Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Helicobacter pylori-associated gastric mucosal injury, interleukin (IL) -8, a potent leukocyte chemoattractant, is produced by epithelial cells infected by H. pylori and directs neutrophils to the gastric mucosa. According to previous studies, the IL-8 production requires direct contact between the bacteria and epithelial cells. The aims of the present study were to determine whether an H. pylori water extract (HPE) induces IL-8 production by gastric epithelial cells and to characterize IL-8-inducing substances in HPE. Extracts were prepared from a standard strain and from strains obtained from patients with gastric ulcers. After addition of HPE to MKN 45 cells, a gastric cancer cell line, IL-8 in supernatants and IL-8 mRNA were measured by immunoassay and reverse transcription-polymerase chain reaction, respectively. For characterization, active fractions obtained by gel filtration of standard-strain HPE were treated by heating or trypsinization. To study the signal pathway leading to IL-8 production, inhibitors for protein kinase A (PKA), protein kinase C (PKC), or protein tyrosine kinase (PTK) were incubated with MKN45 cells before HPE stimulation. HPE from the standard strain and one of these clinical strains induced IL-8 production. Lipopolysaccharide or cagA in the strains showed no correlation with IL-8 concentration. Standard-strain HPE induced IL-8 mRNA expression in MKN 45 cells. Gel filtration localized activity to a low-molecular-weight fraction of about 7 kDa, which was resistant to heat and trypsin digestion. PKC inhibitors significantly blocked HPE-induced IL-8 production by MKN 45 cells; however, the PKA inhibitor or PTK inhibitors showed a partial inhibitory effect. HPE contains a nonprotein substance of low molecular weight that is responsible for IL-8 induction in gastric epithelial cells. This induction is mainly dependent on the activation of PKC but partially also dependent on PKA or PTK.
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PMID:Helicobacter pylori water extract induces interleukin-8 production by gastric epithelial cells. 1006 6

Helicobacter pylori has been widely recognized as an important human pathogen responsible for chronic gastritis, peptic ulcers, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma. Little is known about the natural history of this infection since patients are usually recognized as having the infection only after years or decades of chronic disease. Several animal models of H. pylori infection, including those with different species of rodents, nonhuman primates, and germ-free animals, have been developed. Here we describe a new animal model in which the clinical, pathological, microbiological, and immunological aspects of human acute and chronic infection are mimicked and which allows us to monitor these aspects of infection within the same individuals. Conventional Beagle dogs were infected orally with a mouse-adapted strain of H. pylori and monitored for up to 24 weeks. Acute infection caused vomiting and diarrhea. The acute phase was followed by polymorphonuclear cell infiltration, interleukin 8 induction, mononuclear cell recruitment, and the appearance of a specific antibody response against H. pylori. The chronic phase was characterized by gastritis, epithelial alterations, superficial erosions, and the appearance of the typical macroscopic follicles that in humans are considered possible precursors of MALT lymphoma. In conclusion, infection in this model mimics closely human infection and allows us to study those phases that cannot be studied in humans. This new model can be a unique tool for learning more about the disease and for developing strategies for treatment and prevention.
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PMID:A conventional beagle dog model for acute and chronic infection with Helicobacter pylori. 1033 28

The aim of this study was to examine the relation between disease specificity and the virulence factors of Helicobacter pylori isolated from patients with gastric cancer (GC), duodenal ulcer (DU), and gastritis (GS). Altogether 18 isolates obtained from patients with GC, 28 isolates from DU patients, and 13 isolates from GS patients were analyzed. All isolates were tested for the presence of the cagA gene, and genotyping of the vacA gene was done by the polymerase chain reaction. Production of VacA protein and expression of vacuolating cytotoxic activity in the H. pylori culture supernatant were examined. The serum antibody titers against purified VacA and CagA proteins were determined by enzyme-linked immunosorbent assay (ELISA). Interleukin-8 (IL-8) production by AGS cells in response to H. pylori isolates was measured by an hIL-8 ELISA kit. Genetic analysis of vacA revealed that most of the clinical isolates were classified into the S1a type by signal sequence typing. There were no differences in cagA detection rates, vacuolating cytotoxin activity, or mean antibody titers against VacA and CagA protein among the three groups. The mean IL-8 concentrations in the supernatants of AGS cells were similar in the three groups. In this study, there was no difference in virulence factors of H. pylori among isolates from GC, DU, and GS.
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PMID:Divergence of virulence factors of Helicobacter pylori among clinical isolates does not correlate with disease specificity. 1061 58

