Inflammation, Atrophy, Gastric Cancer: Connecting the Molecular Dots
2005; Elsevier BV; Volume: 129; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2005.07.038
ISSN1528-0012
Autores Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoIt has now been 30 years since Pelayo Correa published his overview of mucosal changes preceding the appearance of gastric cancer. The basis for chronic inflammation progressing to mucosal atrophy, intestinal metaplasia, then distal gastric cancer evolved from the study of gastric cancer registries in the US and other westernized countries since the mid–20th century. There are at least 2 types of gastric cancer arising from the epithelium that can be genetically defined. The diffuse type is remarkable for its poorly differentiated phenotype in which the glandular architecture is completely lost. Diffuse gastric cancer is strongly associated with mutations in the E-cadherin gene-reducing expression of this transmembrane cell adhesion receptor. Both the trigger and histopathologic steps in the progression of diffuse gastric cancer are incompletely understood. However, due to the interaction of E-cadherin protein with cytoplasmic β-catenin, dysregulation of cell adhesion, polarity, and the cytoskeleton are likely to play prominent roles. Although adenomatous polyposis coli (APC) regulates cellular levels of β-catenin, mutations at the APC locus are rare.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar This underscores the role of E-cadherin and the cytoskeleton in the genesis of diffuse gastric cancer rather than activation of the Wnt-APC-β-catenin pathway and downstream transcriptional events.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 2Bienz M. beta-Catenin a pivot between cell adhesion and Wnt signalling.Curr Biol. 2005; 15: R64-R67Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar By contrast according to the Correa paradigm, well-differentiated, intestinal-type gastric cancer arises in the setting of chronic inflammation. It is this cancer type that is most closely associated with chronic Helicobacter pylori infection, and for which precursor atrophic lesions (eg, pseudopyloric gland and intestinal metaplasias) have been reported (Figure 1). Therefore, the emphasis here will be to review the molecular steps leading to intestinal-type gastric cancer.Location, Location, LocationAbout 60% to 80% of intestinal-type cancers arise from the gastric antrum with a preference for the lesser curvature. The gastric epithelium is not homogenous but, in fact, is divided into 3 distinct regions, the (upper) cardia, (middle) corpus, and (lower) antrum, with the transitional zone from the oxyntic to antral glands occurring at the incisura. Although many older cancer registries did not distinguish between these locations, it has become more apparent that classification of the cancer site provides additional clues as to the etiology and behavior of transformed cells. For example, the most rapidly emerging class of gastric adenocarcinoma in the US appeared to arise in the cardia.3Corley D.A. Kubo A. Influence of site classification on cancer incidence rates an analysis of gastric cardia carcinomas.J Natl Cancer Inst. 2004; 96: 1383-1387Crossref PubMed Scopus (82) Google Scholar However, with improved categorization, it has now been realized that the sharp rise in proximal cancers is due to adenocarcinoma of the esophagus rather than the cardia, with the incidence of cardia cancers relatively stable compared with the more rapidly declining distal cancers.3Corley D.A. Kubo A. Influence of site classification on cancer incidence rates an analysis of gastric cardia carcinomas.J Natl Cancer Inst. 2004; 96: 1383-1387Crossref PubMed Scopus (82) Google Scholar In addition, H pylori infection appears to protect against rather than correlate with adenocarcinoma of the esophagus. This would suggest that proximal cancer emerges under conditions that do not favor H pylori infection, eg, gastric atrophy and high pH. However, the protective effect does not appear to be related to atrophy-induced hypochlorhydria.4Ye W. Held M. Lagergren J. Engstrand L. Blot W.J. McLaughlin J.K. Nyren O. Helicobacter pylori infection and gastric atrophy risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia.J Natl Cancer Inst. 2004; 96: 388-396Crossref PubMed Scopus (305) Google ScholarClassically atrophy of the corpus, a stimulus for hypergastrinemia due to reduced acid secretion, precedes the development of antral cancer. However, when histologic mapping of the entire stomach was performed in subjects previously infected with H pylori, primarily antral atrophy was found with extension of the antral-type glands (pseudopyloric gland metaplasia) into the corpus in about 40% of the cases.5El-Zimaity H.M. Ota H. Graham D.Y. Akamatsu T. Katsuyama T. Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2002; 94: 1428-1436Crossref PubMed Scopus (139) Google Scholar Since there is a lack of G cells in an atrophic antrum due to replacement by intestinal metaplasia, gastrin levels will be low and contribute to oxyntic gland hyposecretion. However, before significant antral atrophy, inflammatory cytokines can actually stimulate gastrin expression and secretion.6Zavros Y. Rathinavelu S. Kao J.Y. Todisco A. DelValle J. Weinstock J.V. Low M.J. Merchant J.L. Treatment of Helicobacter gastritis with interleukin-4 requires somatostatin.Proc Natl Acad Sci. 2003; 100: 12944-12949Crossref PubMed Scopus (88) Google Scholar Gastrin is a growth factor for the acid-producing parietal cells, suggesting a likely role for gastrin deficiency in the subsequent atrophy of this cellular compartment. Whether due to parietal cell hyposecretion or actual loss, the resulting hypochlorhydria indicates substantive atrophic changes in the gastric mucosa that presage neoplastic transformation. A mouse model of hypergastrinemia has implicated gastrin in the eventual appearance of a hyperproliferative mucous cell compartment accompanying oxyntic atrophy and dysplasia in the corpus by 20 months, and within 8 months when Helicobacter is present.7Wang T.C. Dangler C.A. Chen D. Goldenring J.R. Koh T. Raychowdhury R. Coffey R.J. Ito S. Varro A. Dockray G.J. Fox J.G. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer.Gastroenterology. 2000; 118: 36-47Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar Nevertheless, hypogastrinemia without Helicobacter predisposes the epithelium to tumors specifically in the distal stomach by 12 months.8Zavros Y. Eaton K.A. Kang W. Rathinavelu S. Katukuri V. Kao J.Y. Samuelson L.C. Merchant J.L. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.Oncogene. 2005; 24: 2354-2366Crossref PubMed Scopus (120) Google Scholar Thus, gastrin is not required for the development of distal gastric cancer. The divergent locations of the tumors in these 2 mouse models raise the possibility that the molecular steps leading to gastric neoplasia in the corpus versus the antrum also differ. Collectively, the models support what has been implied from human studies, that loss of parietal function or cells creates an environment poised to undergo transformation. One hypothesis to consider is whether substances are secreted with acid that normally can suppress antral proliferation and subsequently are lost with atrophy of the oxyntic glands (Figure 1).Environmental Triggers: Inflammation Versus BacteriaThe dramatic decline in gastric cancer during the past century correlating with improvements in food storage has placed the etiologic focus squarely on environmental factors.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 9Tsugane S. Salt, salted food intake, and risk of gastric cancer epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (253) Google Scholar Ingestion of a high-salt diet, smoked foods rich in nitrates, and contaminated water teeming with H pylori appear to be the major environmental inducers of gastric cancer, but for different reasons. High salt disrupts the gastric mucosal barrier,9Tsugane S. Salt, salted food intake, and risk of gastric cancer epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (253) Google Scholar while N-nitroso mutagens formed from dietary nitrates by bacteria flourishing in a hypochlorhydric stomach damage DNA. Understanding the role of H pylori in triggering mucosal changes has been dominant perhaps because there is now the possibility that cancer can be prevented with antibiotics directed at a single organism. Yet, it is still unclear which molecular signals actually initiate the program of irreversible transformation.A number of articles have suggested mechanisms by which H pylori might trigger carcinogenesis. Most studies cite well-known bacterial factors that activate various kinase cascades, such as CagA or peptidoglycans, which bind cellular proteins like the phosphatase SHP-2, the receptor c-Met or defense protein Nod 1. Yet when studying animal models or human subjects, it is impossible to distinguish whether bacterial products or the host inflammatory response is ultimately responsible for neoplastic transformation. Although transgenic expression of individual H pylori proteins as putative oncoproteins has not been directly tested, the ability to infuse inflammatory cytokines into mice or express cytokine genes from tissue-specific promoters provides an opportunity to evaluate the contribution of the immune response separate from the organism. Such infusions have revealed that proinflammatory cytokines are capable of inducing parietal cell atrophy and mucous neck cell hypertrophy.6Zavros Y. Rathinavelu S. Kao J.Y. Todisco A. DelValle J. Weinstock J.V. Low M.J. Merchant J.L. Treatment of Helicobacter gastritis with interleukin-4 requires somatostatin.Proc Natl Acad Sci. 2003; 100: 12944-12949Crossref PubMed Scopus (88) Google Scholar, 10Kang W. Rathinavelu S. Samuelson L.C. Merchant J.L. Interferon gamma induction of gastric mucous neck cell hypertrophy.Lab Invest. 2005; 85: 702-715Crossref PubMed Scopus (75) Google Scholar More recently it has been shown that the transformed gastric epithelium in mice infected with H pylori develops from bone marrow-derived progenitor cells.11Houghton J. 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 (1039) Google Scholar Although this event appears to be rare and cannot be verified in human stomach, it is suggestive that some gastric epithelial cancers transdifferentiate from or possibly fuse to infiltrating hematopoetic cells, re-enforcing the importance of the immune response.Understanding the epithelial program modified by H pylori colonization is an area of intense study because of the availability of mouse and tissue culture models with clear parallels to the human phenotype. Nevertheless, the in vivo sites of colonization and strain variations will complicate defining the molecular steps leading from colonization to cancer. Couple these bacterial attributes with the host response and one is left with a complex genetic program that may prove daunting to dissect. In this case, microarray and proteomic analyses of different cellular compartments will be important to determine whether bacterial strain variation alters the genetic programs activated in the different regions of the stomach and glands.Although emphasis has primarily been on the mucosal effects, how injury at the luminal surface perturbs the mesenchyme should also be examined due to its essential instructive effects on the epithelium. The Wnt-APC-β-catenin signaling pathway plays a central role in the epithelial-mesenchymal crosstalk,2Bienz M. beta-Catenin a pivot between cell adhesion and Wnt signalling.Curr Biol. 2005; 15: R64-R67Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar and may be overlooked due to the paucity of mutations at the APC locus in gastric cancer. However, the APC locus is commonly methylated in gastrointestinal stromal tumors, suggesting that epigenetic changes in APC should be considered for gastric adenocarcinomas.Connecting the Molecular DotsNumerous genes have already been implicated in gastric transformation. However, an essential question that emerges is how to organize the known alterations into a temporal sequence of events. The earliest alterations in the gastric mucosa invariably involve epigenetic changes, eg, hypermethylation.12Kang G.H. Lee H.J. Hwang K.S. Lee S. Kim J.H. Kim J.S. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation.Am J Pathol. 2003; 163: 1551-1556Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Although the mechanism by which inflammation stimulates DNA methyltransferases has not been widely pursued, apparently nitric oxide can stimulate the activity of these enzymes that in turn mediate epigenetic gene silencing.13Hmadcha A. Bedoya F.J. Sobrino F. Pintado E. Methylation-dependent gene silencing induced by interleukin 1beta via nitric oxide production.J Exp Med. 1999; 190: 1595-1604Crossref PubMed Scopus (181) Google Scholar It is known that several genes inactivated in atrophic mucosa are due to hypermethylation and include p16, MLH1, MGMT, and Runx3.12Kang G.H. Lee H.J. Hwang K.S. Lee S. Kim J.H. Kim J.S. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation.Am J Pathol. 2003; 163: 1551-1556Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Candidate gene analysis and microarray studies of human tumors have revealed a number of genetic markers.14Yuasa Y. Control of gut differentiation and intestinal-type gastric carcinogenesis.Nat Rev Cancer. 2003; 3: 592-600Crossref PubMed Scopus (278) Google Scholar Moreover, several transgenic mouse models have confirmed a significant contribution from growth regulatory genes, exclusive of Helicobacter, eg, TFF1, the IL-6 receptor subunit gp130, and Runx3.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google ScholarKnowledge of histologic changes that occur in the mucosa, for example, the appearance of pseudopyloric glands and intestinal metaplasia, has prompted interest in the genes responsible for these phenotypes. Understanding the genetic signals that distinguish stomach from small bowel epithelium will be useful in assembling the molecular steps responsible for developmental patterning in the proximal gut that becomes recapitulated in the transforming stomach. Recently, it has been shown that the antrum is developmentally more closely related to the small bowel than the corpus. Extending this logic further suggests that pseudopyloric glands in the corpus and intestinal metaplasia might represent sequential manifestations of the gastric injury response. In other words, the appearance of the antral-like mucous cells is perhaps another but incomplete form of intestinalization. In addition to the increased level of proliferation or decreased apoptotic rate accompanying these atrophic lesions, the loss of gastric-specific genes and emergence of intestine-specific genes has been observed. Gastric specific genes encoding H+, K+-ATPase, Muc5AC and intrinsic factor are lost and intestine-related genes appear with intestinal metaplasia, eg, Cdx2, Muc2, TFF3, villin.8Zavros Y. Eaton K.A. Kang W. Rathinavelu S. Katukuri V. Kao J.Y. Samuelson L.C. Merchant J.L. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.Oncogene. 2005; 24: 2354-2366Crossref PubMed Scopus (120) Google Scholar Thus, it will be from careful analysis first of the cellular phenotype then to temporal identification of the genetic changes that a consistent paradigm of gastric transformation will emerge (Figure 2).Figure 2Schematic time line of mucosal phenotypes and genetic changes in response to chronic gastritis. Bacterial colonization generates an immune response. In the acid competent stomach, the microbial trigger is H pylori; whereas, in the hypochlorhydric stomach other bacterial species can flourish. Chronic inflammation in the stomach consists of Th1 interferon gamma-secreting cells, as well as neutrophils and macrophages. Byproducts of inflammation (oxidative stress) stimulate DNA methyltransferases (DNMT). Interferon gamma stimulates mucous neck cell hypertrophy.10Kang W. Rathinavelu S. Samuelson L.C. Merchant J.L. Interferon gamma induction of gastric mucous neck cell hypertrophy.Lab Invest. 2005; 85: 702-715Crossref PubMed Scopus (75) Google Scholar Helicobacter infection stimulates proliferation of mucous neck cells, which are phenotypically similar to antral pyloric glands. Pseudopyloric gland metaplasia represents antral-type glands in the corpus and is a form of glandular atrophy. These pseudopyloric glands are TFF2, Muc6 positive, and thus may be synonomous with the mucous neck cell hypertrophy and hyperplasia that responds to proinflammatory cytokines. Intestinal metaplastic cells expressing enterocyte markers, eg, villin, TFF3, Muc2, Cdx2, can appear in the antrum or corpus emerging from an epithelial landscape of pseudopyloric gland metaplasia.5El-Zimaity H.M. Ota H. Graham D.Y. Akamatsu T. Katsuyama T. Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2002; 94: 1428-1436Crossref PubMed Scopus (139) Google Scholar The appearance of atrophic glands results in hypochlorhydria due either to loss of oxnytic gland function or cells. Dysplastic cells lose indicators of gastric differentiation. Transformed epithelium will exhibit functional and histologic evidence of unregulated growth, eg, loss of contact inhibition. There can be a 30 to 50 year lag between the appearance of atrophic glands and cancer. However, an exact time line and sequence of genetic alterations has yet to be firmly established.View Large Image Figure ViewerDownload (PPT)Note added in proof: In support of STAT3 hyperactivation in antral gastric cancer, see Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu HJ, Ernst M. Nature Medicine 2005;11:845–852. It has now been 30 years since Pelayo Correa published his overview of mucosal changes preceding the appearance of gastric cancer. The basis for chronic inflammation progressing to mucosal atrophy, intestinal metaplasia, then distal gastric cancer evolved from the study of gastric cancer registries in the US and other westernized countries since the mid–20th century. There are at least 2 types of gastric cancer arising from the epithelium that can be genetically defined. The diffuse type is remarkable for its poorly differentiated phenotype in which the glandular architecture is completely lost. Diffuse gastric cancer is strongly associated with mutations in the E-cadherin gene-reducing expression of this transmembrane cell adhesion receptor. Both the trigger and histopathologic steps in the progression of diffuse gastric cancer are incompletely understood. However, due to the interaction of E-cadherin protein with cytoplasmic β-catenin, dysregulation of cell adhesion, polarity, and the cytoskeleton are likely to play prominent roles. Although adenomatous polyposis coli (APC) regulates cellular levels of β-catenin, mutations at the APC locus are rare.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar This underscores the role of E-cadherin and the cytoskeleton in the genesis of diffuse gastric cancer rather than activation of the Wnt-APC-β-catenin pathway and downstream transcriptional events.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 2Bienz M. beta-Catenin a pivot between cell adhesion and Wnt signalling.Curr Biol. 2005; 15: R64-R67Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar By contrast according to the Correa paradigm, well-differentiated, intestinal-type gastric cancer arises in the setting of chronic inflammation. It is this cancer type that is most closely associated with chronic Helicobacter pylori infection, and for which precursor atrophic lesions (eg, pseudopyloric gland and intestinal metaplasias) have been reported (Figure 1). Therefore, the emphasis here will be to review the molecular steps leading to intestinal-type gastric cancer. Location, Location, LocationAbout 60% to 80% of intestinal-type cancers arise from the gastric antrum with a preference for the lesser curvature. The gastric epithelium is not homogenous but, in fact, is divided into 3 distinct regions, the (upper) cardia, (middle) corpus, and (lower) antrum, with the transitional zone from the oxyntic to antral glands occurring at the incisura. Although many older cancer registries did not distinguish between these locations, it has become more apparent that classification of the cancer site provides additional clues as to the etiology and behavior of transformed cells. For example, the most rapidly emerging class of gastric adenocarcinoma in the US appeared to arise in the cardia.3Corley D.A. Kubo A. Influence of site classification on cancer incidence rates an analysis of gastric cardia carcinomas.J Natl Cancer Inst. 2004; 96: 1383-1387Crossref PubMed Scopus (82) Google Scholar However, with improved categorization, it has now been realized that the sharp rise in proximal cancers is due to adenocarcinoma of the esophagus rather than the cardia, with the incidence of cardia cancers relatively stable compared with the more rapidly declining distal cancers.3Corley D.A. Kubo A. Influence of site classification on cancer incidence rates an analysis of gastric cardia carcinomas.J Natl Cancer Inst. 2004; 96: 1383-1387Crossref PubMed Scopus (82) Google Scholar In addition, H pylori infection appears to protect against rather than correlate with adenocarcinoma of the esophagus. This would suggest that proximal cancer emerges under conditions that do not favor H pylori infection, eg, gastric atrophy and high pH. However, the protective effect does not appear to be related to atrophy-induced hypochlorhydria.4Ye W. Held M. Lagergren J. Engstrand L. Blot W.J. McLaughlin J.K. Nyren O. Helicobacter pylori infection and gastric atrophy risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia.J Natl Cancer Inst. 2004; 96: 388-396Crossref PubMed Scopus (305) Google ScholarClassically atrophy of the corpus, a stimulus for hypergastrinemia due to reduced acid secretion, precedes the development of antral cancer. However, when histologic mapping of the entire stomach was performed in subjects previously infected with H pylori, primarily antral atrophy was found with extension of the antral-type glands (pseudopyloric gland metaplasia) into the corpus in about 40% of the cases.5El-Zimaity H.M. Ota H. Graham D.Y. Akamatsu T. Katsuyama T. Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2002; 94: 1428-1436Crossref PubMed Scopus (139) Google Scholar Since there is a lack of G cells in an atrophic antrum due to replacement by intestinal metaplasia, gastrin levels will be low and contribute to oxyntic gland hyposecretion. However, before significant antral atrophy, inflammatory cytokines can actually stimulate gastrin expression and secretion.6Zavros Y. Rathinavelu S. Kao J.Y. Todisco A. DelValle J. Weinstock J.V. Low M.J. Merchant J.L. Treatment of Helicobacter gastritis with interleukin-4 requires somatostatin.Proc Natl Acad Sci. 2003; 100: 12944-12949Crossref PubMed Scopus (88) Google Scholar Gastrin is a growth factor for the acid-producing parietal cells, suggesting a likely role for gastrin deficiency in the subsequent atrophy of this cellular compartment. Whether due to parietal cell hyposecretion or actual loss, the resulting hypochlorhydria indicates substantive atrophic changes in the gastric mucosa that presage neoplastic transformation. A mouse model of hypergastrinemia has implicated gastrin in the eventual appearance of a hyperproliferative mucous cell compartment accompanying oxyntic atrophy and dysplasia in the corpus by 20 months, and within 8 months when Helicobacter is present.7Wang T.C. Dangler C.A. Chen D. Goldenring J.R. Koh T. Raychowdhury R. Coffey R.J. Ito S. Varro A. Dockray G.J. Fox J.G. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer.Gastroenterology. 2000; 118: 36-47Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar Nevertheless, hypogastrinemia without Helicobacter predisposes the epithelium to tumors specifically in the distal stomach by 12 months.8Zavros Y. Eaton K.A. Kang W. Rathinavelu S. Katukuri V. Kao J.Y. Samuelson L.C. Merchant J.L. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.Oncogene. 2005; 24: 2354-2366Crossref PubMed Scopus (120) Google Scholar Thus, gastrin is not required for the development of distal gastric cancer. The divergent locations of the tumors in these 2 mouse models raise the possibility that the molecular steps leading to gastric neoplasia in the corpus versus the antrum also differ. Collectively, the models support what has been implied from human studies, that loss of parietal function or cells creates an environment poised to undergo transformation. One hypothesis to consider is whether substances are secreted with acid that normally can suppress antral proliferation and subsequently are lost with atrophy of the oxyntic glands (Figure 1). About 60% to 80% of intestinal-type cancers arise from the gastric antrum with a preference for the lesser curvature. The gastric epithelium is not homogenous but, in fact, is divided into 3 distinct regions, the (upper) cardia, (middle) corpus, and (lower) antrum, with the transitional zone from the oxyntic to antral glands occurring at the incisura. Although many older cancer registries did not distinguish between these locations, it has become more apparent that classification of the cancer site provides additional clues as to the etiology and behavior of transformed cells. For example, the most rapidly emerging class of gastric adenocarcinoma in the US appeared to arise in the cardia.3Corley D.A. Kubo A. Influence of site classification on cancer incidence rates an analysis of gastric cardia carcinomas.J Natl Cancer Inst. 2004; 96: 1383-1387Crossref PubMed Scopus (82) Google Scholar However, with improved categorization, it has now been realized that the sharp rise in proximal cancers is due to adenocarcinoma of the esophagus rather than the cardia, with the incidence of cardia cancers relatively stable compared with the more rapidly declining distal cancers.3Corley D.A. Kubo A. Influence of site classification on cancer incidence rates an analysis of gastric cardia carcinomas.J Natl Cancer Inst. 2004; 96: 1383-1387Crossref PubMed Scopus (82) Google Scholar In addition, H pylori infection appears to protect against rather than correlate with adenocarcinoma of the esophagus. This would suggest that proximal cancer emerges under conditions that do not favor H pylori infection, eg, gastric atrophy and high pH. However, the protective effect does not appear to be related to atrophy-induced hypochlorhydria.4Ye W. Held M. Lagergren J. Engstrand L. Blot W.J. McLaughlin J.K. Nyren O. Helicobacter pylori infection and gastric atrophy risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia.J Natl Cancer Inst. 2004; 96: 388-396Crossref PubMed Scopus (305) Google Scholar Classically atrophy of the corpus, a stimulus for hypergastrinemia due to reduced acid secretion, precedes the development of antral cancer. However, when histologic mapping of the entire stomach was performed in subjects previously infected with H pylori, primarily antral atrophy was found with extension of the antral-type glands (pseudopyloric gland metaplasia) into the corpus in about 40% of the cases.5El-Zimaity H.M. Ota H. Graham D.Y. Akamatsu T. Katsuyama T. Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2002; 94: 1428-1436Crossref PubMed Scopus (139) Google Scholar Since there is a lack of G cells in an atrophic antrum due to replacement by intestinal metaplasia, gastrin levels will be low and contribute to oxyntic gland hyposecretion. However, before significant antral atrophy, inflammatory cytokines can actually stimulate gastrin expression and secretion.6Zavros Y. Rathinavelu S. Kao J.Y. Todisco A. DelValle J. Weinstock J.V. Low M.J. Merchant J.L. Treatment of Helicobacter gastritis with interleukin-4 requires somatostatin.Proc Natl Acad Sci. 2003; 100: 12944-12949Crossref PubMed Scopus (88) Google Scholar Gastrin is a growth factor for the acid-producing parietal cells, suggesting a likely role for gastrin deficiency in the subsequent atrophy of this cellular compartment. Whether due to parietal cell hyposecretion or actual loss, the resulting hypochlorhydria indicates substantive atrophic changes in the gastric mucosa that presage neoplastic transformation. A mouse model of hypergastrinemia has implicated gastrin in the eventual appearance of a hyperproliferative mucous cell compartment accompanying oxyntic atrophy and dysplasia in the corpus by 20 months, and within 8 months when Helicobacter is present.7Wang T.C. Dangler C.A. Chen D. Goldenring J.R. Koh T. Raychowdhury R. Coffey R.J. Ito S. Varro A. Dockray G.J. Fox J.G. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer.Gastroenterology. 2000; 118: 36-47Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar Nevertheless, hypogastrinemia without Helicobacter predisposes the epithelium to tumors specifically in the distal stomach by 12 months.8Zavros Y. Eaton K.A. Kang W. Rathinavelu S. Katukuri V. Kao J.Y. Samuelson L.C. Merchant J.L. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.Oncogene. 2005; 24: 2354-2366Crossref PubMed Scopus (120) Google Scholar Thus, gastrin is not required for the development of distal gastric cancer. The divergent locations of the tumors in these 2 mouse models raise the possibility that the molecular steps leading to gastric neoplasia in the corpus versus the antrum also differ. Collectively, the models support what has been implied from human studies, that loss of parietal function or cells creates an environment poised to undergo transformation. One hypothesis to consider is whether substances are secreted with acid that normally can suppress antral proliferation and subsequently are lost with atrophy of the oxyntic glands (Figure 1). Environmental Triggers: Inflammation Versus BacteriaThe dramatic decline in gastric cancer during the past century correlating with improvements in food storage has placed the etiologic focus squarely on environmental factors.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 9Tsugane S. Salt, salted food intake, and risk of gastric cancer epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (253) Google Scholar Ingestion of a high-salt diet, smoked foods rich in nitrates, and contaminated water teeming with H pylori appear to be the major environmental inducers of gastric cancer, but for different reasons. High salt disrupts the gastric mucosal barrier,9Tsugane S. Salt, salted food intake, and risk of gastric cancer epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (253) Google Scholar while N-nitroso mutagens formed from dietary nitrates by bacteria flourishing in a hypochlorhydric stomach damage DNA. Understanding the role of H pylori in triggering mucosal changes has been dominant perhaps because there is now the possibility that cancer can be prevented with antibiotics directed at a single organism. Yet, it is still unclear which molecular signals actually initiate the program of irreversible transformation.A number of articles have suggested mechanisms by which H pylori might trigger carcinogenesis. Most studies cite well-known bacterial factors that activate various kinase cascades, such as CagA or peptidoglycans, which bind cellular proteins like the phosphatase SHP-2, the receptor c-Met or defense protein Nod 1. Yet when studying animal models or human subjects, it is impossible to distinguish whether bacterial products or the host inflammatory response is ultimately responsible for neoplastic transformation. Although transgenic expression of individual H pylori proteins as putative oncoproteins has not been directly tested, the ability to infuse inflammatory cytokines into mice or express cytokine genes from tissue-specific promoters provides an opportunity to evaluate the contribution of the immune response separate from the organism. Such infusions have revealed that proinflammatory cytokines are capable of inducing parietal cell atrophy and mucous neck cell hypertrophy.6Zavros Y. Rathinavelu S. Kao J.Y. Todisco A. DelValle J. Weinstock J.V. Low M.J. Merchant J.L. Treatment of Helicobacter gastritis with interleukin-4 requires somatostatin.Proc Natl Acad Sci. 2003; 100: 12944-12949Crossref PubMed Scopus (88) Google Scholar, 10Kang W. Rathinavelu S. Samuelson L.C. Merchant J.L. Interferon gamma induction of gastric mucous neck cell hypertrophy.Lab Invest. 2005; 85: 702-715Crossref PubMed Scopus (75) Google Scholar More recently it has been shown that the transformed gastric epithelium in mice infected with H pylori develops from bone marrow-derived progenitor cells.11Houghton J. 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 (1039) Google Scholar Although this event appears to be rare and cannot be verified in human stomach, it is suggestive that some gastric epithelial cancers transdifferentiate from or possibly fuse to infiltrating hematopoetic cells, re-enforcing the importance of the immune response.Understanding the epithelial program modified by H pylori colonization is an area of intense study because of the availability of mouse and tissue culture models with clear parallels to the human phenotype. Nevertheless, the in vivo sites of colonization and strain variations will complicate defining the molecular steps leading from colonization to cancer. Couple these bacterial attributes with the host response and one is left with a complex genetic program that may prove daunting to dissect. In this case, microarray and proteomic analyses of different cellular compartments will be important to determine whether bacterial strain variation alters the genetic programs activated in the different regions of the stomach and glands.Although emphasis has primarily been on the mucosal effects, how injury at the luminal surface perturbs the mesenchyme should also be examined due to its essential instructive effects on the epithelium. The Wnt-APC-β-catenin signaling pathway plays a central role in the epithelial-mesenchymal crosstalk,2Bienz M. beta-Catenin a pivot between cell adhesion and Wnt signalling.Curr Biol. 2005; 15: R64-R67Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar and may be overlooked due to the paucity of mutations at the APC locus in gastric cancer. However, the APC locus is commonly methylated in gastrointestinal stromal tumors, suggesting that epigenetic changes in APC should be considered for gastric adenocarcinomas. The dramatic decline in gastric cancer during the past century correlating with improvements in food storage has placed the etiologic focus squarely on environmental factors.