excised by endoscopic mucosal resection. Fifty-one category 3 tissue samples and 56 category 4 samples were evaluated by RUNX3 staining and subclassifed by immunophenotype (CD10, MUC5A and MUC6). In GED and its normal surrounding tissue, infection of Helicobacter pylori (H. pylori) was examined by silver stain. Also, Cag A status was assessed by polymerase chain reaction. Results: Positive expression of RUNX3 was observed in 27 (52.9%) cases of the 51 category 3 lesions, whereas in the 56 category 4 lesions, 18 (32.1%) cases had positive immunoreactivity for RUNX3 (P = 0.02). Between immunophenotype and positive RUNX3 expression, there were no significant differences. In category 3 lesions, RUNX3-positive, Cag A-positive rate was 50% (5/10), and RUNX3-negative, Cag A-positive rate was 50% (12/16) (P = 0.19). In category 4 lesions, RUNX3-positive, Cag A-positive rate was 28.5% (2/7), whereas RUNX3-negative, Cag A-positive rate was 71.4% (15/21) (P = 0.04). Conclusion: The expression of RUNX3 is negative correlation with H. pylori Cag A status in GED. The loss of expression of RUNX3 might be a very early event in the progression of gastric carcinogenesis.

Mitochondrial microsatellite instability in gastric cancer and gastric epithelial dysplasia as a precancerous lesion

Background: Genetic instability in gastric cancer represents a key molecular step that occurs early in the carcinogenesis process. To clarify the role of genetic instability in the progression from gastric dysplasia to gastric cancer, mitochondrial microsatellite instability (mtMSI) was studied in gastric cancer and gastric dysplasia. Methods: DNA was isolated from paired normal and tumoral tissues in 24 patients with gastric dysplasia (low grade) and 49 patients with gastric cancer. mtMSI was analyzed using eight microsatellite markers. mtMSI in gastric dysplasia was studied prospectively to elucidate the relation between mtMSI and gastric carcinogenesis. Results: mtMSI was found in 5 (10.2%) of 49 gastric cancer patients. The mtMSI phenotype was not associated with age, gender, and Helicobacter pylori infection. However, all of the mtMSI was found in intestinal-type gastric cancer (20.8%, p = 0.02). In gastric dysplasia, mtMSI was detected in 3 (12.5%) of 24 patients with gastric dysplasia. mtMSI-positive gastric dysplasia showed a poor prognosis statistically compared to mtMSI negative through progression to high-grade dysplasia or gastric cancer. Conclusions: These data suggest that mtMSI may be an early and important event in the progression of gastric carcinogenesis, especially in intestinal-type gastric cancer.

Aberrant DNA Methylation in Non-Neoplastic Gastric Mucosa of H. Pylori Infected Patients and Effect of Eradication

Gene promoter methylation is an epigenetic event leading to gene silencing. This mechanism is particularly relevant in cancer since it can interfere with the activity of specific "suppressor" genes. To evaluate promoter methylation of CDH1, p16, APC, MLH1, and COX2 in patients with H. pylori (Hp) infection before and after eradication. Fifty-seven dyspeptic outpatients who had never performed previous endoscopy or Hp testing and treatment underwent clinical interview, endoscopy with three paired gastric biopsy specimens from the antrum, angulus, and corpus, and (13)C-urea breath test (UBT). Biopsies were scored for the presence of Hp and intestinal metaplasia (IM). DNA methylation of five tumor-related genes (CDH1, p16, MLH1, APC, and COX2) was evaluated by methylation-specific PCR in each biopsy. Infected patients were given a standard eradicating treatment and, after 1 yr, underwent endoscopy with biopsies and UBT. Hp infection was found in 45 patients. IM was detected in 17 out of 45 (38%) infected patients. Mean number of methylated genes was 0, 1.1 +/- 0.9, and 1.6 +/- 0.9 among the 12 Hp-/IM-, the 28 Hp+/IM-, and the 17 Hp+/IM+ patients, respectively (P < 0.0001). Specifically, promoter hypermethylation of CDH1, p16, APC, MLH1, and COX2 was found in 68%, 25%, 7%, 0%, and 14% of Hp+/IM- patients and in 71%, 29%, 35%, 12%, and 12% of Hp+/IM+ patients. No significant difference was found among the three groups of patients as far as age, smoking, alcohol, meat and vegetable consumption, and family history of gastric cancer were considered. Twenty-three out of 45 (51%) infected patients underwent the 1-yr follow-up endoscopy: 17 out of 23 (74%) were successfully eradicated. After Hp eradication, CDH1, p16, and APC methylation significantly decreased while COX2 methylation completely disappeared. Conversely, MLH1 methylation did not change significantly in patients with IM. Hp infection is associated with promoter methylation of genes which are relevant in the initiation and progression of gastric carcinogenesis. While CDH1 methylation seems to be an early event in Hp gastritis, MLH1 methylation occurs late along with IM. Hp eradication is able to significantly reduce gene methylation thus delaying or reversing Hp-induced gastric carcinogenesis.

