Skip to main content

Advertisement

SpringerLink
Log in

Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells

  • Invited Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Nakamura K, Sugano H, Takagi K (1968) Carcinoma of the stomach in incipient phase: its histogenesis and histological appearances. Gann 59:251–258

    CAS  PubMed  Google Scholar 

  2. Lauren P (1965) The two histological main types of gastric carcinoma. Diffuse and so-called intestinal type carcinoma: an attempt at histological classification. Acta Pathol Microbiol Scand 64:31–49

    Article  CAS  PubMed  Google Scholar 

  3. Vauhkonen M, Vauhkonen H, Sipponen P (2006) Pathology and molecular biology of gastric cancer. Best Pract Res Clin Gastroenterol 20:651–674

    Article  CAS  PubMed  Google Scholar 

  4. Yasui W, Oue N, Ito R et al (2004) Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implications. Cancer Sci 95:385–392

    Article  CAS  PubMed  Google Scholar 

  5. Oue N, Sentani K, Sakamoto N et al (2015) Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype. Cancer Sci 106:951–958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kupzig S, Korolchuk V, Rollason R et al (2003) Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic 4:694–709

    Article  CAS  PubMed  Google Scholar 

  7. Goto T, Kennel SJ, Abe M et al (1994) A novel membrane antigen selectively expressed on terminally differentiated human B cells. Blood 84:1922–1930

    CAS  PubMed  Google Scholar 

  8. Cai D, Cao J, Li Z et al (2009) Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis. BMC Cancer 9:102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang W, Nishioka Y, Ozaki S et al (2009) HM1.24 (CD317) is a novel target against lung cancer for immunotherapy using anti-HM1.24 antibody. Cancer Immunol Immunother 58:967–976

    Article  PubMed  Google Scholar 

  10. Mukai S, Oue N, Oshima T et al (2017) Overexpression of transmembrane protein BST2 is associated with poor survival of patients with esophageal, gastric, or colorectal cancer. Ann Surg Oncol 24:594–602

    Article  PubMed  Google Scholar 

  11. Liu W, Cao Y, Guan Y et al (2018) BST2 promotes cell proliferation, migration and induces NF-kappaB activation in gastric cancer. Biotechnol Lett 40:1015–1027

    Article  CAS  PubMed  Google Scholar 

  12. Chen WV, Maniatis T (2013) Clustered protocadherins. Development 140:3297–3302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mukai S, Oue N, Oshima T et al (2017) Overexpression of PCDHB9 promotes peritoneal metastasis and correlates with poor prognosis in patients with gastric cancer. J Pathol 243:100–110

    Article  CAS  PubMed  Google Scholar 

  14. Sekino Y, Oue N, Mukai S et al (2019) Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients. Prostate 79:234–242

    Article  CAS  PubMed  Google Scholar 

  15. Liu JY, Jiang L, He T et al (2019) NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-kappaB/Snail axis and predicts outcome of the patients. Cell Death Dis 10:162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yasui W, Oue N, Kuniyasu H et al (2001) Molecular diagnosis of gastric cancer: present and future. Gastric Cancer 4:113–121

    Article  CAS  PubMed  Google Scholar 

  17. Huang KK, Ramnarayanan K, Zhu F et al (2018) Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell 33(137–150):e5

    Google Scholar 

  18. Jiang Y, Qi X, Liu X et al (2017) Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis. Oncotarget 8:33444–33456

    PubMed  PubMed Central  Google Scholar 

  19. Oue N, Sentani K, Yokozaki H et al (2001) Promoter methylation status of the DNA repair genes hMLH1 and MGMT in gastric carcinoma and metaplastic mucosa. Pathobiology 69:143–149

    Article  CAS  PubMed  Google Scholar 

  20. Zou XP, Zhang B, Zhang XQ et al (2009) Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions. Hum Pathol 40:1534–1542

    Article  CAS  PubMed  Google Scholar 

  21. Oue N, Mitani Y, Aung PP et al (2005) Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol 207:185–198

    Article  CAS  PubMed  Google Scholar 

  22. Tatematsu M, Tsukamoto T, Inada K (2003) Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia. Cancer Sci 94:135–141

    Article  CAS  PubMed  Google Scholar 

  23. Endoh Y, Tamura G, Ajioka Y et al (2000) Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype. Am J Pathol 157:717–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yokozaki H, Shitara Y, Fujimoto J et al (1999) Alterations of p73 preferentially occur in gastric adenocarcinomas with foveolar epithelial phenotype. Int J Cancer 83:192–196

    Article  CAS  PubMed  Google Scholar 

  25. Endoh Y, Tamura G, Watanabe H et al (1999) The common 18-base pair deletion at codons 418-423 of the E-cadherin gene in differentiated-type adenocarcinomas and intramucosal precancerous lesions of the stomach with the features of gastric foveolar epithelium. J Pathol 189:201–206

