Metaplasia as a Premalignant Pathology in the Stomach
2007; Elsevier BV; Volume: 132; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2007.03.074
ISSN1528-0012
Autores Tópico(s)Gastrointestinal disorders and treatments
ResumoSee “Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice” by Nam KT, Varro A, Coffey RJ, and Goldenring JR, on page 1804. See “Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice” by Nam KT, Varro A, Coffey RJ, and Goldenring JR, on page 1804. Epithelial metaplasia is the process by which an organ-specific epithelium is replaced by another. It is common in the gut (particularly in the esophagus and stomach, which is often replaced by intestinal epithelium) as well as the lung and cervix, and may be considered an adaptive differentiation response to chronic inflammation or injury leading to increased susceptibility to carcinogenesis.1Delvenne P. Hubert P. Jacobs N. Epithelial metaplasia: an inadequate environment for tumour immunity?.Trends Immunol. 2004; 25: 169-173Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar The most commonly recognized metaplasia of the upper gut is intestinal metaplasia (IM), which is associated with chronic gastric acid reflux or Helicobacter pylori infection. The phenotype consists of mucus-secreting goblet cells and true enterocytes with long microvilli and expressing intestinal plasma membrane-specific enzymes in both the stomach and esophagus (Barrett’s esophagus), and may also include endocrine and Paneth cells in the former. Although IM had been identified many decades previously,2Correa P. A human model of gastric carcinogenesis.Cancer Res. 1988; 48: 3554-3560PubMed Google Scholar Correa first suggested that H pylori infection of the stomach leads to the continuum of gastritis, fundic stomach atrophy (predominantly parietal and chief cell loss) and premalignant IM in susceptible hosts, as a prelude to the most common intestinal-type adenocarcinoma.2Correa P. A human model of gastric carcinogenesis.Cancer Res. 1988; 48: 3554-3560PubMed Google Scholar Subsequent studies have confirmed a close association between IM progression and gastric carcinoma (both intestinal and diffuse3Boussioutas A. Li H. Liu J. Waring P. Lade S. Holloway A.J. Taupin D.R. Gorringe K. Haviv I. Desmond P.V. Bowtell D.D. Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer.Cancer Res. 2003; 63: 2569-2577PubMed Google Scholar), with odds ratios of progression to neoplasia ranging from 5 to 29 depending on the population studied.4Filipe M.I. Munoz N. Matko I. Kato I. Pompe-Kirn V. Jutersek A. Teuchmann S. Benz M. Prijon T. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia.Int J Cancer. 1994; 57: 324-329Crossref PubMed Scopus (386) Google Scholar, 5You W.C. Li J.Y. Blot W.J. Chang Y.S. Jin M.L. Gail M.H. Zhang L. Liu W.D. Ma J.L. Hu Y.R. Mark S.D. Correa P. Fraumeni J.F. Xu G.W. Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer.Int J Cancer. 1999; 83: 615-619Crossref PubMed Scopus (146) Google Scholar, 6Uemura N. Okamoto S. Yamamoto S. Matsumura N. Yamaguchi S. Yamakido M. Taniyama K. Sasaki N. Schlemper R.J. Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001; 345: 784-789Crossref PubMed Scopus (3569) Google Scholar IM is now considered a true preneoplastic lesion of the stomach, associated with mutated differentiation and growth pathways. There are several subtypes of IM currently recognized, based mainly on differences in mucin histochemistry and morphology.7Matsukura N. Suzuki K. Kawachi T. Aoyagi M. Sugimura T. Kitaoka H. Numajiri H. Shirota A. Itabashi M. Hirota T. Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas.J Natl Cancer Inst. 1980; 65: 231-240PubMed Google Scholar, 8Jass J.R. Filipe M.I. A variant of intestinal metaplasia associated with gastric carcinoma: a histochemical study.Histopathology. 1979; 3: 191-199Crossref PubMed Scopus (146) Google Scholar, 9Teglbjaerg P.S. Nielson H.O. “Small intestinal type” and “colonic type” intestinal metaplasia of the human stomach, and their relationship to the histogenetic types of gastric adenocarcinoma.Acta Pathol Microbiol Scand (A). 