Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(2):135–141. doi: 10.1111/j.1349-7006.2003.tb01409.x

Stem cells and gastric cancer: Role of gastric and intestinal mixed intestinal metaplasia

Masae Tatematsu 1,✉, Tetsuya Tsukamoto 1, Kenichi Inada 1
PMCID: PMC11160206  PMID: 12708487

Abstract

All of the different types of stomach epithelial cells are known to be derived from a single progenitor cell in each gland. Similarly, cancers develop from single cells, based on data from clonality analysis in C3H/HeN ↔ BALB/c chimeric mice. Using gastric and intestinal epithelial cell markers, intestinal metaplasia (IM) can be divided into two major types: a gastric and intestinal (GI) mixed type, and a solely intestinal (I) type. Ectopic expression of Cdx genes and down‐regulation of Sox2 in isolated single GI mixed IM glands suggests abnormal differentiation of stem cells that can produce both gastric (G) and I type cells. Similarly, phenotypic expression of gastric cancer cells of each histological type can be clearly classified into G and I type epithelial cells. The heterogeneity of phenotypic expression of gastric cancer cells in individual cancers is assumed to reflect this intrinsic potential for differentiation in two directions. Gastric cancers at early stages, independent of the histological type, mainly consist of G type cells, and phenotypic shift from G to I type expression is clearly observed with progression. The data thus suggest IM may not be a preneoplastic change in gastric carcinoma, but rather that cells of the I type may appear independently in the gastric mucosa in IM and in gastric cancers. Intestinalization of gastric mucosa and cancer cells may represent a kind of homeotic transformation. Whether disturbance of the regulation of Sox2 and Cdx genes may be of importance to the biological behavior of gastric cancers should therefore be clarified in future studies. (Cancer Sci 2003; 94: 135–141)