    Article  CAS  PubMed  Google Scholar 

  26. Endoh Y, Sakata K, Tamura G et al (2000) Cellular phenotypes of differentiated-type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways. J Pathol 191:257–263

    Article  CAS  PubMed  Google Scholar 

  27. Wu LB, Kushima R, Borchard F et al (1998) Intramucosal carcinomas of the stomach: phenotypic expression and loss of heterozygosity at microsatellites linked to the APC gene. Pathol Res Pract 194:405–411

    Article  CAS  PubMed  Google Scholar 

  28. Motoshita J, Oue N, Nakayama H et al (2005) DNA methylation profiles of differentiated-type gastric carcinomas with distinct mucin phenotypes. Cancer Sci 96:474–479

    Article  CAS  PubMed  Google Scholar 

  29. Benahmed F, Gross I, Gaunt SJ, et al (2008) Multiple regulatory regions control the complex expression pattern of the mouse Cdx2 homeobox gene. Gastroenterology 135:1238–1247, 47e1–3

  30. Hinoi T, Lucas PC, Kuick R et al (2002) CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology 123:1565–1577

    Article  CAS  PubMed  Google Scholar 

  31. Naito Y, Oue N, Hinoi T et al (2012) Reg IV is a direct target of intestinal transcriptional factor CDX2 in gastric cancer. PLoS ONE 7:e47545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Anami K, Oue N, Noguchi T et al (2010) Search for transmembrane protein in gastric cancer by the Escherichia coli ampicillin secretion trap: expression of DSC2 in gastric cancer with intestinal phenotype. J Pathol 221:275–284

    Article  CAS  PubMed  Google Scholar 

  33. Takakura Y, Hinoi T, Oue N et al (2010) CDX2 regulates multidrug resistance 1 gene expression in malignant intestinal epithelium. Cancer Res 70:6767–6778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tajima Y, Shimoda T, Nakanishi Y et al (2003) Association of gastric and intestinal phenotypic marker expression of gastric carcinomas with tumor thymidylate synthase expression and response to postoperative chemotherapy with 5-fluorouracil. J Cancer Res Clin Oncol 129:683–690

    Article  CAS  PubMed  Google Scholar 

  35. Mitani Y, Oue N, Matsumura S et al (2007) Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy. Oncogene 26:4383–4393

    Article  CAS  PubMed  Google Scholar 

  36. Kobayashi K, Nakahori Y, Miyake M et al (1998) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394:388–392

    Article  CAS  PubMed  Google Scholar 

  37. Oo HZ, Sentani K, Mukai S et al (2016) Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer. Gastric Cancer 19:443–452

    Article  CAS  PubMed  Google Scholar 

  38. Yang Y, Zhao W, Xu QW et al (2014) IQGAP3 promotes EGFR-ERK signaling and the growth and metastasis of lung cancer cells. PLoS ONE 9:e97578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Johnson M, Sharma M, Henderson BR (2009) IQGAP1 regulation and roles in cancer. Cell Signal 21:1471–1478

    Article  CAS  PubMed  Google Scholar 

  40. Kim H, White CD, Sacks DB (2011) IQGAP1 in microbial pathogenesis: targeting the actin cytoskeleton. FEBS Lett 585:723–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mataraza JM, Briggs MW, Li Z et al (2003) IQGAP1 promotes cell motility and invasion. J Biol Chem 278:41237–41245

    Article  CAS  PubMed  Google Scholar 

  42. Schmidt VA, Chiariello CS, Capilla E et al (2008) Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1 dependent. Mol Cell Biol 28:1489–1502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nojima H, Adachi M, Matsui T et al (2008) IQGAP3 regulates cell proliferation through the Ras/ERK signalling cascade. Nat Cell Biol 10:971–978

    Article  CAS  PubMed  Google Scholar 

  44. Oue N, Yamamoto Y, Oshima T et al (2018) Overexpression of the transmembrane protein IQGAP3 is associated with poor survival of patients with gastric cancer. Pathobiology 85:192–200

    Article  CAS  PubMed  Google Scholar 

  45. Bessede E, Dubus P, Megraud F et al (2015) Helicobacter pylori infection and stem cells at the origin of gastric cancer. Oncogene 34:2547–2555

    Article  CAS  PubMed  Google Scholar 

  46. Wakamatsu Y, Sakamoto N, Oo HZ et al (2012) Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int 62:112–119

    Article  PubMed  Google Scholar 

  47. Takaishi S, Okumura T, Wang TC (2008) Gastric cancer stem cells. J Clin Oncol 26:2876–2882

    Article  PubMed  Google Scholar 

  48. Takaishi S, Okumura T, Tu S et al (2009) Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27:1006–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Oue N, Mukai S, Imai T et al (2016) Induction of KIFC1 expression in gastric cancer spheroids. Oncol Rep 36:349–355

