Mucosa Of Gastric Cancer Patients Research Articles

Telomere length shortening in gastric mucosa is a field effect associated with increased risk of gastric cancer.

Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03±0.3 vs. 2.82±0.19 vs. 0.82±0.07 vs. 0.29±0.09, P<0.0001). In non-neoplastic mucosa of GC patients, shorter telomeres were found significantly more often than in that of GC free subjects (age, sex, and H. pylori adjusted odds ratio=7.81, 95% confidence interval=4.71-12.9, P<0.0001). Telomere shortening in non-neoplastic mucosa was associated with chronic inflammation (P=0.0018) and intestinal metaplasia (P<0.0001). No significant associations were found between relative telomere length and clinicopathological features of GC and overall survival. Telomere shortening in gastric mucosa reflects a field effect in an early stage of carcinogenesis and is associated with an increased risk of GC. Telomere length in GC is not associated with clinicopathological features or prognosis.

Decreased expression of gastrokine 1 in gastric mucosa of gastric cancer patients.

To investigate the expression of gastrokine 1 (GKN1) in normal gastric mucosa, precancerous lesions and gastric cancer tissues, and to analyse its correlations with tumour site and pathological pattern. Thirty gastric cancer patients (12 cases of diffuse type and 18 cases of intestinal type), 13 atrophic gastritis patients and 15 healthy volunteers with almost normal gastric mucosa (superficial gastritis) were enrolled in this study. Helicobacter pylori (H. pylori) infection was examined in all subjects. All gastric mucosa biopsy specimens were obtained. Cancer-adjacent specimens were taken from corresponding gastric cancer patients. Immunohistochemistry and real-time PCR were performed to determine the expressions of the GKN1 protein and mRNA, respectively. H. pylori infection had no significant association with age, gender, tumour site or pathological pattern in all subjects. Compared with the superficial gastritis and atrophic gastritis groups, the expression of GKN1 protein (P = 0.011) and mRNA (P < 0.001) in gastric cancer was significantly decreased. The GKN1 mRNA level in diffuse type gastric cancer was significantly lower than in intestinal type gastric cancer (0.296 ± 0.076 vs 0.525 ± 0.164, P < 0.001). Compared with almost normal gastric mucosa, GKN1 expression in the gastric mucosa of gastric cancer patients is decreased; this is associated with progression and prognosis of gastric cancer.

The Interleukin-6 Family Cytokine Interleukin-11 Regulates Homeostatic Epithelial Cell Turnover and Promotes Gastric Tumor Development

Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer. We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancer patients. We then determined the transcriptional and translational outcomes of IL-11 overexpression in normal gastric mucosa and identified a novel gene signature important early in the progression toward gastric tumorigenesis. IL-11 was up-regulated significantly in 4 diverse mouse models of gastric pathology as well as in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor alpha significantly reduced HKbeta-/- mouse fundic hyperplasia and ablated gp130(757F/F) mouse tumorigenesis. Exogenous IL-11 but not IL-6 activated oncogenic signal transducer and activator of transcription-3, and altered expression of novel proliferative and cytoprotective genes RegIII-beta, RegIII-gamma, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130(757F/F) and HKbeta-/- tumors as well as nonneoplastic mucosa of gastric cancer patients. One week of chronic IL-11 administration in wild-type mice sustained the gene signature, causing pretumorigenic changes in both antrum and fundus. Increased gastric IL-11 alters expression of proliferative and cytoprotective genes and promotes pretumorigenic cellular changes.

CpG Island Hypermethylation of Tumor‐Suppressor Genes in H. pylori‐Infected Non‐Neoplastic Gastric Mucosa Is Linked with Gastric Cancer Risk

Gastric carcinogenesis involves CpG island hypermethylation (CIHM) of tumor-suppressor genes. Although the CIHM of these genes occurs in non-neoplastic gastric cells, it is unclear whether this epigenetic alteration is linked with aging and/or gastric cancer risk. We investigated this linkage in noncancerous gastric mucosa infected with H. pylori. Noncancerous corpus mucosa was endoscopically obtained from H. pylori-positive gastric cancer patients (n = 34), and age-matched H. pylori-positive noncancerous controls (n = 68). Genomic DNA retrieved from the mucosa was subjected to methylation-specific polymerase chain reaction for p16, Ecad, and DAPK genes. Linkage between CIHM and clinicopathologic factors was evaluated. CIHM rates of DAPK, Ecad, and p16 promoters were significantly higher in noncancerous gastric mucosa of gastric cancer patients (91, 88, and 68%, respectively) than in noncancerous controls (71, 53, and 25%, respectively). Multivariate regression analysis showed a significant linkage between CIHM in noncancerous mucosa and coexistence of gastric cancer. Significant linkage between polymorphoneutrophil infiltration and CIHM was observed except for CIHM of p16. No linkage was observed between CIHM and other parameters, including age. High CIHM status (all three tested genes methylated) was associated with an increased risk of gastric cancer, with an odds ratio of 9.8 (95% confidence interval, 3.8-25.3). In a subset of the H. pylori-infected population, CIHM of tumor-suppressor genes in noncancerous gastric mucosa is linked with the risk of gastric cancer and polymorphoneutrophil infiltration, but not aging. CIHM is a potential marker of gastric cancer risk.