References

  • 1. Lauren P. The two histological main types of gastric carcinoma: diffuse and so‐called intestinal‐type carcinoma: an attempt at a histo‐clinical classification. Acta Pathol Microbiol Scand 1965; 64: 31–49. [DOI] [PubMed] [Google Scholar]
  • 2. Tatematsu M, Fukami H, Yamamoto M, Nakanishi H, Masui T, Kusakabe N, Sakakura T. Clonal analysis of glandular stomach carcinogenesis in C3H/ HeN↔BALB/c chimeric mice treated with N‐methyl‐N‐nitrosourea. Cancer Lett 1994; 83: 37–42. [DOI] [PubMed] [Google Scholar]
  • 3. Tatematsu M, Furihata C, Katsuyama T, Hasegawa R, Nakanowatari J, Saito D, Takahashi M, Matsushima T, Ito N. Independent induction of intestinal metaplasia and gastric cancer in rats treated with N‐methyl‐N'‐nitro‐N‐ni‐trosoguanidine. Cancer Res 1983; 43: 1335–41. [PubMed] [Google Scholar]
  • 4. Tatematsu M, Furihata C, Katsuyama T, Miki K, Honda H, Konishi Y, Ito N. Gastric and intestinal phenotypic expressions of human signet ring cell carcinomas revealed by their biochemistry, mucin histochemistry, and ultrastructure. Cancer Res 1986; 46: 4866–72. [PubMed] [Google Scholar]
  • 5. Tatematsu M, Ichinose M, Miki K, Hasegawa R, Kato T, Ito N. Gastric and intestinal phenotypic expression of human stomach cancers as revealed by pepsinogen immunohistochemistry and mucin histochemistry. Acta Pathol Jpn 1990; 40: 494–504. [DOI] [PubMed] [Google Scholar]
  • 6. Yuasa H, Inada K, Watanabe H, Tatematsu M. A phenotypic shift from gastric‐intestinal to solely intestinal cell types in intestinal metaplasia in rat stomach following treatment with X‐rays. J Toxicol Pathol 2002; 15: 85–93. [Google Scholar]
  • 7. Katsuyama T, Spicer SS. Histochemical differentiation of complex carbohydrates with variants of the concanavalin A‐horseradish peroxidase method. J Histochem. Cytochem. 1978; 26: 233–50. [DOI] [PubMed] [Google Scholar]
  • 8. Tatematsu M, Katsuyama T, Fukushima S, Takahashi M, Shirai T, Ito N, Nasu T. Mucin histochemistry by paradoxical concanavalin A staining in experimental gastric cancers induced in Wistar rats by N‐methyl‐N‐nitro‐N‐ni‐trosoguanidine or 4‐nitroquinoline 1‐oxide. J Natl Cancer Inst 1980; 64: 835–43. [PubMed] [Google Scholar]
  • 9. Furihata C, Tatematsu M, Miki K, Katsuyama T, Sudo K, Miyagi N, Kubota T, Jin SS, Kodama K, Ito N, Konishi Y, Suzuki K, Matsushima T. Gastric‐and intestinal‐type properties of human gastric cancers transplanted into nude mice. Cancer Res 1984; 44: 727–33. [PubMed] [Google Scholar]
  • 10. Tatematsu M, Furihata C, Katsuyama T, Mera Y, Inoue T, Matsushima T, Ito N. Immunohistochemical demonstration of pyloric gland‐type cells with low‐pepsinogen isozyme 1 in preneoplastic and neoplastic tissues of rat stomachs treated with N‐methyl‐N'‐nitro‐N‐nitrosoguanidine. J Natl Cancer Inst 1987; 78: 771–7. [PubMed] [Google Scholar]
  • 11. Tatematsu M, Katsuyama T, Furihata C, Fukushima S, Shirai T, Kato T, Ito N. Cellular differentiation and histogenesis of rat glandular stomach cancers. Jpn J Cancer Res 1990; 81: 760–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Iwata H, Itzkowitz SH, Werther JL, Hayashi K, Nakamura H, Ichinose M, Miki K, Tatematsu M. Expression of sialosyl‐Tn in intestinal type cancer cells of human gastric cancers. Acta Pathol Jpn 1993; 43: 646–53. [DOI] [PubMed] [Google Scholar]
  • 13. Inada K, Nakanishi H, Fujimitsu Y, Shimizu N, Ichinose M, Miki K, Nakamura S, Tatematsu M. Gastric and intestinal mixed and solely intestinal types of intestinal metaplasia in the human stomach. Pathol Int 1997; 47: 831–41. [DOI] [PubMed] [Google Scholar]
  • 14. Inada K, Tanaka H, Nakanishi H, Tsukamoto T, Ikehara Y, Tatematsu K, Nakamura S, Porter EM, Tatematsu M. Identification of Paneth cells in pyloric glands associated with gastric and intestinal mixed‐type intestinal metaplasia of the human stomach. Virchows Arch 2001; 439: 14–20. [DOI] [PubMed] [Google Scholar]
