Gastric Cancer

, Volume 9, Issue 3, pp 156–166 | Cite as

Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization

  • Tetsuya Tsukamoto
  • Tsutomu Mizoshita
  • Masae Tatematsu
Review article


Helicobacter pylori plays a causative role in the development of chronic atrophic gastritis, intestinal metaplasia (IM), and stomach cancer. Although IM has long attracted attention as a putative preneoplastic lesion for stomach cancers, its clinicopathologic significance has yet to be clarified in detail. Using gastric and intestinal epithelial cell markers, IM was here divided into two major types: a gastric-and-intestinal (GI) mixed type and a solely intestinal (I) type. In the former, gastric and intestinal phenotypic markers appeared not only at the glandular but also at the cellular level. Furthermore, neuroendocrine cells also showed intestinalization along with their exocrine counterparts. In animal models, GI-type IM was found to appear first, followed by the solely I type. Summarizing these data, it was suggested that IM might be caused by the gradual intestinalization of stem cells from the GI to the I type. The molecular mechanisms of IM include the ectopic expression of CDX1, CDX2, OCT-1, and members of the Erk pathway. Suppression of the expression of gastric transcription factors such as SOX2, genes that are involved in the Sonic hedgehog pathway, and RUNX3, a tumor suppressor gene, could be additional relevant alterations. The expression of PDX1 may also be associated with pseudopyloric gland metaplasia and IM. Detailed analysis of gene regulation may shed light on the molecular bases of gastric lesions, leading to strategies for chemoprevention.

Key words

Gastric-and-intestinal mixed-type intestinal metaplasia Stem cell Transcription factor 


