1 Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2007 Vol: 20(12):1286-1297. DOI: 10.1038/modpathol.3800968

CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer.

Intestinal metaplasia is a key event in multistep gastric carcinogenesis. CDX2, a master regulator of intestinal phenotype, was shown to play a tumor-suppressive role in colon cancer. However, it was reported to be expressed in nearly all gastric intestinal metaplasia and many gastric cancers. As CDX2 is differentially expressed in normal stomach and intestine, we sought to relate the CDX2 expression to gastrointestinal differentiation along gastric carcinogenesis. The expression of CDX2 protein in gastric intestinal metaplasia, dysplasia and cancer was examined and related to their gastrointestinal differentiation. CDX2 expression was significantly decreased in incomplete intestinal metaplasia, which expresses both gastric mucins (MUC5AC and MUC6) and intestinal mucin (MUC2), compared with complete intestinal metaplasia, which expresses intestinal mucin (MUC2) only. Although incomplete intestinal metaplasia morphologically resembles colon, its CDX2 expression was apparently lower than that in the normal colon. Moreover, CDX2 expression was progressively reduced in gastric dysplasia and cancer. The CDX2 expression in gastric cancer was also inversely correlated with the expression of gastric mucins. As incomplete intestinal metaplasia is associated with higher risk of gastric cancer, its lower CDX2 expression compared with that in complete intestinal metaplasia and normal colon epithelium resolved the current contradiction between the tumor-suppressive role of CDX2 in the colon and the high prevalence of CDX2 in intestinal metaplasia. Further decrease of CDX2 expression in gastric dysplasia and cancer suggests that CDX2 plays a similar anticarcinogenic role in intestinal metaplasia as it does in colon. Intestinal metaplasia or dysplasia with low expression of CDX2 may serve as predictive markers for gastric cancer.

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Figures
Figure 1: Immunohistochemistry staining of MUC2 (a), MUC5AC (b), MUC6 (c), CDX2 (d) and Ki67 (f) and ABPAS staining (e) in a focus of complete IM (left part) and an adjacent focus of incomplete IM (right part). Besides the presence of MUC2-positive goblet cells, incomplete IM expressed gastric mucins (MUC5AC in almost all glands and Muc6 in several deeper glands) in goblet cells and columnar cells, while complete IM only expressed MUC5AC in few goblet cells but not in the absorptive cells. The CDX2 expression was significantly decreased in the incomplete IM than that in complete IM. Figure 2: Immunohistochemistry staining of MUC2 (a), MUC5AC (b), MUC6 (c) and CDX2 (d) in a focus of mosaic IM. The CDX2 expression in the incomplete IM glands, which expressed both gastric mucins and intestinal mucin (the glands pointed by arrows) was significantly lower compared with other complete IM glands, which only expressed intestinal mucin. Figure 3: The CDX2 expression in colon cancer (b) was significantly decreased compared with that in normal colon (a). The tissues in A and B were from the same patient. Figure 4: Immunohistochemistry staining of MUC2 (a), MUC5AC (b), MUC6 (c), CDX2 (d) in a biopsy of gastric dysplasia. The CDX2 expression was lost in the dysplastic glands, which were also incomplete IM with expression of both gastric and intestinal mucins. Figure 5: The relationship between the CDX2 score and expression of MUC2, MUC5AC and MUC6 in intestinal type of gastric cancer; (b) the relationship between the CDX2 score and expression of MUC2, MUC5AC and MUC6 in diffuse type of gastric cancer; (c) the expression of CDX2 in gastric cancer with different expression pattern of gastrointestinal markers. Figure 6: Immunohistochemistry staining of MUC2 (a) MUC5AC (b) MUC6 (c) CDX2 (d) in a case of gastric cancer. The left upper part of gastric cancer cells with strong CDX2 expression expressed less gastric mucins (MUC5AC and MUC6) than the right lower part of cancer cells with weak CDX2 expression. Figure 7: The expression of CDX2 is initially increased in IM and then progressively decreased along Correa's cascade of gastric carcinogenesis.
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References
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    • . . . Several studies claimed that only type III of IM is associated with an increased risk of gastric cancer,9, 10, 11 but other reports cast doubt on it.12, 13, 14 Different subtypes of IM may coexist in the same foci, and this mosaic pattern complicates efforts at subtyping.14 . . .
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    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
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    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
  17. Mallo GV, Rechreche H, Frigerio JM, et al. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int J Cancer 1997;74:35-44 , .
    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
  18. Choi BJ, Kim CJ, Cho YG, et al. Altered expression of CDX2 in colorectal cancers. APMIS 2006;114:50-54 , .
    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
  19. Mallo GV, Soubeyran P, Lissitzky JC, et al. Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. J Biol Chem 1998;273:14030-14036 , .
    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
  20. Gendron FP, Mongrain S, Laprise P, et al. The CDX2 transcription factor regulates furin expression during intestinal epithelial cell differentiation. Am J Physiol Gastrointest Liver Physiol 2006;290:G310-G318 , .
    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
  21. Aoki K, Tamai Y, Horiike S, et al. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice. Nat Genet 2003;35:323-330 , .
    • . . . Although a recent report showed the increase of CDX2 mRNA and protein in human colorectal cancer,15 several studies have demonstrated that CDX2 mRNA and protein was reduced or lost in human colorectal cancer.16, 17, 18 Exogenous CDX2 expression in colon cancer cell lines inhibited the proliferation, invasion and migration of cancer cells while promoting the expression of genes characteristic of mature enterocytes.19, 20 It was reported that mice doubly heterozygous for APC716 and Cdx2+/- develop six times more colonic polyps than their APC716 and Cdx2+/+ littermates.21 Furthermore, the carcinogen azoxymethane induced invasive adenocarcinoma of the distal colon in Cdx2+/- mice but not in wild-type littermates.22 . . .
  22. Bonhomme C, Duluc I, Martin E, et al. The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Gut 2003;52:1465-1471 , .
  23. Silberg DG, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 2002;122:689-696 , .
    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29, 30, 32 . . .
  24. Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun 2002;294:470-479 , .
    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29, 30, 32 . . .
  25. Mutoh H, Sakurai S, Satoh K, et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res 2004;64:7740-7747 , .
    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29, 30, 32 . . .
  26. Almeida R, Silva E, Santos-Silva F, et al. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol 2003;199:36-40 , .
    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29, 30, 32 . . .
    • . . . This is consistent with previous studies that suggested that intestinal differentiation markers are not exclusive to intestinal type of gastric cancer and that diffuse type of gastric cancer also can have features of intestinal differentiation in a high proportion of cases.26, 44 Whether intestinalization is also involved in the carcinogenesis of diffuse type of gastric cancer is not clear yet. . . .
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    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29, 30, 32 . . .
  28. Fan Z, Li J, Dong B, et al. Expression of Cdx2 and hepatocyte antigen in gastric carcinoma: correlation with histologic type and implications for prognosis. Clin Cancer Res 2005;11:6162-6170 , .
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  30. Seno H, Oshima M, Taniguchi MA, et al. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications. Int J Oncol 2002;21:769-774 , .
    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29 . . .
    • . . . It is often observed that stronger CDX2 expression was associated with better differentiation of gastric cancer tissues28, 29, 30, 32 and cell lines.39 Further decrease of CDX2 in incomplete IM may lead to a less differentiated state and more instability . . .
  31. Dang LH, Chen F, Knock SA, et al. CDX2 does not suppress tumorigenicity in the human gastric cancer cell line MKN45. Oncogene 2005;25:2048-2059 , .
    • . . . Using Cdx2 transgenic mice, two groups have reported that the expression of Cdx2 transformed the gastric mucosa into intestinal metaplastic Mucosa,23, 24 and in one model it progressed to gastric cancer.25 Several studies showed CDX2 expression in nearly all IM and many gastric cancers, suggesting that ectopic CDX2 expression is involved in gastric carcinogenesis.26, 27, 28, 29, 30 It was also reported that the disruption of CDX2 did not affect the tumorigenic potential in a gastric cancer cell line.31 On the other hand, most of the studies so far have demonstrated that positive CDX2 expression in gastric cancer was significantly correlated with better differentiation and prognosis.28, 29, 30, 32 . . .
  32. Mizoshita T, Tsukamoto T, Nakanishi H, et al. Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol 2003;129:727-734 , .
  33. Reis CA, David L, Correa P, et al. Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res 1999;59:1003-1007 , .
    • . . . This is in agreement with previous studies that showed incomplete IM with co-expression of intestinal and gastric mucins, while complete IM with de novo expression of intestinal mucin but decreased expression of gastric mucins.33, 34 In a few glands within the foci of complete IM, MUC5AC and MUC6 were expressed in both goblet cells and columnar cells and this demonstrated the 'mosaic' pattern of IM subtypes (Figure 2). . . .
  34. Rocha AS, Soares P, Machado JC, et al. Mucoepidermoid carcinoma of the thyroid: a tumour histotype characterised by P-cadherin neoexpression and marked abnormalities of E-cadherin/catenins complex. Virchows Arch 2002;440:498-504 , .
    • . . . This is in agreement with previous studies that showed incomplete IM with co-expression of intestinal and gastric mucins, while complete IM with de novo expression of intestinal mucin but decreased expression of gastric mucins.33, 34 In a few glands within the foci of complete IM, MUC5AC and MUC6 were expressed in both goblet cells and columnar cells and this demonstrated the 'mosaic' pattern of IM subtypes (Figure 2). . . .
  35. Tatematsu M, Tsukamoto T, Inada K. Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia. Cancer Sci 2003;94:135-141 , .
    • . . . Each gastric gland is known to be of monoclonal origin.35 Therefore, the mosaic patterns of the gastric and intestinal mucins within a single gland suggest that induction of gastric or intestinal phenotype is unstable at dysplasia and probably occurs after gland formation in dysplasia . . .
  36. Mizoshita T, Tsukamoto T, Tanaka H, et al. Colonic and small-intestinal phenotypes in gastric cancers: relationships with clinicopathological findings. Pathol Int 2005;55:611-618 , .
    • . . . Using MUC5AC and MUC6 as the markers of gastric differentiation and MUC2 as the marker of intestinal differentiation, the gastric cancers were classified into four categories: G type, positive for one or both gastric mucins (MUC5AC and MUC6) only; GI type, positive for intestinal mucin (MUC2) and at least one of the gastric mucins (MUC5AC and MUC6); I type, positive for intestinal mucin (MUC2) only; N type, none of the MUC2, MUC5AC and MUC6 are positive.36 The 70 gastric cancer cases were classified into 20 cases of G type, 26 cases of GI type, 14 cases of I type and 10 cases of N type . . .
  37. Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther 2002;16:1209-1216 , .
    • . . . Various factors, such as Helicobacter pylori infection37 and bile reflux,38 could induce ectopical CDX2 expression in normal stomach, which leads to intestinalization . . .
  38. Debruyne PR, Witek M, Gong L, et al. Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells. Gastroenterology 2006;130:1191-1206 , .
    • . . . Various factors, such as Helicobacter pylori infection37 and bile reflux,38 could induce ectopical CDX2 expression in normal stomach, which leads to intestinalization . . .
  39. Bai Y, Akiyama Y, Nagasaki H, et al. Distinct expression of CDX2 and GATA4/5, development-related genes, in human gastric cancer cell lines. Mol Carcinog 2000;28:184-188 , .
    • . . . It is often observed that stronger CDX2 expression was associated with better differentiation of gastric cancer tissues28, 29, 30, 32 and cell lines.39 Further decrease of CDX2 in incomplete IM may lead to a less differentiated state and more instability . . .
  40. Yagi OK, Akiyama Y, Yuasa Y. Genomic structure and alterations of homeobox gene CDX2 in colorectal carcinomas. Br J Cancer 1999;79:440-444 , .
    • . . . The mutation and rearrangements of CDX2 gene was shown to be infrequent in colon cancer.40 Lorentz et al41 showed that the activation of PKC pathway by RAS might be responsible for the downregulation of CDX2 expression in colon cancer . . .
  41. Lorentz O, Cadoret A, Duluc I, et al. Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras. Oncogene 1999;18:87-92 , .
    • . . . The mutation and rearrangements of CDX2 gene was shown to be infrequent in colon cancer.40 Lorentz et al41 showed that the activation of PKC pathway by RAS might be responsible for the downregulation of CDX2 expression in colon cancer . . .
  42. Yuasa Y, Nagasaki H, Akiyama Y, et al. Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. Carcinogenesis 2005;26:193-200 , .
    • . . . Recently, the CDX2 promoter methylation was implicated in the downregulation of CDX2 in gastric cancer patients42 and colorectal cancer patients.43 Further studies of the mechanisms of CDX2 downregulation in gastric carcinogenesis are needed. . . .
  43. Kawai H, Tomii K, Toyooka S, et al. Promoter methylation downregulates CDX2 expression in colorectal carcinomas. Oncol Rep 2005;13:547-551 , .
    • . . . Recently, the CDX2 promoter methylation was implicated in the downregulation of CDX2 in gastric cancer patients42 and colorectal cancer patients.43 Further studies of the mechanisms of CDX2 downregulation in gastric carcinogenesis are needed. . . .
  44. Carneiro F, Moutinho-Ribeiro M, David L, et al. Signet ring cell carcinoma of the stomach: a morphometric, ultrastructural, and DNA cytometric study. Ultrastruct Pathol 1992;16:603-614 , .
    • . . . This is consistent with previous studies that suggested that intestinal differentiation markers are not exclusive to intestinal type of gastric cancer and that diffuse type of gastric cancer also can have features of intestinal differentiation in a high proportion of cases.26, 44 Whether intestinalization is also involved in the carcinogenesis of diffuse type of gastric cancer is not clear yet. . . .
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