  • 15. Tajima Y, Shimoda T, Nakanishi Y, Yokoyama N, Tanaka T, Shimizu K, Saito T, Kawamura M, Kusano M, Kumagai K. Gastric and intestinal phenotypic marker expression in gastric carcinomas and its prognostic significance: immunohistochemical analysis of 136 lesions. Oncology 2001; 61: 212–20. [DOI] [PubMed] [Google Scholar]
  • 16. Fialkow PJ. Clonal origin of human tumors. Biochim Biophys Acta 1976; 458: 283–321. [DOI] [PubMed] [Google Scholar]
  • 17. Kakizoe T, Tanooka H, Tanaka K, Sugimura T. Single‐cell origin of bladder cancer induced by N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine in mice with cellular mosaicism. Gann 1983; 74: 462–5. [PubMed] [Google Scholar]
  • 18. Nomura S, Esumi H, Job C, Tan SS. Lineage and clonal development of gastric glands. Dev Biol 1998; 204: 124–35. [DOI] [PubMed] [Google Scholar]
  • 19. Kusakabe M, Yokoyama M, Sakakura T, Nomura T, Hosick HL, Nishizuka Y. A novel methodology for analysis of cell distribution in chimeric mouse organs using a strain specific antibody. J Cell Biol 1988; 107: 257–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Tatematsu M, Masui T, Fukami H, Yamamoto M, Nakanishi H, Inada K, Kusakabe M, Sakakura T. Primary monoclonal and secondary polyclonal growth of colon neoplastic lesions in C3H/HeN↔BALB/c chimeric mice treated with 1,2‐dimethylhydrazine immunohistochemical detection of C3H strain‐specific antigen and simple sequence length polymorphism analysis of DNA. Int J Cancer 1996; 66: 234–8. [DOI] [PubMed] [Google Scholar]
  • 21. Stemmermann GN, Hayashi T. Intestinal metaplasia of the gastric mucosa: a gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst 1968; 41: 627–34. [PubMed] [Google Scholar]
  • 22. Morson BC. Carcinoma arising from areas of intestinal metaplasia in the gastric mucosa. Br J Cancer 1955; 9: 377–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52: 6735–40. [PubMed] [Google Scholar]
  • 24. You WC, Blot WJ, Li JY, Chang YS, Jin ML, Kneller R, Zhang L, Han ZX, Zeng XR, Liu WD, Zhao L, Correa P, Fraumeni JJF, Xu GW. Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res 1993; 53: 1317–21. [PubMed] [Google Scholar]
  • 25. Kawachi T, Kogure K, Tanaka N, Tokunaga A, Sugimura T. Studies of intestinal metaplasia in the gastric mucosa by detection of disaccharidases with “Tes‐Tape.” J Natl Cancer Inst 1974; 53: 19–30. [PubMed] [Google Scholar]
  • 26. Matsukura 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: 231–40. [PubMed] [Google Scholar]
  • 27. Teglbjaerg PS, Nielsen HO. “Small intestinal type' and “colonic type” intestinal metaplasia of the human stomach, and their relationship to the histoge‐netic types of gastric adenocarcinoma. Acta Pathol Microbiol Scand [A] 1978; 86A: 351–5. [DOI] [PubMed] [Google Scholar]
  • 28. Segura DI, Montero C. Histochemical characterization of different types of intestinal metaplasia in gastric mucosa. Cancer 1983; 52: 498–503. [DOI] [PubMed] [Google Scholar]
  • 29. Jass JR, Filipe MI. A variant of intestinal metaplasia associated with gastric carcinoma: a histochemical study. Histopathology 1979; 3: 191–9. [DOI] [PubMed] [Google Scholar]
  • 30. Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell. Anat Rec 1993; 236: 259–79. [DOI] [PubMed] [Google Scholar]
  • 31. Ponder BA, Schmidt GH, Wilkinson MM, Wood MJ, Monk M, Reid A. Derivation of mouse intestinal crypts from single progenitor cells. Nature 1985; 313: 689–91. [DOI] [PubMed] [Google Scholar]
  • 32. Hattori T, Fujita S. Tritiated thymidine autoradiographic study of cell migration and renewal in the pyloric mucosa of golden hamsters. Cell Tissue Res 1976; 175: 49–57. [DOI] [PubMed] [Google Scholar]
  • 33. Ichinose M, Tsukada S, Fujimitsu Y, Tatematsu M, Matsubara Y, Yahagi N, Oka M, Suzuki T, Shimizu Y, Yonezawa S, Kageyama T, Miki K, Fukamachi H. Proliferation, differentiation and morphogenesis of fetal rat glandular stomach transplanted under the kidney capsule of syngeneic hosts. Dev Growth Differ 1997; 39: 635–42. [DOI] [PubMed] [Google Scholar]