  1. 1.
    Warren, JR, Marshall, BJ 1983Unidentified curved bacilli on gastric epithelium in active chronic gastritisLancet112735Google Scholar
  2. 2.
    Forman, D, Newell, DG, Fullerton, F, Yarnell, JW, Stacey, AR, Wald, N,  et al. 1991Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigationBMJ30213025PubMedCrossRefGoogle Scholar
  3. 3.
    Nomura, A, Stemmermann, GN, Chyou, PH, Kato, I, Perez-Perez, GI, Blaser, MJ 1991 Helicobacter pylori infection and gastric carcinoma among Japanese Americans in HawaiiN Engl J Med32511326PubMedCrossRefGoogle Scholar
  4. 4.
    Parsonnet, J, Friedman, GD, Vandersteen, DP, Chang, Y, Vogelman, JH, Orentreich, N,  et al. 1991 Helicobacter pylori infection and the risk of gastric carcinomaN Engl J Med325112731PubMedCrossRefGoogle Scholar
  5. 5.
    Uemura, N, Okamoto, S, Yamamoto, S, Matsumura, N, Yamaguchi, S, Yamakido, M,  et al. 2001 Helicobacter pylori infection and the development of gastric cancerN Engl J Med3457849PubMedCrossRefGoogle Scholar
  6. 6.
    Sepulveda, AR, Coelho, LG 2002 Helicobacter pylori and gastric malignanciesHelicobacter73742PubMedCrossRefGoogle Scholar
  7. 7.
    Walker, MM 2003Is intestinal metaplasia of the stomach reversible?Gut5214PubMedCrossRefGoogle Scholar
  8. 8.
    IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Infection with Helicobacter pylori. In: Schistosomes, Liver Flukes and Helicobacter pylori, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 61. World Health Organization/International Agency for Research on Cancer, Lyon, 1994, pp. 177–241Google Scholar
  9. 9.
    Kawachi, T, Kurisu, M, Numanyu, N, Sasajima, K, Sano, T 1976Precancerous changes in the stomachCancer Res3626737PubMedGoogle Scholar
  10. 10.
    Matsukura, N, Suzuki, K, Kawachi, T, Aoyagi, M, Sugimura, T, Kitaoka, H,  et al. 1980Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomasJ Natl Cancer Inst6523140PubMedGoogle Scholar
  11. 11.
    Morson, BC 1955Carcinoma arising from areas of intestinal metaplasia in the gastric mucosaBr J Cancer937785PubMedGoogle Scholar
  12. 12.
    Filipe, MI, Ramachandra, S 1995The histochemistry of intestinal mucins: changes in diseaseWhitehead, R eds. Gastrointestinal and oesophageal pathologyChurchill LivingstoneEdinburgh7395Google Scholar
  13. 13.
    Filipe, MI, Potet, F, Bogomoletz, WV, Dawson, PA, Fabiani, B, Chauveinc, P,  et al. 1985Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer. Preliminary data from a prospective study from three centresGut26131926PubMedGoogle Scholar
  14. 14.
    Filipe, MI, Munoz, N, Matko, I, Kato, I, Pompe-Kirn, V, Jutersek, A,  et al. 1994Intestinal metaplasia types and the risk of gastric cancer: a cohort study in SloveniaInt J Cancer573249PubMedGoogle Scholar
  15. 15.
    Matsukuma, A, Mori, M, Enjoji, M 1990Sulphomucin-secreting intestinal metaplasia in the human gastric mucosa. An association with intestinal-type gastric carcinomaCancer6668994PubMedCrossRefGoogle Scholar
  16. 16.
    Rokkas, T, Filipe, MI, Sladen, GE 1991Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed upGut3211103PubMedGoogle Scholar
  17. 17.
    Silva, S, Filipe, MI 1986Intestinal metaplasia and its variants in the gastric mucosa of Portuguese subjects: a comparative analysis of biopsy and gastrectomy materialHum Pathol1798895PubMedGoogle Scholar
  18. 18.
    You, WC, Blot, WJ, Li, JY, Chang, YS, Jin, ML, Kneller, R,  et al. 1993Precancerous gastric lesions in a population at high risk of stomach cancerCancer Res53131721PubMedGoogle Scholar
  19. 19.
    Stemmermann, GN 1994Intestinal metaplasia of the stomach. A status reportCancer7455664PubMedCrossRefGoogle Scholar
  20. 20.
    Kato, Y, Kitagawa, T, Yanagisawa, A, Kubo, K, Utsude, T, Hiratsuka, H,  et al. 1992Site-dependent development of complete and incomplete intestinal metaplasia types in the human stomachJpn J Cancer Res8317883PubMedGoogle Scholar
  21. 21.
    Lauren, P 1965The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classificationActa Pathol Microbiol Scand643149PubMedGoogle Scholar
  22. 22.
    Yuasa, Y 2003Control of gut differentiation and intestinal-type gastric carcinogenesisNat Rev Cancer3592600PubMedCrossRefGoogle Scholar
  23. 23.
    Kusakabe, M, Yokoyama, M, Sakakura, T, Nomura, T, Hosick, HL, Nishizuka, Y 1988A novel methodology for analysis of cell distribution in chimeric mouse organs using a strain specific antibodyJ Cell Biol10725765PubMedCrossRefGoogle Scholar