Cytokines have been proposed to play an important role in Helicobacter pylori-associated gastroduodenal diseases, but the exact mechanism of the cytokine induction remains unclear. H. pylori urease, a major component of the soluble proteins extracted from bacterial cells, is considered to be one of the virulence factors for the inflammation in the gastric mucosa that is produced in H. pylori infection. However, the response of human gastric epithelial cells to the stimulation of urease has not been investigated. In the present study, we used human gastric epithelial cells in a primary culture system and examined whether H. pylori urease stimulates the gastric epithelial cells to induce proinflammatory cytokines by reverse transcription-PCR and enzyme-linked immunosorbent assay. First, by using peripheral blood mononuclear cells (PBMC) and a gastric cancer cell line (MKN-45 cells), we confirmed the ability of purified H. pylori urease to induce the production of proinflammatory cytokines. Furthermore, we demonstrated that the human gastric epithelial cells produced interleukin-6 (IL-6) and tumor necrosis factor alpha, but not IL-8, following stimulation with purified urease. The patterns of cytokine induction differed among human PBMC, MKN-45 cells, and human gastric epithelial cells. These results suggest that the human gastric epithelial cells contribute to the induction of proinflammatory cytokines by the stimulation of H. pylori urease, indicating that the epithelial cells were involved in the mucosal inflammation that accompanied H. pylori infection.
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PMID:Cytokine expression and production by purified Helicobacter pylori urease in human gastric epithelial cells. 1063 31

Two major markers of virulence have been described in H. pylori. The first is a secreted protein (VacA) that is toxic to human cells in tissue culture. This cytotoxin causes vacuolation of epithelial cells in vitro and induces epithelial cell damage in mice. The second is a 40-Kb pathogenicity island for which the gene cagA (cytotoxin-associated gene A) is a marker. Approximately 60% of H. pylori isolates in Western countries are cagA+. The protein encoded by cagA+ has a molecular weight of 120-140 kDa and exhibits sequence heterogeneity among strains isolated from Western and Eastern countries. Although no specific function has been identified for CagA, there is increasing evidence that cagA+ strains are associated with increased intensity of gastric inflammation and increased mucosal concentration of particular cytokines including interleukin 8. Inactivation of picB (Hp 0544) or any of several other genes in the cag island ablates the enhanced IL-8 secretion of human gastric epithelial cells in tissue culture. Furthermore, persons colonized with cagA+ strains have an increased risk of developing more severe gastric diseases such as peptic ulcer and distal (non-cardia) gastric cancer than those harboring cagA- strains. We investigated the role of cagA status in both gastroduodenal and extragastroduodenal disease with H. pylori. Among the diseases limited to the antrum and body of the stomach and the duodenum, we demonstrated a correlation between CagA seropositivity and peptic ulcer disease. We also showed correlation between distal gastric cancer rated and CagA prevalence in populations in both developed and developing countries. In addition, we found that for several Asian populations, the relationship between CagA seropositivity and gastroduodenal diseases was complex. For extragastroduodenal diseases, our results confirmed previous reports that demonstrated that CagA status did not play a role in diseases such as rheumatoid arthritis and hyperemesis gravidarum. However, we found a clear negative association between the presence of a positive response to CagA and esophageal diseases. Therefore, CagA seropositivity (and thus gastric carriage) is associated with increased risks of certain diseases (involving the lower stomach and duodenum) and decreased risks of GERD and its sequelae. This apparent paradox can best be explained by differences in the interaction of cagA+ and cagA- strains with their hosts.
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PMID:The role of CagA status in gastric and extragastric complications of Helicobacter pylori. 1069 63