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 9Tsugane S. Salt, salted food intake, and risk of gastric cancer epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (253) Google Scholar Ingestion of a high-salt diet, smoked foods rich in nitrates, and contaminated water teeming with H pylori appear to be the major environmental inducers of gastric cancer, but for different reasons. High salt disrupts the gastric mucosal barrier,9Tsugane S. Salt, salted food intake, and risk of gastric cancer epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (253) Google Scholar while N-nitroso mutagens formed from dietary nitrates by bacteria flourishing in a hypochlorhydric stomach damage DNA. Understanding the role of H pylori in triggering mucosal changes has been dominant perhaps because there is now the possibility that cancer can be prevented with antibiotics directed at a single organism. Yet, it is still unclear which molecular signals actually initiate the program of irreversible transformation. A number of articles have suggested mechanisms by which H pylori might trigger carcinogenesis. Most studies cite well-known bacterial factors that activate various kinase cascades, such as CagA or peptidoglycans, which bind cellular proteins like the phosphatase SHP-2, the receptor c-Met or defense protein Nod 1. Yet when studying animal models or human subjects, it is impossible to distinguish whether bacterial products or the host inflammatory response is ultimately responsible for neoplastic transformation. Although transgenic expression of individual H pylori proteins as putative oncoproteins has not been directly tested, the ability to infuse inflammatory cytokines into mice or express cytokine genes from tissue-specific promoters provides an opportunity to evaluate the contribution of the immune response separate from the organism. Such infusions have revealed that proinflammatory cytokines are capable of inducing parietal cell atrophy and mucous neck cell hypertrophy.6Zavros Y. Rathinavelu S. Kao J.Y. Todisco A. DelValle J. Weinstock J.V. Low M.J. Merchant J.L. Treatment of Helicobacter gastritis with interleukin-4 requires somatostatin.Proc Natl Acad Sci. 2003; 100: 12944-12949Crossref PubMed Scopus (88) Google Scholar, 10Kang W. Rathinavelu S. Samuelson L.C. Merchant J.L. Interferon gamma induction of gastric mucous neck cell hypertrophy.Lab Invest. 2005; 85: 702-715Crossref PubMed Scopus (75) Google Scholar More recently it has been shown that the transformed gastric epithelium in mice infected with H pylori develops from bone marrow-derived progenitor cells.11Houghton J. 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 (1039) Google Scholar Although this event appears to be rare and cannot be verified in human stomach, it is suggestive that some gastric epithelial cancers transdifferentiate from or possibly fuse to infiltrating hematopoetic cells, re-enforcing the importance of the immune response. Understanding the epithelial program modified by H pylori colonization is an area of intense study because of the availability of mouse and tissue culture models with clear parallels to the human phenotype. Nevertheless, the in vivo sites of colonization and strain variations will complicate defining the molecular steps leading from colonization to cancer. Couple these bacterial attributes with the host response and one is left with a complex genetic program that may prove daunting to dissect. In this case, microarray and proteomic analyses of different cellular compartments will be important to determine whether bacterial strain variation alters the genetic programs activated in the different regions of the stomach and glands. Although emphasis has primarily been on the mucosal effects, how injury at the luminal surface perturbs the mesenchyme should also be examined due to its essential instructive effects on the epithelium. The Wnt-APC-β-catenin signaling pathway plays a central role in the epithelial-mesenchymal crosstalk,2Bienz M. beta-Catenin a pivot between cell adhesion and Wnt signalling.Curr Biol. 2005; 15: R64-R67Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar and may be overlooked due to the paucity of mutations at the APC locus in gastric cancer. However, the APC locus is commonly methylated in gastrointestinal stromal tumors, suggesting that epigenetic changes in APC should be considered for gastric adenocarcinomas. Connecting the Molecular DotsNumerous genes have already been implicated in gastric transformation. However, an essential question that emerges is how to organize the known alterations into a temporal sequence of events. The earliest alterations in the gastric mucosa invariably involve epigenetic changes, eg, hypermethylation.12Kang G.H. Lee H.J. Hwang K.S. Lee S. Kim J.H. Kim J.S. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation.Am J Pathol. 2003; 163: 1551-1556Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Although the mechanism by which inflammation stimulates DNA methyltransferases has not been widely pursued, apparently nitric oxide can stimulate the activity of these enzymes that in turn mediate epigenetic gene silencing.13Hmadcha A. Bedoya F.J. Sobrino F. Pintado E. Methylation-dependent gene silencing induced by interleukin 1beta via nitric oxide production.J Exp Med. 1999; 190: 1595-1604Crossref PubMed Scopus (181) Google Scholar It is known that several genes inactivated in atrophic mucosa are due to hypermethylation and include p16, MLH1, MGMT, and Runx3.12Kang G.H. Lee H.J. Hwang K.S. Lee S. Kim J.H. Kim J.S. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation.Am J Pathol. 2003; 163: 1551-1556Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Candidate gene analysis and microarray studies of human tumors have revealed a number of genetic markers.14Yuasa Y. Control of gut differentiation and intestinal-type gastric carcinogenesis.Nat Rev Cancer. 2003; 3: 592-600Crossref PubMed Scopus (278) Google Scholar Moreover, several transgenic mouse models have confirmed a significant contribution from growth regulatory genes, exclusive of Helicobacter, eg, TFF1, the IL-6 receptor subunit gp130, and Runx3.