  24. 24.
    Tatematsu, M, Fukami, H, Yamamoto, M, Nakanishi, H, Masui, T, Kusakabe, N,  et al. 1994Clonal analysis of glandular stomach carcinogenesis in C3H/HeNk<->lBALB/c chimeric mice treated with N-methyl-N-nitrosoureaCancer Lett833742PubMedCrossRefGoogle Scholar
  25. 25.
    Tatematsu, M, Masui, T, Fukami, H, Yamamoto, M, Nakanishi, H, Inada, K,  et al. 1996Primary monoclonal and secondary polyclonal growth of colon neoplastic lesions in C3H/HeNk<->lBALB/c chimeric mice treated with 1,2-dimethylhydrazine: immunohistochemical detection of C3H strain-specific antigen and simple sequence length polymorphism analysis of DNAInt J Cancer662348PubMedCrossRefGoogle Scholar
  26. 26.
    Tsukamoto T, Yamamoto M, Fukami H, Yoshikawa A, Sakai H, Hirata A, et al. Susceptibility to colon carcinogenesis in C3Hk-lC57BL/6 chimeric mice reflects both tissue microenvironment and genotype. Cancer Lett 2006 (in press)Google Scholar
  27. 27.
    Fialkow, PJ 1976Clonal origin of human tumorsBiochim Biophys Acta458283321PubMedGoogle Scholar
  28. 28.
    Kakizoe, T, Tanooka, H, Tanaka, K, Sugimura, T 1983Single-cell origin of bladder cancer induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in mice with cellular mosaicismGann744625PubMedGoogle Scholar
  29. 29.
    Nomura, S, Kaminishi, M, Sugiyama, K, Oohara, T, Esumi, H 1998Clonal analysis of isolated intestinal metaplastic glands of stomach using X-linked polymorphismGut426638PubMedCrossRefGoogle Scholar
  30. 30.
    Winton, DJ, Blount, MA, Ponder, BA 1988A clonal marker induced by mutation in mouse intestinal epitheliumNature3334636PubMedCrossRefGoogle Scholar
  31. 31.
    Park, HS, Goodlad, RA, Wright, NA 1995Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagensAm J Pathol147141627PubMedGoogle Scholar
  32. 32.
    Potten, CS 1998Stem cells in gastrointestinal epithelium: numbers, characteristics and deathPhilos Trans R Soc Lond B Biol Sci35382130PubMedCrossRefGoogle Scholar
  33. 33.
    Katsuyama, T, Spicer, SS 1978Histochemical differentiation of complex carbohydrates with variants of the concanavalin A-horseradish peroxidase methodJ Histochem Cytochem2623350PubMedGoogle Scholar
  34. 34.
    Tatematsu, M, Katsuyama, T, Fukushima, S, Takahashi, M, Shirai, T, Ito, N,  et al. 1980Mucin histochemistry by paradoxical concanavalin A staining in experimental gastric cancers induced in Wistar rats by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline 1-oxideJ Natl Cancer Inst6483543PubMedGoogle Scholar
  35. 35.
    Furihata, C, Tatematsu, M, Miki, K, Katsuyama, T, Sudo, K, Miyagi, N,  et al. 1984Gastric- and intestinal-type properties of human gastric cancers transplanted into nude miceCancer Res4472733PubMedGoogle Scholar
  36. 36.
    Tatematsu, M, Furihata, C, Katsuyama, T, Mera, Y, Inoue, T, Matsushima, T,  et al. 1987Immunohistochemical 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-nitrosoguanidineJ Natl Cancer Inst787717PubMedGoogle Scholar
  37. 37.
    Tatematsu, M, Katsuyama, T, Furihata, C, Fukushima, S, Shirai, T, Kato, T,  et al. 1990Cellular differentiation and histogenesis of rat glandular stomach cancersJpn J Cancer Res817607PubMedGoogle Scholar
  38. 38.
    Iwata, H, Itzkowitz, SH, Werther, JL, Hayashi, K, Nakamura, H, Ichinose, M,  et al. 1993Expression of sialosyl-Tn in intestinal type cancer cells of human gastric cancersActa Pathol Jpn4364653PubMedGoogle Scholar
  39. 39.
    Inada, K, Nakanishi, H, Fujimitsu, Y, Shimizu, N, Ichinose, M, Miki, K,  et al. 1997Gastric and intestinal mixed and solely intestinal types of intestinal metaplasia in the human stomachPathol Int4783141PubMedCrossRefGoogle Scholar
  40. 40.
    Inada, K, Tanaka, H, Nakanishi, H, Tsukamoto, T, Ikehara, Y, Tatematsu, K,  et al. 2001Identification of Paneth cells in pyloric glands associated with gastric and intestinal mixed-type intestinal metaplasia of the human stomachVirchows Arch4391420PubMedCrossRefGoogle Scholar
  41. 41.
    Tajima, Y, Shimoda, T, Nakanishi, Y, Yokoyama, N, Tanaka, T, Shimizu, K,  et al. 2001Gastric and intestinal phenotypic marker expression in gastric carcinomas and its prognostic significance: immunohistochemical analysis of 136 lesionsOncology6121220PubMedCrossRefGoogle Scholar
  42. 42.
    Kawachi, T, Kogure, K, Tanaka, N, Tokunaga, A, Sugimura, T 1974Studies of intestinal metaplasia in the gastric mucosa by detection of disaccharidases with “Tes-Tape”J Natl Cancer Inst531930PubMedGoogle Scholar
