Spasmolytic Polypeptide-Expressing Metaplasia and Intestinal Metaplasia: Time for Reevaluation of Metaplasias and the Origins of Gastric Cancer

Gastric adenocarcinoma of the intestinal type is believed to develop through a series of histopathologic stages, originally described by Correa,1Correa P. A human model of gastric carcinogenesis.Cancer Res. 1988; 48: 3554-3560PubMed Google Scholar that include chronic gastritis, gastric atrophy, intestinal metaplasia, dysplasia, and finally cancer. Intestinal metaplasia has been the focus of great fascination by many pathologists, because it was unexpected to find intestinal type mucosa containing goblet cells in the body or antrum of the stomach. Numerous studies have implicated intestinal metaplasia as a useful biomarker for gastric cancer risk, and even possibly a precursor to gastric malignancy. However, this evidence has been largely correlative. In patients with gastric cancer, intestinal metaplasia is frequently found in the stomach, even with early gastric cancer. Intestinal metaplasia is much more prevalent in high-risk areas for gastric cancer compared with low-risk areas. Finally, in several studies where serial endoscopies and biopsies were performed, patients with intestinal metaplasia, particularly type III, frequently developed gastric cancer.2Rokkas T. Filipe M.I. Sladen G.E. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up.Gut. 1991; 32: 1110-1113Crossref PubMed Scopus (210) Google Scholar Intestinal metaplasia has been used as the key biomarker in studies of Helicobacter pylori eradication or gastric cancer prevention, defining the preneoplastic lesion often considered the “point of no return.”3Zivny J. Wang T.C. Yantiss R. et al.2003 Role of therapy or monitoring in preventing progression to gastric cancer.J Clin Gastroenterol. 2003; 36: S50-S60Crossref PubMed Scopus (23) Google Scholar Indeed, because the gastric cancers that developed in this setting also showed intestinal differentiation, it seemed logical to conclude that the cancers arose directly from these intestinal metaplastic cells. Nevertheless, in contrast with other neoplasms, little genetic mutational evidence exists to implicate intestinal metaplastic lineages as true direct precursors of gastric neoplasia. Recent investigations have also highlighted the existence of a second metaplastic lineage, spasmolytic polypeptide-expressing metaplasia (SPEM).4Schmidt P.H. Lee J.R. Joshi V. et al.Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma.Lab Invest. 1999; 79: 639-646PubMed Google Scholar SPEM is a metaplastic mucous cell lineage with phenotypic characteristics of deep antral gland cells including strong expression of trefoil factor 2 (TFF2, previously designated as spasmolytic polypeptide). In the past, this underappreciated mucous lineage was described with various names, including pseudopyloric metaplasia or mucous metaplasia or antralization of the corpus, but mostly the lineage was ignored. Indeed, it is now appreciated that atrophy of the corpus and body of the stomach is always associated with the development of SPEM. In addition, SPEM is at least as strongly associated with the development of gastric cancer as intestinal metaplasia.5Lax I. Bellot F. Honegger A. et al.Functional analysis of the ligand binding site of EGF-receptor utilizing chimeric chicken/human receptor molecules.EMBO J. 1989; 8: 421-427Crossref PubMed Scopus (142) Google Scholar Moreover, whereas intestinal metaplasia tends to be spotty or multifocal, SPEM typically appears diffusely throughout the body and corpus of the stomach in patients who progress to gastric cancer.6El-Zimaity H.M.T. Ota H. Graham D.Y. et al.Patterns of gastric atrophy in intestinal type gastric carcinoma.Cancer. 2003; 94: 1428-1436Crossref Scopus (139) Google Scholar SPEM is not simply an expansion of antral type mucosa, because gastrin cells are not present and SPEM cells express a number of proteins, such as HE-4, that are not expressed in the antrum.7Nozaki K. Ogawa M. Williams J.A. et al.A molecular signature of gastric metaplasia arising in response to acute parietal cell loss.Gastroenterology. 2008; 134: 511-521Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar However, both the precise connection between intestinal metaplasia and SPEM and the relationship between SPEM and gastric cancer remain unclear. Recent studies have examined the cellular origin of SPEM in mice. These investigations have demonstrated that SPEM develops in the fundus in the setting of parietal cell loss after chronic Helicobacter infection,8Fox J.G. Li X. Cahill R.J. et al.Hypertrophic gastropathy in Helicobacter felis-Infected wild type C57BL/6 mice and p53 hemizygous transgenic mice.Gastroenterology. 1996; 110: 155-166Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 9Wang T.C. Dangler C.A. Chen D. et al.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 (512) Google Scholar acute parietal cell loss owing to treatment with DMP-77710 or chronic genetic parietal cell ablation by transgenically expressed toxin.11Bredemeyer A.J. Geahlen J.H. Weis V.G. et al.The gastric epithelial progenitor cell niche and differentiation of the zymogenic (chief) cell lineage.Dev Biol. 2009; 325: 211-224Crossref PubMed Scopus (73) Google Scholar These studies have led to accumulating evidence that SPEM may originate from transdifferentiation of mature chief cells into SPEM.7Nozaki K. Ogawa M. Williams J.A. et al.A molecular signature of gastric metaplasia arising in response to acute parietal cell loss.Gastroenterology. 2008; 134: 511-521Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar In the case of H felis infection, gastritis cystica profunda and dysplasia evolve from preexisting regions of SPEM.12Houghton J. Stoicov C. Nomura S. et al.Gastric cancer originating from bone marrow derived cells.Science. 2004; 306: 1568-1571Crossref PubMed Scopus (1043) Google Scholar Still, these studies have not been able to address intestinal metaplasia because Helicobacter-infected mice do not typically develop intestinal metaplasia. Intestinal goblet cells do develop in the fundus of transgenic mice where cdx2, a transcription factor, which is a master developmental regulator of intestinal differentiation, is targeted to the stomach using elements of the H+/K+-ATPase β subunit promoter.13Mutoh H. Hakamata Y. Sato K. et al.Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice.Biochem Biophys Res Commun. 2002; 294: 470-479Crossref PubMed Scopus (229) Google Scholar, 14Silberg D.G. Sullivan J. Kang E. et al.Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice.Gastroenterology. 2002; 122: 689-696Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar Interestingly, amphiregulin-deficient mice developed SPEM after 6 months of age, and a subset of mice did go on to develop goblet cell intestinal metaplasia.15Nam K.T. Lee H.J. Mok H. et al.Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia.Gastroenterology. 2009; 136: 1288-1296Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar In that case, compound glands containing both SPEM and intestinal metaplasia were clearly present. Although murine studies have not been able to clarify the relationship between intestinal metaplasia and SPEM, studies in Mongolian gerbils have provided additional insights. Mongolian gerbils develop both SPEM and intestinal metaplasia in the fundus after infection with H pylori.16Yoshizawa N. Takenaka Y. Yamaguchi H. et al.Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori.Lab Invest. 2006; 87: 1265-1276Crossref Scopus (74) Google Scholar In Mongolian gerbils, intestinal metaplasia developed in preexisting SPEM glands and mixed glands expressing both SPEM and intestinal metaplasia were clearly present.16Yoshizawa N. Takenaka Y. Yamaguchi H. et al.Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori.Lab Invest. 2006; 87: 1265-1276Crossref Scopus (74) Google Scholar All of these studies have supported the notion that intestinal metaplasia may develop from preexisting SPEM. No published studies in humans have addressed directly the question of the relationship of SPEM to intestinal metaplasia in humans. We have therefore examined the morphologic characteristics of SPEM and intestinal metaplasia in gastric resections specimens exclusively from the fundus. These studies have uncovered several critical observations about the induction of metaplasias in the stomach. First, SPEM can develop as a very localized phenomenon. Figure 1 demonstrates that SPEM can develop in single or groups of glands surrounded by regions with normal appearing mucous neck cells in the fundic mucosa. At times, these SPEM gland groups are associated with adjacent areas with the appearance of mucous neck cell hyperplasia. These regions do not seem to interact with regions of intestinal metaplasia. The focal phenotype of SPEM glands suggests that they may act as part of a normal local reparative mechanism for the gastric mucosa. We have also sought to determine whether there is a relationship between SPEM glands and intestinal metaplasia in gastric resections. Examination of resection sections containing regions of both SPEM and intestinal metaplasia led to identification of regions with compound glands where SPEM cells were observed in the deep portions of the glands with intestinal metaplastic lineages in the luminal portions of the glands (Figure 2). Thus, goblet cells staining with either Alcian blue or Muc2 were observed on the luminal aspects of glands that contain PAS-positive and TFF2-staining SPEM at their bases (Figure 2). It is important to emphasize that these were not residual pyloric type glands, because these sections were taken from areas surrounded by corpus mucosa. Although we did observe scattered proliferative Ki67-positive cells within SPEM, in regions with intestinal metaplasia immediately adjacent to or overlying SPEM, we observed strong staining for Ki67 in cells within the region demarcating the zone between SPEM and intestinal metaplasia (Figure 2). Many of the Ki67-positive cells were also stained for MUC2. Thus, we observed clear evidence for the existence of intestinal metaplasia emanating from SPEM. The elevated proliferation in intestinal metaplasia adjacent to SPEM may indicate a transition or secondary differentiation of SPEM into intestinal metaplasia. These data indicate that the standard concept proposed by Professor Correa now merits further expansion or modification (Figure 3). Work in mouse models and human tissue suggests that loss of parietal cells leads initially to the induction of SPEM. With chronic inflammation in the setting of parietal cell loss, SPEM may give rise to a further differentiation into intestinal metaplasia. This evolution of mucous cell metaplastic lineages has been noted previously for the ulcer-associated lineages identified in patients with inflammatory bowel disease.17Wright N.A. Pike C. Elia G. Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells.Nature. 1990; 343: 82-85Crossref PubMed Scopus (426) Google Scholar Although these findings create a strategy for the induction and progression of metaplastic lineages in humans, they do not address the actual origin of gastric adenocarcinoma. It is particularly exciting to consider that, if SPEM is derived from chief cell transdifferentiation, then chief cells themselves, or a subset of chief cells, represent an unrecognized progenitor population that can be induced in the pathologic stomach. Given the more differentiated nature of intestinal metaplasia, it now seems somewhat less likely that gastric cancer arises from a goblet cell-containing epithelium. Still, we must acknowledge that at present it remains uncertain whether either SPEM or intestinal metaplasia is a true precursor for cancer. Nevertheless, it seems likely that evolution of intestinal metaplasia from SPEM may lead to a hyperproliferative state in which the infected and inflamed mucosa may be more susceptible to establishment of deleterious mutations in stem or progenitor populations. Thus, SPEM and intestinal metaplasia may be commensals for the neoplastic process rather than true direct precursors. Taken together, this work suggests that a broader view of metaplastic initiation and preneoplastic progression is merited in evaluating gastric carcinogenesis.