Up-regulation of inducible nitric oxide synthase in Helicobacter pylori-associated gastritis may represent an increased risk factor to develop gastric carcinoma of the intestinal type

AbstractThe enzyme inducible nitric oxide synthase (iNOS) is part of the host innate defense system against bacterial infection. During chronic inflammation, like that seen with a Helicobacter pylori infection, constant nitric oxide production may lead to tissue and DNA damage, thus increasing the patient's risk for developing cancer. Several investigations on iNOS expression in H. pylori-associated gastritis have resulted in conflicting data. Therefore, we investigated the association between chronic H. pylori infection and iNOS expression in samples from stomach carcinoma patients as well as in antral biopsies from patients with H. pylori-associated gastritis. iNOS expression was analyzed by means of reverse transcriptase (RT)-PCR and quantified by competitive RT-PCR. To study in situ localization of iNOS in biopsy samples, immunohistochemistry was performed. iNOS enzyme activity was quantified using an arginine/citrulline assay. A significant increase in iNOS mRNA signal was only present in one-third of the analyzed patient biopsies with H. pylori-associated gastritis. These biopsies showed a 90% association with intestinal metaplasia and a 100% association with CagA-positive H. pylori. Intestinal metaplasia is discussed to be one step in the carcinogenesis of stomach cancer. Quantitation of iNOS transcripts and iNOS enzyme activity in non-cancerous mucosa of gastric cancer patients revealed a significant increase in iNOS transcripts and iNOS activity only in the mucosa of patients with stomach cancer of the intestinal type but not in the diffuse type. Our results support the hypothesis that CagA-positive H. pylori strains are associated with the expression and activity of iNOS, and therefore might contribute to the development of intestinal metaplasia leading to gastric cancer of the intestinal type.

Cancer-associated strains of Helicobacter pylori stimulate DNA synthesis in IEC-6 cells.

To determine whether water extracts of Helicobacter pylori strains, which express CagA, can influence DNA synthesis in untransformed intestinal epithelial cells in vitro. We used water extracts produced from H. pylori strains (A, B, C), collected from gastric mucosa of gastric cancer patients. Strain A was CagA+/VacA+ whereas strains B and C were CagA+/VacA-. Water extracts from Helicobacter mustelae and Escherichia coli were used as controls. IEC-6 cells (small intestinal epithelial cell line from germ-free rats) were incubated with various concentrations of the bacterial extracts for 24 h. The cells were labelled with [3H]methylthymidine for 4 h and thereafter processed for autoradiography. DNA synthesis was evaluated by the labelling index (LI%). Water extracts from CagA-positive strains of H. pylori, with or without the capacity to produce vacuolating toxins, increased the LI in a dose-related manner (P < 0.05). The water extracts of E. coli significantly increased the LI (P < 0.001), whereas the water extracts of H. mustelae did not affect DNA synthesis. Cancer-associated, CagA-positive strains of H. pylori stimulate DNA synthesis in epithelial cells in vitro, independently of their ability to produce VacA toxin. Our findings suggest that unknown mitogenic components of H. pylori may contribute to the increased cell proliferation observed in the histological stages preceding gastric cancer.

Inducible nitric oxide synthase and nitrotyrosine in gastric mucosa of gastric cancer patients

AIM: Recent studies have shown that Helicobacter pylori (Hp) infection is etiologically associated with gastric cancer. However, the role of Hp in carcinogenesis is unknown. Hp infection leads to a sustained production of the reactive nitrogen species which cause DNA damage. In this study, we examined the expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine in human non-cancerous gastric mucosa. MATERIALS and METHODS: A total of 93 archival gastric biopsy specimens were used. The 34 biopsy specimens from gastric cancer patients were obtained two years or more before diagnosis of gastric cancer (Group A). The other 59 specimens were from the patients who had no evidence of gastric cancer during long term follow-up (Group B). These two groups were age and gender matched. Immunohistochemical analysis was performed to examine the expression of iNOS and nitrotyrosine. RESULTS:

Krebs Cycle, Pentose Phosphate Pathway, and Glycolysis in the Uninvolved Gastric Mucosa of Peptic Ulcer and Gastric Cancer Patients

Uninvolved gastric mucosa from duodenal ulcer, gastric ulcer, and gastric cancer patients was incubated with [1-14C]glucose and [6-14C]glucose in order to assess the relative contributions of the pentose phosphate pathway and Krebs cycle to glucose metabolism. [14C]Glucose counts retained by the tissue, glycolysis, and pyruvate formation were also measured. Tumor tissue from the cancer patients was included in the study. Less than 1.2% of the glucose entering the tissues was metabolized via the pentose phosphate pathway; suggesting that this pathway plays a minor role in energy production from glucose. The major determinant of energy production was the Krebs cycle. Its contribution to glucose metabolism was greatest in the body mucosa of duodenal ulcer patients, less in the uninvolved body mucosa of gastric ulcer patients, and lower still in the corresponding body mucosa of gastric cancer patients. The low levels of Krebs cycle activity seen in the latter tissue resembled those of uninvolved antral mucosa. The smallest Krebs cycle contribution was seen in tumor tissue. [14C]Glucose counts retained by the tissue and glycolysis both tended to vary inversely with Krebs cycle activity among the tissues studied. Thus, both were small in the body mucosa of noncancer patients and somewhat larger in the body mucosa of cancer patients, in uninvolved antral mucosa and in tumor tissue.

LDH Isoenzyme Pattern of Uninvolved Gastric Mucosa of Patients with Gastric Carcinoma and Benign Gastric Disease

The LDH isoenzyme pattern of the uninvolved mucosa of gastric cancer patients differs as regards the LDH isoenzyme pattern from that of similar tissue of patients with benign gastric disease; the former tissue is characterised by a high M/H ratio of the LDH isoenzymes (M and H sub-units). A high M/H ratio characterises antral mucosa when the latter is compared with fundic mucosa. Mucosa showing superficial and atrophic gastritis also has a higher M/H ratio, whereas the presence of intestinal metaplasia does not appear to influence the M/H ratio. These observations are consistent with the concept that the tissue from which the cancer arose may possess a pre-malignant biochemical lesion.