CagA+H pyloriinfection is associated with polarization of T helper cell immune responses in gastric carcinogenesis

To characterize the immune responses including local and systemic immunity induced by infection with H pylori, especially with CagA+ H pylori strains and the underlying immunopathogenesis. A total of 711 patients with different gastric lesions were recruited to determine the presence of H pylori infection and cytotoxin associated protein A (CagA), the presence of T helper (Th) cells and regulatory T (Treg) cells in peripheral blood mononuclear cells (PBMCs), expression of plasma cytokines, and RNA and protein expression of IFN-gamma and IL-4 in gastric biopsies and PBMCs were determined by rapid urease test, urea [(14)C] breath test, immunoblotting test, flow cytometry , real time RT-PCR and immunohistochemistry. Of the patients, 629 (88.47%) were infected with H pylori; 506 (71.16%) with CagA+ and 123 (17.30%) with CagA- strains. Among patients infected with CagA+ H pylori strains, Th1-mediated cellular immunity was associated with earlier stages of gastric carcinogenesis, while Th2-mediated humoral immunity dominated the advanced stages and was negatively associated with an abundance of Treg cells. However, there was no such tendency in Th1/Th2 polarization in patients infected with CagA- H pylori strains and those without H pylori infection. Polarization of Th cell immune responses occurs in patients with CagA+ H pylori infection, which is associated with the stage and severity of gastric pathology during the progression of gastric carcinogenesis. This finding provides further evidence for a causal role of CagA+ H pylori infection in the immunopathogenesis of gastric cancer.

Helicobacter pylori and the progression of gastric cancer: a 10-year cohort study

To search the role of Helicobacter pylori (H. pylori) in the progression of gastric carcinogenesis. A cohort study was conducted by cluster randomized sampling in Linqu County, a rural area in Shandong Province in northeast China, where the mortality of gastric cancer (GC) is among the highest in the world. In 1989-1990, a gastroscopic examination and serum test was launched among subjects aged 35-64 from 14 randomized villages. Histological diagnosis of gastric mucosa and enzyme-linked immunosorbent assay was used to detect gastric lesions and anti-H. pylori of all participants. A repeated gastroscopic screening was offered to all cohort members in 1994 and 1999 respectively, and all the GC cases, regardless of natural ones or ones by gastroscopy, were registered in the follow-up periods. Fifty-eight cases of GC were identified in 2469 subjects during the 10-year follow-up, 44 were observed in 1603 H. pylori-positive persons (2.74%) and 14 in 866 H. pylori-negative persons (1.62%). The incidence rate of GC in H. pylori-positive is significantly higher than in H. pylori-negative (OR = 1.871, 95% CI: 1.012 - 3.459). There was no significant difference in the progression of gastric carcinogenesis between H. pylori-positive and H. pylori-negative (P > 0.05) among subjects with normal or superficial gastritis (SG) at baseline. In contrast, the significant difference was found in baseline chronic gastritis (CAG) group (P < 0.01), and the GC incidence rate in H. pylori-positive (7/615) is higher than in H. pylori-negative (0/470, P = 0.019). The difference of gastric lesions between H. pylori-positive and H. pylori-negative in subjects with intestinal metaplasia (IM) and dysplasia (DYS) at baseline was statistically significant after a 10-year follow-up (P < 0.05, P < 0.01, respectively), but the GC incidence rate in H. pylori-positive is similar to the rate in H. pylori-negative at the two groups (17/573 and 7/224 in IM group, P = 0.907; 19/368 and 7/122 in DYS group, P = 0.806). H. pylori is a key risk factor that prompts the transition from chronic atrophic gastritis to advanced precancerous lesions and influences the whole progression of precancerous gastric lesions. H. pylori, perhaps can not cause GC directly, increases the risk of GC in company with other carcinogens. H. pylori seemingly has no important effect on the development of GC when gastric mucosa is normal or superficial gastritis, but this conclusion is required to be further confirmed.

Changes of host natural killer cell activity in F344 rats during gastric carcinogenesis induced by N-methylnitrosourea.

To evaluate the role of NK cells during gastric carcinogenesis, especially in early stage of tumorigenesis, the changes of NK activity was examined. Rats were given N-methylnitrosourea (MNU) at a concentration of 100 ppm in their drinking water for 15 weeks. Rats were sacrificed sequentially on week 15, 18, 20, and 40 of the experimental period. Histological changes such as mild erosion, regenerative changes, focal or severe atypical lesions and invasive adenocarcinoma were observed sequentially in the pyloric region. Adenomatous hyperplasia was induced in majority of the rat stomach in MNU-treated group and incidence of adenocarcinoma was 20% in 40 weeks of MNU-treated group. There was no difference in NK activity until week 20, however, it was increased in MNU-treated rats at 40 week, when compared to that of untreated control group. From week 15, the ratio of pepsinogen altered pyloric gland (PAPG) between untreated control and MNU-treated rats was progressively increased, but there was no significant increment in the number of PAPG in MNU-treated rats after 20 weeks. NK activity was increased in MNU-treated rats, when compared to that of untreated control group. These results suggest that PAPG is a relatively good marker for the evaluation of progression of gastric carcinogenesis and increased NK activity is shown, especially in early stage of gastric carcinogenesis.

Loss of heterozygosity during the development and progression of differentiated adenocarcinoma of the stomach.

In a recent allelotypic analysis of differentiated adenocarcinoma of the stomach, loss of heterozygosity (LOH) was found frequently on chromosomes 2q, 4p, 5q, 6p, 11q, 14q, 17p, 18q, and 21q. To clarify the sequence of these chromosomal losses during gastric carcinogenesis, microsatellite analysis of the chromosome arms described above was performed in 25 early and 29 advanced differentiated adenocarcinomas of the stomach. LOH on these chromosome arms fell within a range of 20-50 per cent. On 4p, 7q, 14q, 17p, and 21q, LOH was detected at a similar frequency in both early and advanced carcinomas, while LOH on 2q, 5q, 6p, 11q, and 18q was observed more than twice as frequently in advanced than in early lesions. Mean fractional allelic losses (FALs) were 0.221 in early and 0.413 in advanced carcinomas, representing a significant difference P < 0.05). These results suggest that LOH on 4p, 7q, 14q, 17p, and 21q is a relatively early event, while LOH on 2q, 5q, 6p, 11q, and 18q typically accumulates during the progression of gastric carcinogenesis.