1978; 86A: 351-355Google Scholar Type I or complete metaplasia is most like small intestine in histomorphology and occurs first, whereas types II and III are incomplete and progressively become more colonic in morphology and increasingly associated with oncogenic transformation.10Filipe M.I. Potet F. Bogomoletz W.V. Dawson P.A. Fabiani B. Chauveinc P. Fenzy A. Gazzard B. Goldfain D. Zeegen R. Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer Preliminary data from a prospective study from three centres.Gut. 1985; 26: 1319-1326Crossref PubMed Scopus (183) Google Scholar Alternative classifications based on differentiation status and both gastric and intestinal markers also exist.11Tsukamoto T. Mizoshita T. Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization.Gastric Cancer. 2006; 9: 156-166Crossref PubMed Scopus (47) Google Scholar The molecular mechanisms underlying the development and progression of IM are still not completely understood. Microsatellite instability, mutations in p53, up-regulation of c-myc, cyclooxygenase (COX)-2, and telomerase, down-regulation of p27, and loss of heterozygosity of antigen-presenting cells have all been associated with the development of IM,12Nardonne G. Rocco A. Malfertheiner P. Helicobacter pylori and molecular events in precancerous lesions.Aliment Pharmacol Ther. 2004; 20: 261-270Crossref PubMed Scopus (118) Google Scholar as has the renewed expression of homeobox genes that normally act as transcription factors regulating intestinal development such as CDX1 and CDX2,13Yuasa Y. Control of gut differentiation and intestinal-type gastric carcinogenesis.Nat Rev Cancer. 2003; 3: 592-600Crossref PubMed Scopus (275) Google Scholar PDX1,13Yuasa Y. Control of gut differentiation and intestinal-type gastric carcinogenesis.Nat Rev Cancer. 2003; 3: 592-600Crossref PubMed Scopus (275) Google Scholar and OCT114Sakai H. Eishi Y. Li X.L. Akiyama Y. Miyake S. Takizawa T. Konishi N. Tatematsu M. Koike M. Yuasa Y. PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas.Gut. 2004; 53: 323-330Crossref PubMed Scopus (62) Google Scholar (Figure 1). Transgenic mouse models of CDX1 and -215Silberg D.G. Sullivan J. Kang E. Moffett J. Sund N.J. Sackett S.D. Kaestner K.H. Cdx2 extopic expression induces gastric intestinal metaplasia in transgenic mice.Gastroenterology. 2002; 122: 689-696Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 16Mutoh H. Sakurai S. Satoh K. Osawa H. Hakamata Y. Takeuchi T. Sugano K. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice.Gut. 2004; 53: 1416-1423Crossref PubMed Scopus (121) Google Scholar, 17Mutoh H. Hakamata Y. Satoh K. Eda A. Yanaka I. Honda S. Osawa H. Kaneko Y. Sugano K. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice.Biochem Biophys Res Commun. 2002; 294: 470-479Crossref PubMed Scopus (226) Google Scholar show true intestinalization of the gastric mucosa (unlike many mouse genetic models in which the metaplasia develops in the absence of true enterocytes, goblet, Paneth, and endocrine cells), and the CDX2 transgenic progresses to invasive adenocarcinoma in the absence of H pylori,18Mutoh H. Sakurai S. Satoh K. Tamada K. Kita H. Osawa H. Tomiyama T. Sato Y. Yamamoto H. Isoda N. Yoshida T. Ido K. Sugano K. Development of gastric carcinoma from intestinal metaplasia in CDX2-transgenic mice.Cancer Res. 2004; 64: 7740-7747Crossref PubMed Scopus (149) Google Scholar providing strong evidence for a causal link between IM and gastric oncogenesis. A regulator of stomach development, Sox2, is lost during intestinal metaplastic progression in concert with the increase in CDX1 and CDX2, suggesting that its down-regulation may be a necessary precursor event in the expression of these intestine-specific transcriptional regulators.19Tsukamoto T. Inada K. Tanaka H. Mizoshita T. Mihara M. Ushijima T. Yamamura Y. Nakamura S. Tatematsu M. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia.J Cancer Res Clin Oncol. 2004; 130: 135-145Crossref PubMed Scopus (126) Google Scholar Other important genes in the development of IM include RUNX3, a gut associated transcription factor and tumour suppressor that is deactivated by epigenetic silencing in IM20Kim T.Y. Lee H.J. Hwang K.S. Lee M. Kim J.W. Bang Y.J. Kang G.H. Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma.Lab Invest. 2004; 84: 479-484Crossref PubMed Scopus (196) Google Scholar; TFF3, the goblet cell-associated trefoil factor that is induced in the stomach early in the development of IM in both humans and rats21Taupin D.R. Pedersen J. Familari M. Cook G. Yeomans N.D. Giraud A.S. Augmented intestinal trefoil factor (TFF3) and loss of pS2 (TFF1) expression precedes metaplastic differentiation of gastric epithelium.Lab Invest. 2001; 81: 397-408Crossref PubMed Scopus (89) Google Scholar and that has recently been shown to be induced by CDX222Shimada T. Koike T. Yamagata M. Yoneda M. Hiraishi H. Regulation of TFF3 expression by homeodomain protein CDX2.Regul Pept. 2007; 140: 81-87Crossref PubMed Scopus (23) Google Scholar; and Sonic hedgehog, a parietal cell morphogen, the expression of which is lost in IM in humans23van den Brink G.R. Hardwick J.C. Nielsen C. Xu C. ten Kate F.J. Glickman J. van Deventer S.J. Roberts D.J. Peppelenbosch M.P. Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract.Gut. 2002; 51: 628-633Crossref PubMed Scopus (142) Google Scholar and, when ablated by homologous recombination in mice, leads to metaplastic development24Ramalhos-Santos M. Melton D.A. McMahon A.P. Hedgehog signals regulate multiple aspects of gastrointestinal development.Development. 2000; 127: 2763-2772PubMed Google Scholar (Figure 1). Indeed, atrophic gastritis, especially parietal cell loss with its plethora of associated regulatory products that modulate gastric maturation and growth, is likely to be an important permissive event preceding intestinal metaplastic development in the stomach. Finally, although loss or gain of pivotal developmental genes that promote or inhibit IM have been identified, the upstream regulatory events linking this metaplasia with chronic inflammation or damage at the molecular level remain obscure. In the last 10 years a second gastric metaplasia associated with neoplastic progression has been recognized in the stomach of both rodents and humans. The so-called spasmolytic polypeptide expressing metaplasia (SPEM) lineage, named for its characteristic expression of spasmolytic polypeptide (now TFF2) was first observed in the fundic mucosae of C57Bl6 (but not BALB.c or C3H/HeJ) mice infected with H felis,25Wang T.C. Goldenring J.R. Dangler C. Ito S. Mueller A. Jeon W.K. Koh T.J. Fox J.G. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection.Gastroenterology. 1998; 114: 675-689Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar and was subsequently shown to be associated with preneoplastic changes in that model26Nomura S. Baxter T. Yamaguchi H. Leys C. Vartapetian A.B. Fox J.G. Lee J.R. Wang T.C. Goldenring J.R. Spasmolytic polypeptide expressing metaplasia to preneoplasia in H felis-infected mice.Gastroenterology. 2004; 127: 582-594Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar (Figure 1). SPEM has been identified in almost 70% of biopsies from human fundic glands exhibiting H pylori-associated gastritis, and is almost invariably associated with gastric adenocarcinomas,27Schmidt P.H. Lee J.R. Playford R.J. Poulsom R. Wright N.A. Goldenring J.R. Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma.Lab Invest. 1999; 79: 639-646PubMed Google Scholar supporting the view that it may represent a cellular template for oncogenic transformation. The SPEM lineage resembles cells of the deep antral glands of the stomach, as well as the Brunners glands of the duodenum, and appears to have some common histochemical and morphologic characteristics with the previously recognized pseudopyloric metaplasia of intestine and biliary tract, and the global gut ulcer–associated cell lineage.28Wright N.A. Poulsom R. Stamp G.W. Hall P.A. Jeffrey R.E. Longcroft J.M. Rio M.C. Tomasetto C. Chambon P. Epidermal growth factor (EGF/URO) induces expression of regulatory peptides in damaged human gastrointestinal tissues.J Pathol. 1990; 162: 279-284Crossref PubMed Scopus (206) Google Scholar Recent studies have shown that TFF2 expression is dispensable for SPEM occurrence, but that defective EGF receptor signaling accelerates its development.29Ogawa M. Nomura S. Varro A. Wang T.C. Goldenring J.R. Altered metaplastic response of waved-2 EGF receptor mutant mice to acute oxyntic atrophy.