Numerous epidemiological studies demonstrated the association between Helicobacter pylori (H. pylori) infection and gastric cancer but the mechanism of the involvement of H. pylori in gastric cancerogenesis remains virtually unknown. This study was designed to determine the seropositivity of H. pylori and cytotoxin associated gene A (CagA), serum gastrin and gastric lumen gastrin levels under basal conditions and following stimulation with histamine in gastric cancer patients and controls. 100 gastric cancer patients aging from 21 to 60 years and 300 gender- and age-adjusted controls hospitalized with non-ulcer dyspepsia (NUD) entered this study. 13C-Urea Breath Test (UBT), serum immunoglobulin (IgG) antibodies to H. pylori and CagA were used to assess the H. pylori infection and serum levels of IL-1beta, IL-8 and TNFalpha were measured by enzyme-linked immunosorbent assay (ELISA) to evaluate the degree of gastric inflammation by H. pylori . Gastrin-17 mRNA and gastrin receptors (CCK(B)) mRNA expression in gastric mucosal samples taken by biopsy from the macroscopically intact fundic and antral mucosa as well as from the gastric tumor was determined using RT-PCR. The overall H. pylori seropositivity in gastric cancer patients at age 21-60 years was about 92%, compared, respectively, to 68%, in controls. A summary odds ratio (OR) for gastric cancer in H. pylori infected patients was about 5.0 . The H. pylori CagA seropositivity in gastric cancer patients was about 58.5% compared to 32.4% in controls, giving the summary OR for gastric cancer in CagA positive patients about 8.0. The prevalence of H. pylori- and H. pylori CagA-seropositivity was significantly higher in cancers than in controls, irrespective of the histology of gastric tumor (intestinal, diffuse or mixed type). Median IL-1beta and IL-8 reached significantly higher values in gastric cancer patients (9.31 and 30.8 pg/ml) than in controls (0.21 and 3.12, respectively). In contrast, median serum gastrin in cancers (as total group) was several folds higher (62.6 pM) than in controls (19.3 pM). Also median luminal gastrin concentration in gastric cancer patients was many folds higher (310 pM) than in controls (20 pM). This study shows for the first time that cancer patients are capable of releasing large amounts of gastrin into the gastric lumen to increase luminal hormone concentration to the level that was recently reported to stimulate the growth of H. pylori. There was no any correlation between plasma gastrin levels and gastric luminal concentration of gastrin suggesting that: 1) luminal gastrin originates from different source than plasma hormone, most probably from the cancer cells, 2) cancer cells are capable of expressing gastrin and releasing it mainly into the gastric juice and 3) the gastric cancer cells are equipped with gastrin-specific (CCK(B)) receptor so they exhibit the self-growth promoting activity in autocrine fashion. This notion is supported by direct detection of gastrin mRNA and gastrin receptor (CCK(B)-receptors) mRNA using RT-PCR in cancer tissue. To our knowledge this is the first study showing an important role of gastrin as self-stimulant of cancer cells in patients infected with H. pylori. Basal and histamine maximally stimulated acid outputs were significantly lower in gastric cancer patients than in controls despite of enhanced gastrin release, particularly in cancer patients and this might reflect the mucosal inflammatory changes (increased serum levels of proinflammtory interleukins - IL-1beta and IL-8), that are known to increase gastrin release. We conclude that: 1) H. pylori infected patients, particularly those showing CagA-seropositivity, are at greatly increased risk of development of gastric cancer, 2) H. pylori-infected cancer patients produce significantly more IL-1beta and IL-8 that might reflect an H. (ABSTRACT TRUNCATED)
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PMID:Role of gastrin in gastric cancerogenesis in Helicobacter pylori infected humans. 1069 65

A number of putative virulence factors for Helicobacter pylori have been identified including cagA, vacA and iceA. The criteria for a true virulence factor includes meeting the tests of biologically plausibility with the associations being both experimentally and epidemiologically consistent. Although disease-specific associations have been hypothesized/claimed, there are now sufficient data to conclusively state that none of these putative virulence factors have disease specificity. CagA has been claimed to be associated with increased mucosal IL-8 and inflammation, increased density of H. pylori in the antrum, duodenal ulcer (DU), gastric cancer, and protection against Barrett's cancer. Only the increase in IL-8/inflammation is direct and substantiated. Different H. pylori strains with functional cag pathogenicity islands do not vary in virulance as it has been shown that mucosal IL-8 levels are proportional to the number of cagA + H. pylori independent of the disease from which the H. pylori were obtained. It is now known that the density of either cagA + and cagA-H. pylori in the antrum of patients with H. pylori gastritis is the same. In contrast, the mean density of H. pylori in the antrum in DU is greater than in the antrum of patients with H. pylori gastritis. Of interest, the density of H. pylori is higher in the corpus of patients with H. pylori gastritis than those with DU, suggesting that acid secretion plays a critical role in these phenomena. The presence of a functional cag pathogenicity island increases inflammation and it is likely that any factor that results in an increase in inflammation also increases the risk of a symptomatic outcome. Nevertheless, the presence of a functional cag pathogenicity island has no predictive value for the presence, or the future development of a clinically significant outcome. The hypothesis that iceA has disease specificity has not been confirmed and there is currently no known biological or epidemiological evidence for a role for iceA as a virulence factor in H. pylori-related disease. The claim that vacA genotyping might prove clinically useful, e.g. to predict presentation such as duodenal ulcer, has been proven wrong. Analysis of the worldwide data show that vacA genotype s1 is actually a surrogate for the cag pathogenicity island. There is now evidence to suggest that virulence is a host-dependent factor. The pattern of gastritis has withstood the test of time for its relation to different H. pylori-related diseases (e.g. antral predominant gastritis with duodenal ulcer disease). The primary factors responsible for the different patterns of gastritis in response to an H. pylori infection are environmental (e.g. diet), with the H. pylori strain playing a lesser role. Future studies should work to eliminate potential bias before claiming disease associations. Controls must exclude regional or geographic associations related to the common strain circulation and not to the outcome. The authors must also control for both the presence of the factor and for the disease association. The study should be sufficiently large and employ different diseases and ethnic groups for the results to be robust. The findings in the initial sample (data derived hypothesis) should be tested in a new group (hypothesis testing), preferably from another area, before making claims. Finally, it is important to ask whether the results are actually a surrogate for another marker (e.g. vacA s1 for cagA) masquerading for a new finding. Only the cag pathogenicity island has passed the tests of biological plausibility (increased inflammation) and experimental and epidemiological consistency.
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PMID:Disease-specific Helicobacter pylori virulence factors: the unfulfilled promise. 1082 48