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google ScholarKnowledge of histologic changes that occur in the mucosa, for example, the appearance of pseudopyloric glands and intestinal metaplasia, has prompted interest in the genes responsible for these phenotypes. Understanding the genetic signals that distinguish stomach from small bowel epithelium will be useful in assembling the molecular steps responsible for developmental patterning in the proximal gut that becomes recapitulated in the transforming stomach. Recently, it has been shown that the antrum is developmentally more closely related to the small bowel than the corpus. Extending this logic further suggests that pseudopyloric glands in the corpus and intestinal metaplasia might represent sequential manifestations of the gastric injury response. In other words, the appearance of the antral-like mucous cells is perhaps another but incomplete form of intestinalization. In addition to the increased level of proliferation or decreased apoptotic rate accompanying these atrophic lesions, the loss of gastric-specific genes and emergence of intestine-specific genes has been observed. Gastric specific genes encoding H+, K+-ATPase, Muc5AC and intrinsic factor are lost and intestine-related genes appear with intestinal metaplasia, eg, Cdx2, Muc2, TFF3, villin.8Zavros Y. Eaton K.A. Kang W. Rathinavelu S. Katukuri V. Kao J.Y. Samuelson L.C. Merchant J.L. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.Oncogene. 2005; 24: 2354-2366Crossref PubMed Scopus (120) Google Scholar Thus, it will be from careful analysis first of the cellular phenotype then to temporal identification of the genetic changes that a consistent paradigm of gastric transformation will emerge (Figure 2).Note added in proof: In support of STAT3 hyperactivation in antral gastric cancer, see Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu HJ, Ernst M. Nature Medicine 2005;11:845–852. Numerous genes have already been implicated in gastric transformation. However, an essential question that emerges is how to organize the known alterations into a temporal sequence of events. The earliest alterations in the gastric mucosa invariably involve epigenetic changes, eg, hypermethylation.12Kang G.H. Lee H.J. Hwang K.S. Lee S. Kim J.H. Kim J.S. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation.Am J Pathol. 2003; 163: 1551-1556Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Although the mechanism by which inflammation stimulates DNA methyltransferases has not been widely pursued, apparently nitric oxide can stimulate the activity of these enzymes that in turn mediate epigenetic gene silencing.13Hmadcha A. Bedoya F.J. Sobrino F. Pintado E. Methylation-dependent gene silencing induced by interleukin 1beta via nitric oxide production.J Exp Med. 1999; 190: 1595-1604Crossref PubMed Scopus (181) Google Scholar It is known that several genes inactivated in atrophic mucosa are due to hypermethylation and include p16, MLH1, MGMT, and Runx3.12Kang G.H. Lee H.J. Hwang K.S. Lee S. Kim J.H. Kim J.S. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation.Am J Pathol. 2003; 163: 1551-1556Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Candidate gene analysis and microarray studies of human tumors have revealed a number of genetic markers.14Yuasa Y. Control of gut differentiation and intestinal-type gastric carcinogenesis.Nat Rev Cancer. 2003; 3: 592-600Crossref PubMed Scopus (278) Google Scholar Moreover, several transgenic mouse models have confirmed a significant contribution from growth regulatory genes, exclusive of Helicobacter, eg, TFF1, the IL-6 receptor subunit gp130, and Runx3.1Ushijima T. Sasako M. Focus on gastric cancer.Cancer Cell. 2004; 5: 121-125Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Knowledge of histologic changes that occur in the mucosa, for example, the appearance of pseudopyloric glands and intestinal metaplasia, has prompted interest in the genes responsible for these phenotypes. Understanding the genetic signals that distinguish stomach from small bowel epithelium will be useful in assembling the molecular steps responsible for developmental patterning in the proximal gut that becomes recapitulated in the transforming stomach. Recently, it has been shown that the antrum is developmentally more closely related to the small bowel than the corpus. Extending this logic further suggests that pseudopyloric glands in the corpus and intestinal metaplasia might represent sequential manifestations of the gastric injury response. In other words, the appearance of the antral-like mucous cells is perhaps another but incomplete form of intestinalization. In addition to the increased level of proliferation or decreased apoptotic rate accompanying these atrophic lesions, the loss of gastric-specific genes and emergence of intestine-specific genes has been observed. Gastric specific genes encoding H+, K+-ATPase, Muc5AC and intrinsic factor are lost and intestine-related genes appear with intestinal metaplasia, eg, Cdx2, Muc2, TFF3, villin.8Zavros Y. Eaton K.A. Kang W. Rathinavelu S. Katukuri V. Kao J.Y. Samuelson L.C. Merchant J.L. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma.Oncogene. 2005; 24: 2354-2366Crossref PubMed Scopus (120) Google Scholar Thus, it will be from careful analysis first of the cellular phenotype then to temporal identification of the genetic changes that a consistent paradigm of gastric transformation will emerge (Figure 2). Note added in proof: In support of STAT3 hyperactivation in antral gastric cancer, see Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu HJ, Ernst M. Nature Medicine 2005;11:845–852.
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