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G793-G804Crossref PubMed Scopus (23) Google Scholar In addition, laser capture microdissection coupled with cDNA microarray26Nomura S. Baxter T. Yamaguchi H. Leys C. Vartapetian A.B. Fox J.G. Lee J.R. Wang T.C. Goldenring J.R. Spasmolytic polypeptide expressing metaplasia to preneoplasia in H felis-infected mice.Gastroenterology. 2004; 127: 582-594Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar has been used in attempts to characterize genes specific for the SPEM lineage. Although several genes have been identified that are relatively specific for SPEM, to date diagnostically useful markers have not been substantiated; a complicating factor is that TFF2 is also a product of mucus neck cells of the fundic mucosa. Although the SPEM lineage has been well described morphologically in both mouse and human models of gastric carcinogenesis, the local regulatory factors that predispose to development of the lineage, its cellular origins, and the relationship between it and gastric cancer are not well defined. The paper by Nam et al30Nam K.T. Varro A. Coffey R.J. Goldenring J.R. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice.Gastroenterology. 2007; 132: 1804-1819Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar in this issue of Gastroenterology advances our understanding of SPEM progression by casting new light on a specific parietal cell factor that when downregulated in forced oxyntic/parietal cell atrophy may be permissive for SPEM development. In addition, the authors provide morphologic evidence for the cellular origin of SPEM in the chief cell lineage of the fundic glands. In their study, Nam et al30Nam K.T. Varro A. Coffey R.J. Goldenring J.R. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice.Gastroenterology. 2007; 132: 1804-1819Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar compared SPEM development in C57Bl6 mice that lacked one or the other of the EGF receptor ligands transforming growth factor (TGF)-α or amphiregulin (AR), or were wild type for both gene alleles. SPEM was produced by chemically induced atrophy of the oxyntic glands using the well-established neutrophil elastase inhibitor DMP-777 for up to 14 days. This regimen has previously been shown by these authors in other studies to preferentially target fundic parietal cells by acting as a protonophore,29Ogawa M. Nomura S. Varro A. Wang T.C. Goldenring J.R. Altered metaplastic response of waved-2 EGF receptor mutant mice to acute oxyntic atrophy.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G793-G804Crossref PubMed Scopus (23) Google Scholar, 31Ogawa M. Nomura S. Car B.D. Goldenring J.R. Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777.Dig Dis Sci. 2006; 51: 431-439Crossref PubMed Scopus (11) Google Scholar thereby providing a means to deplete parietal cells in the mucosa, and providing a pathologic mimic for an important element of the oxyntic atrophy caused by chronic H pylori infection, but without the attendant inflammation. The outcomes of these treatments were several. First, loss of AR, but not TGF-α, leads to much faster SPEM progression than in wild-type animals. This suggests that, although they activate the same receptor, not all EGFr ligands work in the same way and that under normal circumstances AR may function in part to inhibit SPEM development, at least in C57Bl6 mice. It also reinforces the view that parietal cells produce a range of ligands that regulate gastric differentiation, because TGF-α, but not AR, loss produces foveolar hyperplasia. Because SPEM is associated with Helicobacter-induced pathology in both mice and humans, it might be expected that suppression of AR would result from bacterial infection and consequent oxyntic atrophy. This appears not to be the case; AR is highly expressed in human gastric cancer being regulated in a gastrin-dependent fashion,32Kitadai Y. Yasui W. Yokozaki H. Kuniyasu H. Ayhan A. Haruma K. Kajiyama G. Johnson G.R. Tahara E. Expression of amphiregulin, a novel gene of the epidermal growth factor family, in human gastric carcinomas.Jpn J Cancer Res. 1993; 84: 879-884Crossref PubMed Scopus (42) Google Scholar and recent gene expression profiling in the INS-GAS/H felis gastric cancer