    Article  CAS  PubMed  Google Scholar 

  50. Rath O, Kozielski F (2012) Kinesins and cancer. Nat Rev Cancer 12:527–539

    Article  CAS  PubMed  Google Scholar 

  51. Imai T, Oue N, Nishioka M et al (2017) Overexpression of KIF11 in gastric cancer with intestinal mucin phenotype. Pathobiology 84:16–24

    Article  CAS  PubMed  Google Scholar 

  52. Zhang S, Huang F, Wang Y et al (2016) KIF2A Overexpression and its association with clinicopathologic characteristics and poor prognoses in patients with gastric cancer. Dis Markers 2016:7484516

    PubMed  PubMed Central  Google Scholar 

  53. Zhang H, Ma RR, Wang XJ et al (2017) KIF26B, a novel oncogene, promotes proliferation and metastasis by activating the VEGF pathway in gastric cancer. Oncogene 36:5609–5619

    Article  CAS  PubMed  Google Scholar 

  54. Weil D, Garcon L, Harper M et al (2002) Targeting the kinesin Eg5 to monitor siRNA transfection in mammalian cells. Biotechniques 33:1244–1248

    Article  CAS  PubMed  Google Scholar 

  55. Mills CC, Kolb EA, Sampson VB (2017) Recent advances of cell-cycle inhibitor therapies for pediatric cancer. Cancer Res 77:6489–6498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ando A, Kikuti YY, Kawata H et al (1994) Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region. Immunogenetics 39:194–200

    Article  CAS  PubMed  Google Scholar 

  57. DeLuca JG, Newton CN, Himes RH et al (2001) Purification and characterization of native conventional kinesin, HSET, and CENP-E from mitotic hela cells. J Biol Chem 276:28014–28021

    Article  CAS  PubMed  Google Scholar 

  58. Sekino Y, Oue N, Koike Y et al (2019) KIFC1 inhibitor CW069 induces apoptosis and reverses resistance to docetaxel in prostate cancer. J Clin Med 8:225

    Article  PubMed Central  Google Scholar 

  59. Krzysiak TC, Grabe M, Gilbert SP (2008) Getting in sync with dimeric Eg5. Initiation and regulation of the processive run. J Biol Chem 283:2078–2087

    Article  CAS  PubMed  Google Scholar 

  60. LoRusso PM, Goncalves PH, Casetta L et al (2015) First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors. Invest New Drugs 33:440–449

    Article  CAS  PubMed  Google Scholar 

  61. Network CGAR (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209

    Article  CAS  Google Scholar 

  62. Cristescu R, Lee J, Nebozhyn M et al (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21:449–456

    Article  CAS  PubMed  Google Scholar 

  63. Saito R, Abe H, Kunita A et al (2017) Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1(+) immune cells in Epstein-Barr virus-associated gastric cancer: the prognostic implications. Mod Pathol 30:427–439

    Article  CAS  PubMed  Google Scholar 

  64. Tan P, Yeoh KG (2015) Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology 149:1153–1162

    Article  CAS  PubMed  Google Scholar 

  65. Forbes SA, Beare D, Gunasekaran P et al (2015) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43:D805–D811

    Article  CAS  PubMed  Google Scholar 

  66. Wang K, Yuen ST, Xu J et al (2014) Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46:573–582

    Article  CAS  PubMed  Google Scholar 

  67. Bang YJ, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697

    Article  CAS  PubMed  Google Scholar 

  68. Wilke H, Muro K, Van Cutsem E et al (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15:1224–1235

    Article  CAS  PubMed  Google Scholar 

  69. Wang KL, Wu TT, Choi IS et al (2007) Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer 109:658–667

    Article  CAS  PubMed  Google Scholar 

  70. Lordick F, Kang YK, Chung HC et al (2013) Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 14:490–499

    Article  CAS  PubMed  Google Scholar 

  71. Nakajima M, Sawada H, Yamada Y et al (1999) The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85:1894–1902

    Article  CAS  PubMed  Google Scholar 

  72. Jou E, Rajdev L (2016) Current and emerging therapies in unresectable and recurrent gastric cancer. World J Gastroenterol 22:4812–4823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (C) (18K07016) from the Japan Society for the Promotion of Science. This work was also supported by the Takeda Science Foundation. We thank Mitchell Arico from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Naohide Oue, Kazuhiro Sentani, Naoya Sakamoto, Naohiro Uraoka & Wataru Yasui

Authors
  1. Naohide Oue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuhiro Sentani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoya Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naohiro Uraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wataru Yasui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naohide Oue.

Ethics declarations

Conflict of interest

The authors have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oue, N., Sentani, K., Sakamoto, N. et al. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. Int J Clin Oncol 24, 771–778 (2019). https://doi.org/10.1007/s10147-019-01443-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-019-01443-9

Keywords

Search

Navigation