  43. 43.
    Teglbjaerg, PS, Nielsen, HO 1978“Small intestinal type” and “colonic type” intestinal metaplasia of the human stomach, and their relationship to the histogenetic types of gastric adenocarcinomaActa Pathol Microbiol Scand [A]86A3515Google Scholar
  44. 44.
    Segura, DI, Montero, C 1983Histochemical characterization of different types of intestinal metaplasia in gastric mucosaCancer52498503PubMedCrossRefGoogle Scholar
  45. 45.
    Jass, JR, Filipe, MI 1979A variant of intestinal metaplasia associated with gastric carcinoma: a histochemical studyHistopathology31919PubMedGoogle Scholar
  46. 46.
    Karam, SM, Leblond, CP 1993Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cellAnat Rec23625979PubMedCrossRefGoogle Scholar
  47. 47.
    Ponder, BA, Schmidt, GH, Wilkinson, MM, Wood, MJ, Monk, M, Reid, A 1985Derivation of mouse intestinal crypts from single progenitor cellsNature31368991PubMedCrossRefGoogle Scholar
  48. 48.
    Hattori, T, Fujita, S 1976Tritiated thymidine autoradiographic study of cell migration and renewal in the pyloric mucosa of golden hamstersCell Tissue Res1754957PubMedCrossRefGoogle Scholar
  49. 49.
    Yuasa, H, Inada, K, Watanabe, H, Tatematsu, M 2002A phenotypic shift from gastric-intestinal to solely intestinal cell types in intestinal metaplasia in rat stomach following treatment with X-raysJ Toxicol Pathol158593CrossRefGoogle Scholar
  50. 50.
    Nozaki, K, Shimizu, N, Tsukamoto, T, Inada, K, Cao, X, Ikehara, Y,  et al. 2002Reversibility of heterotopic proliferative glands in glandular stomach of Helicobacter pylori-infected Mongolian gerbils on eradicationJpn J Cancer Res9337481PubMedGoogle Scholar
  51. 51.
    Yamamoto, M, Furihata, C, Ogiu, T, Tsukamoto, T, Inada, K, Hirano, K,  et al. 2002Independent variation in susceptibilities of six different mouse strains to induction of pepsinogen-altered pyloric glands and gastric tumor intestinalization by N-methyl-N-nitrosoureaCancer Lett17912132PubMedCrossRefGoogle Scholar
  52. 52.
    Mallo, GV, Rechreche, H, Frigerio, JM, Rocha, D, Zweibaum, A, Lacasa, M,  et al. 1997Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesisInt J Cancer743544PubMedCrossRefGoogle Scholar
  53. 53.
    Silberg, DG, Furth, EE, Taylor, JK, Schuck, T, Chiou, T, Traber, PG 1997CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epitheliumGastroenterology11347886PubMedCrossRefGoogle Scholar
  54. 54.
    Mizoshita, T, Inada, K, Tsukamoto, T, Kodera, Y, Yamamura, Y, Hirai, T,  et al. 2001Expression 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 stomachGastric Cancer418591PubMedCrossRefGoogle Scholar
  55. 55.
    Eda, A, Osawa, H, Yanaka, I, Satoh, K, Mutoh, H, Kihira, K,  et al. 2002Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasiaJ Gastroenterol3794100PubMedCrossRefGoogle Scholar
  56. 56.
    Satoh, K, Mutoh, H, Eda, A, Yanaka, I, Osawa, H, Honda, S,  et al. 2002Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori Helicobacter71928PubMedCrossRefGoogle Scholar
  57. 57.
    Drummond, F, Sowden, J, Morrison, K, Edwards, YH 1996The caudal-type homeobox protein Cdx-2 binds to the colon promoter of the carbonic anhydrase 1 geneEur J Biochem23667081PubMedCrossRefGoogle Scholar
  58. 58.
    Suh, E, Chen, L, Taylor, J, Traber, PG 1994A homeodomain protein related to caudal regulates intestine-specific gene transcriptionMol Cell Biol14734051PubMedGoogle Scholar
  59. 59.
    Troelsen, JT, Mitchelmore, C, Spodsberg, N, Jensen, AM, Noren, O, Sjostrom, H 1997Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2Biochem J3228338PubMedGoogle Scholar
  60. 60.
    Park, J, Schulz, S, Waldman, SA 2000Intestine-specific activity of the human guanylyl cyclase C promoter is regulated by Cdx2Gastroenterology1198996PubMedCrossRefGoogle Scholar
  61. 61.
    Yamamoto, H, Bai, YQ, Yuasa, Y 2003Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expressionBiochem Biophys Res Commun3008138PubMedCrossRefGoogle Scholar
  62. 62.
    Subramanian, V, Meyer, B, Evans, GS 1998The murine Cdx1 gene product localises to the proliferative compartment in the developing and regenerating intestinal epitheliumDifferentiation64118PubMedCrossRefGoogle Scholar
  63. 63.
    Lickert, H, Domon, C, Huls, G, Wehrle, C, Duluc, I, Clevers, H,  et al. 2000Wnt/beta-catenin signaling regulates the expression of the homeobox gene Cdx1 in embryonic intestineDevelopment127380513PubMedGoogle Scholar