mouse which develops robust SPEM shows AR to be one of the most highly induced genes.33Takaishi S. Wang T.C. Gene expression profiling in a mouse model of Helicobacter-induced gastric cancer.Cancer Sci. 2007; 98: 284-293Crossref PubMed Scopus (60) Google Scholar One explanation for the apparent discrepancy may reside in differences in the mouse strains used in this and the Nam paper, and in the method for inducing atrophy, although in both parietal cell function was severely compromised. More likely is that Helicobacter-induced atrophy and consequent SPEM induction occurs slowly and it may be that induced AR inhibits the metaplastic drive for a time, but that eventually this inhibition is overwhelmed. Whatever the explanation, it is clear that an important unanswered question thrown up by the Nam et al study30Nam K.T. Varro A. Coffey R.J. Goldenring J.R. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice.Gastroenterology. 2007; 132: 1804-1819Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar is the nature of the mechanism by which AR regulates metaplasia. Unlike IM, the paucity of known SPEM-associated developmental or regulatory factors means that targets for AR action are difficult to predict and the biology of AR is not nearly as well defined as that of the other EGF receptor ligands. A further impediment is that SPEM only develops in vivo, and it seems unlikely that nontransformed in vitro systems, which might be more readily amenable to manipulation, could be developed to study it. In addition, because the DMP-777 induced oxyntic atrophy and development of SPEM is independent of bacterial inflammation, probably owing to drug-reduced neutrophil activity,34Nomura S. Yamaguchi H. Ogawa M. Wang T.C. Lee J.R. Goldenring J.R. Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G362-G375Crossref PubMed Scopus (119) Google Scholar and even long-term dosing does not lead to neoplasia,35Goldenring J.R. Ray G.S. Coffey R.J. Meunier P.C. Haley P.J. Barnes T.B. Car B.D. Reversible drug-induced oxyntic atrophy in rats.Gastroenterology. 2000; 118: 1080-1093Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar more physiologically relevant mechanistic studies on the regulatory role of AR in SPEM development need to be carried out in mouse models based on Helicobacter-induced inflammation. The utility of this approach is exemplified by the nature of the immune response after Helicobacter infection in mice or in humans. The dominant Th1 response, with elevated interleukin (IL)-1β, IL-8, TNF-α and interferon (IFN)-γ leads to gastritis and metaplasia when chronic, and studies in mice infected with H felis have confirmed the central and likely interactive role played by the cytokines TNF-α and IFN-γ, which regulate inflammation and metaplasia when infused or when their genes are ablated.36Hasegawa S. Nishikawa S. Miura T. Saito Y. Madarame H. Sekikawa K. Tagawa Y. Iwakura Y. Nakane A. Tumor necrosis factor-α is required for gastritis induced by Helicobacter felis infection in mice.Microbial Pathogenesis. 2004; 34: 119-124Crossref Scopus (18) Google Scholar Two relevant examples are given here. First, infusion of IFN-γ into wild-type C57Bl6 mice for 2 weeks induced SPEM-like cells in the mid fundic glands, which were positive for TFF2, MUC6, and the lectin GSII, and IFN-γ treatment of the human gastric cancer cell line NCI-N87 induced TFF2, MUC6, pepsinogen II, but not intrinsic factor.37Kang W. Rathinavelu S. Samuelson L.G. Merchant J.L. Interferon gamma induction of gastric mucous neck cell hypertrophy.Lab Invest. 2005; 85: 702-715Crossref PubMed Scopus (75) Google Scholar Second, transgenic mice expressing COX-2 and microsomal prostaglandin E synthase (K19-C2mE mice) developed SPEM and infiltrating hyperplastic tumors of the fundic mucosa. Genetic or antibody ablation of TNF-α (but not IL-1-β or Rag1, which depletes the adaptive immune response) strongly suppressed SPEM induction (TFF2 and MUC6 staining was reduced and restricted to the neck zone of fundic glands) and most significantly markedly reduced tumor proliferation.38Oshima M. Oshima H. Matsunaga A. Taketo M.M. Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor α-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice.Cancer Res. 2005; 65: 9147-9151Crossref PubMed Scopus (60) Google Scholar Thus, conditional knockout of AR at different stages of SPEM progression induced by H felis with or without genetic ablation of other relevant regulatory factors such as gastrin, TNF-α, and IFN-γ might be very informative, as would the fate of bone marrow precursors, which have been shown to engraft the stomach as TFF2-expressing epithelial cells, and which may give rise to dysplastic tumors.39Houghton J.M. Stoicov C. Nomura S. Rogers A.B. Carlson J. Li H. Cai X. Fox J.G. Goldenring J.R. Wang T.C. Gastric cancer originating from bone marrow-derived cells.Science. 2004; 306: 1568-1571Crossref PubMed Scopus (1032) Google Scholar The second main finding of the Nam et al paper30Nam K.T. Varro A. Coffey R.J. Goldenring J.R. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice.Gastroenterology. 2007; 132: 1804-1819Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar was the description of a BrdU-positive proliferative zone in the deep fundic glands of DMP-777 treated mice that is distinct from the normal progenitor region of the gland neck, and which was colocalized with intrinsic factor, a chief cell marker. Expansion of this deep proliferative zone was wholly dependent on oxyntic atrophy, because cessation of DPP-777 caused it to regress fully after 14 days. Although total BrdU-positive cells were reduced in AR-null animals, TFF2 and intrinsic factor dual-stained cells were markedly increased over wild type when treated with DMP-777 and the time course correlated with SPEM occurrence. Nam et al30Nam K.T. Varro A. Coffey R.J. Goldenring J.R. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice.Gastroenterology. 2007; 132: 1804-1819Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar conclude that these data are consistent with transdifferentiation of long-lived chief cells, despite their being partially depleted by DMP-777 treatment, into a mucous (TFF2 positive) lineage such as SPEM, and that in doing so some cells (intrinsic factor–positive and labeled for BrdU) also enter the cell cycle. An alternative explanation for the expansion of the TFF2/intrinsic factor expressing cells derived from fundic gland bases following oxyntic atrophy, is that prezymogenic cells, which are the immediate maturation derivatives of mucous neck cells in the mouse,40Karam S.M. Leblond C.P. Dynamics of epithelial cells in the corpus of the mouse stomach III Inward migration of neck cells followed by progressive transformation into zymogenic cells.Anat Rec. 1993; 236: 297-313Crossref PubMed Scopus (181) Google Scholar may be stimulated to express both antigens in response to loss of AR or reduced gastrin drive, in conjunction with parietal cell atrophy. Clearly, lineage tracing studies with multiple markers are required in a cross-section of mouse models in which SPEM occurs, including those in which inflammation accompanies oxyntic atrophy. In conclusion, Nam et al30Nam K.T. Varro A. Coffey R.J. Goldenring J.R. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice.Gastroenterology. 2007; 132: 1804-1819Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar have introduced a new and interesting player into the mix of regulators of gastric metaplasia. Further clarification of the role of AR in SPEM induction and its relationship with neoplasia appears warranted. Potentiation of Oxyntic Atrophy–Induced Gastric Metaplasia in Amphiregulin-Deficient MiceGastroenterologyVol. 132Issue 5PreviewBackground & Aims: The loss of parietal cells from the gastric mucosa (oxyntic atrophy) is a critical step in the pathogenesis of chronic gastritis and gastric adenocarcinoma. Parietal cells are known to secrete epidermal growth factor receptor (EGFR) ligands, which are critical regulators of differentiation in the gastric mucosa. Although all of the actions of EGFR ligands are mediated through a common EGFR protein, individual ligands may produce different physiologic responses. Previous investigations have suggested that a deficit in EGFR signaling in waved-2 mice accelerates the emergence of metaplasia after induction of acute oxyntic atrophy. Full-Text PDF
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