The complete genome sequence revealed a family of 32 outer membrane proteins (OMPs) in Helicobacter pylori. We examined the effect of four OMPs (HP0638, HP0796, HP1501, and babA2) on the production of the proinflammatory cytokine, IL-8. Mutants of the four OMPs, as well as cagE and galE from H. pylori from the U.S. and Japan, were constructed by inserting a chloramphenicol-resistant cassette into the gene. Twenty-two pairs of parental and mutant H. pylori strains, as well as 160 clinical isolates (80 from Japanese and 80 from U.S.), were cocultured with gastric cancer cell lines. IL-8 production in the supernatant and adhesion was assayed by ELISA. HP0796, HP1501, babA2, and galE gene knockouts had no significant effect on IL-8 production. Knockout of the HP0638 gene in 81% of cag-positive strains reduced IL-8 production approximately 50%. The three cag-positive strains in which IL-8 levels were unchanged by HP0638 knockout had five or seven CT dinucleotide repeats in the 5' region, resulting in a frame shift and truncation. Strains with naturally inactive HP0638 gene were all from the U.S.; Japanese strains were always "on" and thus, on average, may be more virulent. Although cag-negative isolates produced a limited IL-8 response, cag-negative strains that contained a functional HP0638 gene produced more than 3-fold greater IL-8 than cag-negative nonfunctional HP0638 strains. We hypothesize that functional HP0638 gene may be an important virulence factor in relation to the risk of clinically significant outcomes of H. pylori infection. We denote HP0638 gene as outer inflammatory protein (oipA).
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PMID:A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. 1085 59

The expression of interleukin 8 (IL-8) by human gastric carcinomas directly correlates with tumor vascularity and disease progression. To determine whether IL-8 can act in an autocrine manner to regulate the expression of other disease-progression genes, we examined the expression of IL-8 receptors IL-8RA (CXCR1) and IL-8RB (CXCR2) in six different human gastric carcinoma cell lines and 38 surgical specimens of human gastric carcinomas. All of the gastric carcinoma cell lines expressed mRNA and protein for IL-8RA and IL-8RB protein. In all surgical specimens, the majority of the tumor cells and small vessel endothelial cells stained positive for IL-8RA and IL-8RB protein. In vitro treatment of human gastric cancer MKN-1 cells with exogenous IL-8 enhanced the expression of epidermal growth factor receptor, type IV collagenase (metalloproteinase-9), vascular endothelial growth factor, and IL-8 mRNA. In contrast, treatment with exogenous IL-8 decreased expression of E-cadherin mRNA. IL-8 treatment increased invasive capacity of MKN-1 cells, which was associated with activity of metalloproteinase-9. Collectively, these results demonstrate that human gastric carcinoma cells express receptors for IL-8 and that IL-8 may play a role in the progressive growth of human gastric carcinoma by autocrine/paracrine mechanisms.
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PMID:Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8. 1091 18

The scenario of multiple genetic and epigenetic alterations found in gastric carcinoma differs depending upon the two histological types, indicating that well differentiated or intestinal type and poorly differentiated or diffuse type gastric carcinomas have different genetic pathways. Cancer-stromal interaction through growth factor/cytokine receptor system which plays a central role in invasion and metastasis, is also different between the two types of stomach cancer. The majority of gastric carcinoma exhibit co-expression of IL-8 and its two receptors that evidently confer tumor angiogenesis. IL-8 increases the expression of EGF receptor, VEGF and IL-8 itself by tumor cells themselves, whereas IL-8 decreases expression of E-Cadherin, associated with increase in expression and activity of MMP-9 by tumor cells. These findings overall suggest that IL-8 produced by gastric cancer cells is used for sustained angiogenesis and tissue invasion and metastasis via autocrine/paracrine manners. On the other hand, co-expression of osteopontin (OPN) and CD44v9 in tumor cells correlates well with the degree of lyiphatic vessel invasion or long distant lymph node metastasis in diffuse type gastric carcinoma, indicating that mutual interaction between OPN and CD44v9 on the tumor cells is implicated in lymphogenous metastasis. In addition to these factors, tumor invasion and metastasis requires telomere maintenance regulated by telomerase activity. The human telomerase catalytic subunit, hTERT, is strongly expressed in almost all primary tumors and nodal metastasis.
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PMID:Molecular aspects of invasion and metastasis of stomach cancer. 1121 48


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