  64. 64.
    Domon-Dell, C, Freund, JN 2002Stimulation of Cdx1 by oncogenic beta-catenin/Tcf4 in colon cancer cells; opposite effect of the CDX2 homeoproteinFEBS Lett518837PubMedCrossRefGoogle Scholar
  65. 65.
    Yuasa, Y, Nagasaki, H, Akiyama, Y, Sakai, H, Nakajima, T, Ohkura, Y,  et al. 2005Relationship between CDX2 gene methylation and dietary factors in gastric cancer patientsCarcinogenesis26193200PubMedCrossRefGoogle Scholar
  66. 66.
    Bowles, J, Schepers, G, Koopman, P 2000Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicatorsDev Biol22723955PubMedCrossRefGoogle Scholar
  67. 67.
    Wood, HB, Episkopou, V 1999Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stagesMech Dev86197201PubMedCrossRefGoogle Scholar
  68. 68.
    Ishii, Y, Rex, M, Scotting, PJ, Yasugi, S 1998Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial-mesenchymal interactionsDev Dyn21346475PubMedCrossRefGoogle Scholar
  69. 69.
    Sakamoto, N, Fukuda, K, Watanuki, K, Sakai, D, Komano, T, Scotting, PJ,  et al. 2000Role for cGATA-5 in transcriptional regulation of the embryonic chicken pepsinogen gene by epithelial-mesenchymal interactions in the developing chicken stomachDev Biol22310313PubMedCrossRefGoogle Scholar
  70. 70.
    Tsukamoto, T, Inada, K, Tanaka, H, Mizoshita, T, Mihara, M, Ushijima, T,  et al. 2004Down regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasiaJ Cancer Res Clin Oncol13013545PubMedCrossRefGoogle Scholar
  71. 71.
    Li, XL, Eishi, Y, Bai, YQ, Sakai, H, Akiyama, Y, Tani, M,  et al. 2004Expression of the SRY-related HMG box protein SOX2 in human gastric carcinomaInt J Oncol2425763PubMedGoogle Scholar
  72. 72.
    Tsukamoto, T, Mizoshita, T, Mihara, M, Tanaka, H, Takenaka, Y, Yamamura, Y,  et al. 2005Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypesHistopathology4664958PubMedCrossRefGoogle Scholar
  73. 73.
    Sakai, H, Eishi, Y, Li, XL, Akiyama, Y, Miyake, S, Takizawa, T,  et al. 2004PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomasGut5332330PubMedCrossRefGoogle Scholar
  74. 74.
    Faller, G, Kirchner, T 2005Immunological and morphogenic basis of gastric mucosa atrophy and metaplasiaVirchows Arch44619PubMedCrossRefGoogle Scholar
  75. 75.
    Verrijzer, CP, Van der Vliet, PC 1993POU domain transcription factorsBiochim Biophys Acta1173121PubMedGoogle Scholar
  76. 76.
    Jin, T, Li, H 2001Pou homeodomain protein OCT1 is implicated in the expression of the caudal-related homeobox gene Cdx-2J Biol Chem276147528PubMedCrossRefGoogle Scholar
  77. 77.
    van den Brink, GR, Hardwick, JC, Nielsen, C, Xu, C, ten Kate, FJ, Glickman, J,  et al. 2002Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tractGut5162833PubMedCrossRefGoogle Scholar
  78. 78.
    Kim, JH, Huang, Z, Mo, R 2005Gli3 null mice display glandular overgrowth of the developing stomachDev Dyn23498491PubMedCrossRefGoogle Scholar
  79. 79.
    Lund, AH, van Lohuizen, M 2002RUNX: a trilogy of cancer genesCancer Cell12135PubMedCrossRefGoogle Scholar
  80. 80.
    Li, QL, Ito, K, Sakakura, C, Fukamachi, H, Inoue, K, Chi, XZ,  et al. 2002Causal relationship between the loss of RUNX3 expression and gastric cancerCell10911324PubMedCrossRefGoogle Scholar
  81. 81.
    Kim, TY, Lee, HJ, Hwang, KS, Lee, M, Kim, JW, Bang, YJ,  et al. 2004Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinomaLab Invest8447984PubMedCrossRefGoogle Scholar
  82. 82.
    Osaki, M, Moriyama, M, Adachi, K, Nakada, C, Takeda, A, Inoue, Y,  et al. 2004Expression of RUNX3 protein in human gastric mucosa, intestinal metaplasia and carcinomaEur J Clin Invest3460512PubMedCrossRefGoogle Scholar
  83. 83.
    Fukamachi, H, Ito, K, Ito, Y 2004Runx3-/- gastric epithelial cells differentiate into intestinal type cellsBiochem Biophys Res Commun3215864PubMedCrossRefGoogle Scholar
  84. 84.
    Tanaka, H, Tsukamoto, T, Mizoshita, T, Inada, K, Ogasawara, N, Cao, X,  et al. 2005Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomachVirchows Arch44780615PubMedCrossRefGoogle Scholar

Copyright information

© International and Japanese Gastric Cancer Association 2006

Authors and Affiliations

  • Tetsuya Tsukamoto
    • 1
  • Tsutomu Mizoshita
    • 1
  • Masae Tatematsu
    • 1
  1. 1.Division of Oncological PathologyAichi Cancer Center Research InstituteNagoyaJapan

Personalised recommendations