  • 34. Macdonald PM, Struhl G. A molecular gradient in early Drosophila embryos and its role in specifying the body pattern. Nature 1986; 324: 537–45. [DOI] [PubMed] [Google Scholar]
  • 35. Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, Jordan BR, Dusetti NJ, Dagorn JC, Lovanna JL. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down‐regulation of Cdxl and Cdx2 mRNA expression during colorectal carcinogenesis. Int J Cancer 1997; 74: 35–44. [DOI] [PubMed] [Google Scholar]
  • 36. Silberg DG, Furth EE, Taylor JK, Schuck T, Chiou T, Traber PG. CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium. Gastroenterology 1997; 113: 478–86. [DOI] [PubMed] [Google Scholar]
  • 37. Mizoshita T, Inada K, Tsukamoto T, Kodera Y, Yamamura Y, Hirai T, Kato T, Joh T, Itoh M, Tatematsu M. Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa–with special emphasis on participation in intestinal metaplasia of the human stomach. Gastric Cancer 2001; 4: 185–91. [DOI] [PubMed] [Google Scholar]
  • 38. Ishii Y, Rex M, Scotting PJ, Yasugi S. Region‐specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial‐mesenchymal interactions. Dev Dyn 1998; 213: 464–75. [DOI] [PubMed] [Google Scholar]
  • 39. Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M. Down regulation of Sox2 and ectopic expression of Cdx1 and Cdx2 during progression of intestinal metaplasia in human stomach, submitted. [DOI] [PubMed]
  • 40. Nakamura K, Sugano H, Takagi K. Carcinoma of the stomach in incipient phase: its histogenesis and histological appearances. Gann 1968; 59: 251–8. [PubMed] [Google Scholar]
  • 41. Sugano H, Nakamura K, Kato Y. Pathological studies of human gastric cancer. Acta Pathol Jpn 1982; 32 Suppl 2: 329–47. [PubMed] [Google Scholar]
  • 42. Sugihara H, Hattori T, Fukuda M, Fujita S. Cell proliferation and differentiation in intramucosal and advanced signet ring cell carcinomas of the human stomach. Virchows Arch A Pathol Anat Histopathol 1987; 411: 117–27. [DOI] [PubMed] [Google Scholar]
  • 43. Fujimori Y, Akamatsu T, Ota H, Katsuyama T. Proliferative markers in gastric carcinoma and organoid differentiation. Hum Pathol 1995; 26: 725–34. [DOI] [PubMed] [Google Scholar]
  • 44. Yoshikawa A, Inada Ki K, Yamachika T, Shimizu N, Kaminishi M, Tatematsu M. Phenotypic shift in human differentiated gastric cancers from gastric to intestinal epithelial cell type during disease progression. Gastric Cancer 1998; 1: 134–41. [DOI] [PubMed] [Google Scholar]
  • 45. Tatematsu M, Katsuyama T, Furihata C, Tsuda H, Ito N. Stable intestinal phenotypic expression of gastric and small intestinal tumor cells induced by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine or methylnitrosourea in rats. Gann 1984; 75: 957–65. [PubMed] [Google Scholar]
  • 46. Yamachika T, Inada K, Fujimitsu Y, Nakamura S, Yamamura Y, Kitou T, Itzkowitz SH, Werther JL, Miki K, Tatematsu M. Intestinalization of gastric signet ring cell carcinomas with progression. Virchows Arch 1997; 431: 103–10. [DOI] [PubMed] [Google Scholar]
  • 47. Bamba M, Sugihara H, Kushima R, Okada K, Tsukashita S, Horinouchi M, Hattori T. Time‐dependent expression of intestinal phenotype in signet ring cell carcinomas of the human stomach. Virchows Arch 2001; 438: 49–56. [DOI] [PubMed] [Google Scholar]
  • 48. Salenius P. On the ontogenesis of the human gastric epithelial cells: a histologic and histochemical study. Acta Anat 1962; 50 Suppl 46: 1–76. [PubMed] [Google Scholar]
  • 49. Bai YQ, Yamamoto H, Akiyama Y, Tanaka H, Takizawa T, Koike M, Kenji Yagi O, Saitoh K, Takeshita K, Iwai T, Yuasa Y. Ectopic expression of home‐odomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett 2002; 176: 47–55. [DOI] [PubMed] [Google Scholar]
  • 50. Mizoshita T, Inada K, Tsukamoto T, Nozaki K, Joh T, Itoh M, Yamamura Y, Ushijima T, Tatematsu M. Products of intestine–specific homeobox genes, Cdx1 and Cdx2, are key molecules in intestinalization of gastric carcinoma cells, submitted.

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES