Accelerated Progression of Gastritis to Dysplasia in the Pyloric Antrum of TFF2−/− C57BL6 × Sv129 Helicobacter pylori-Infected Mice

Fox, James G.; Rogers, Arlin B.; Whary, Mark T.; Ge, Zhongming; Ohtani, Masa; Jones, Evelyn Kurt; Wang, Yichen

doi:10.2353/ajpath.2007.070249

Cited by 92 publications

(134 citation statements)

References 45 publications

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“…These data suggest that TFF2 may play some function in the immune system. In concordance with these findings, we detected an exacerbated inflammatory response to acute injury in TFF2 knock-out animals (27,28). These observations prompted us to look at the possible function of TFF2 in immune cells.…”

supporting

confidence: 72%

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Dubeykovskaya

Dubeykovskiy

Solal-Cohen

et al. 2009

Journal of Biological Chemistry

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106

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The secreted trefoil factor family 2 (TFF2) protein contributes to the protection of the gastrointestinal mucosa from injury by strengthening and stabilizing mucin gels, stimulating epithelial restitution, and restraining the associated inflammation. Although trefoil factors have been shown to activate signaling pathways, no cell surface receptor has been directly linked to trefoil peptide signaling. Here we demonstrate the ability of TFF2 peptide to activate signaling via the CXCR4 chemokine receptor in cancer cell lines. We found that both mouse and human TFF2 proteins (at ϳ0.5 M) activate Ca 2؉ signaling in lymphoblastic Jurkat cells that could be abrogated by receptor desensitization (with SDF-1␣) or pretreatment with the specific antagonist AMD3100 or an anti-CXCR4 antibody. TFF2 pretreatment of Jurkat cells decreased Ca 2؉ rise and chemotactic response to SDF-1␣. In addition, the CXCR4-negative gastric epithelial cell line AGS became highly responsive to TFF2 treatment upon expression of the CXCR4 receptor. TFF2-induced activation of mitogen-activated protein kinases in gastric and pancreatic cancer cells, KATO III and AsPC-1, respectively, was also dependent on the presence of the CXCR4 receptor. Finally we demonstrate a distinct proliferative effect of TFF2 protein on an AGS gastric cancer cell line that expresses CXCR4. Overall these data identify CXCR4 as a bona fide signaling receptor for TFF2 and suggest a mechanism through which TFF2 may modulate immune and tumorigenic responses in vivo.

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supporting

confidence: 72%

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Dubeykovskaya

Dubeykovskiy

Solal-Cohen

et al. 2009

Journal of Biological Chemistry

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106

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“…Previous studies suggest that IFN-c induces proliferation of gastric epithelial cells (32,33). Increased cell proliferation is a biomarker of gastric cancer risk, and reversal to a normal epithelial proliferation has been associated with a reduced gastric cancer risk (34,35).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Eradication Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

Lee

Rickman²,

Rogers³

et al. 2008

Cancer Research

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113

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Helicobacter pylori infection results in chronic gastritis, which may progress to gastric cancer. In this study, we investigated the efficacy of H. pylori eradication in preventing the progression of gastritis to gastric cancer in H. pylori-infected transgenic INS-GAS mice. H. pylori infection induced severe dysplasia and gastric cancer classified as high-grade and lowgrade gastrointestinal intraepithelial neoplasia (GIN) in INS-GAS mice at 28 weeks postinfection (WPI). H. pylori eradication therapy using omeprazole, metronidazole, and clarithromycin was administered p.o. at 8, 12, or 22 WPI. Compared with untreated infected mice, H. pylori eradication at 8, 12, and 22 WPI significantly reduced the severity of dysplasia (P < 0.01). Moreover, H. pylori eradication at 8 WPI completely prevented the development of GIN (P < 0.001).Although not as effective as early antimicrobial treatment, prevention of progression to high-grade GIN was achieved by H. pylori eradication at 12 and 22 WPI (P < 0.05). Consistent with reduced gastric pathology, H. pylori eradication at all time points significantly down-regulated gastric Interferon-;, tumor necrosis factor-A, inducible nitric oxide synthase, and Reg 1 mRNA levels (P < 0.05) and reduced epithelial proliferation in the corpus (P < 0.01) compared with untreated infected mice. We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics are given at an early point of infection, but that eradication therapy given at a later time point delayed the development of severe dysplastic lesions. [Cancer Res 2008;68(9):3540-8]

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“…Tissues were graded by a comparative pathologist (S. Muthupalani) blinded to sample identity for inflammation, epithelial defects, atrophy, hyperplasia, pseudopyloric metaplasia, dysplasia, hyalinosis, and mucous metaplasia, as defined elsewhere (15,39). Gastric lesions were scored on an ascending scale from 0 to 4 using criteria previously described (13,39). A gastric histologic activity index (HAI) was generated by combining scores for all criteria except hyalinosis and mucous metaplasia, which may develop irrespective of helicobacter infection.…”

Section: Methodsmentioning

confidence: 99%

Coinfection with Enterohepatic Helicobacter Species Can Ameliorate or Promote Helicobacter pylori-Induced Gastric Pathology in C57BL/6 Mice

Feng

Muthupalani

et al. 2011

Infect Immun

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To investigate how different enterohepatic Helicobacter species (EHS) influence Helicobacter pylori gastric pathology, C57BL/6 mice were infected with Helicobacter hepaticus or Helicobacter muridarum, followed by H. pylori infection 2 weeks later. Compared to H. pylori-infected mice, mice infected with H. muridarum and H. pylori (HmHp mice) developed significantly lower histopathologic activity index (HAI) scores (P < 0.0001) at 6 and 11 months postinoculation (MPI). However, mice infected with H. hepaticus and H. pylori (HhHp mice) developed more severe gastric pathology at 6 MPI (P ‫؍‬ 0.01), with a HAI at 11 MPI (P ‫؍‬ 0.8) similar to that of H. pylori-infected mice. H. muridarum-mediated attenuation of gastritis in coinfected mice was associated with significant downregulation of proinflammatory Th1 (interlukin-1beta [Il-1␤], gamma interferon [Ifn-␥], and tumor necrosis factor-alpha [Tnf-␣]) cytokines at both time points and Th17 (Il-17A) cytokine mRNA levels at 6 MPI in murine stomachs compared to those of H. pylori-infected mice (P < 0.01). Coinfection with H. hepaticus also suppressed H. pylori-induced elevation of gastric Th1 cytokines Ifn-␥ and Tnf-␣ (P < 0.0001) but increased Th17 cytokine mRNA levels (P ‫؍‬ 0.028) at 6 MPI. Furthermore, mRNA levels of Il-17A were positively correlated with the severity of helicobacter-induced gastric pathology (HhHp>H. pylori>HmHp) (at 6 MPI, r 2 ‫؍‬ 0.92, P < 0.0001; at 11 MPI, r 2 ‫؍‬ 0.82, P < 0.002). Despite disparate effects on gastritis, colonization levels of gastric H. pylori were increased in HhHp mice (at 6 MPI) and HmHp mice (at both time points) compared to those in mono-H. pylori-infected mice. These data suggest that despite consistent downregulation of Th1 responses, EHS coinfection either attenuated or promoted the severity of H. pylori-induced gastric pathology in C57BL/6 mice. This modulation was related to the variable effects of EHS on gastric interleukin 17 (IL-17) responses to H. pylori infection.

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Accelerated Progression of Gastritis to Dysplasia in the Pyloric Antrum of TFF2−/− C57BL6 × Sv129 Helicobacter pylori-Infected Mice

Cited by 92 publications

References 45 publications

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Helicobacter pylori Eradication Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

Coinfection with Enterohepatic Helicobacter Species Can Ameliorate or Promote Helicobacter pylori-Induced Gastric Pathology in C57BL/6 Mice

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