Skip to main content

Advertisement

SpringerLink
Log in

Cancer stem cells: the ‘heartbeat’ of gastric cancer

  • Review
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Gastric cancer (GC) remains one of the most common cancers worldwide. Its prevalence is still on the rise in the developing countries due to the ageing population. The cancer stem cell (CSC) theory provides a new insight into the interpretation of tumor initiation, aggressive growth, recurrence, and metastasis of cancer, as well as the development of new strategies for cancer treatment. This review will focus on the progress of biomarkers and signaling pathways of CSCs, the complex crosstalk networks between the microenvironment and CSCs, and the development of therapeutic approaches against CSCs, predominantly focusing on GC.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  2. Gill S, Shah A, Le N, Cook EF, Yoshida EM. Asian ethnicity-related differences in gastric cancer presentation and outcome among patients treated at a Canadian cancer center. J Clin Oncol. 2003;21:2070–6.

    Article  PubMed  Google Scholar 

  3. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  PubMed  CAS  Google Scholar 

  4. Visvader JE. Cells of origin in cancer. Nature. 2011;469:314–22.

    Article  PubMed  CAS  Google Scholar 

  5. Furth J, Kahn M. The transmission of leukaemia of mice with a single cell. Am J Cancer. 1937;31:276–82.

    Google Scholar 

  6. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    Article  PubMed  CAS  Google Scholar 

  7. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.

    Article  PubMed  CAS  Google Scholar 

  8. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.

    PubMed  CAS  Google Scholar 

  9. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

    Article  PubMed  CAS  Google Scholar 

  10. Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 2005;65:9328–37.

    Article  PubMed  CAS  Google Scholar 

  11. Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology. 2008;47:919–28.

    Article  PubMed  CAS  Google Scholar 

  12. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.

    Article  PubMed  CAS  Google Scholar 

  13. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    Article  PubMed  CAS  Google Scholar 

  14. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.

    Article  PubMed  CAS  Google Scholar 

  15. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.

    Article  PubMed  CAS  Google Scholar 

  16. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 2007;104:10158–63.

    Article  PubMed  CAS  Google Scholar 

  17. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA. 2007;104:973–8.

    Article  PubMed  CAS  Google Scholar 

  18. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells-perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66:9339–44.

    Article  PubMed  CAS  Google Scholar 

  19. Brabletz S, Schmalhofer O, Brabletz T. Gastrointestinal stem cells in development and cancer. J Pathol. 2009;217:307–17.

    Article  PubMed  CAS  Google Scholar 

  20. Qiao XT, Gumucio DL. Current molecular markers for gastric progenitor cells and gastric cancer stem cells. J Gastroenterol. 2011;46:855–65.

    Article  PubMed  CAS  Google Scholar 

  21. Dewi DL, Ishii H, Kano Y, Nishikawa S, Haraguchi N, Sakai D, et al. Cancer stem cell theory in gastrointestinal malignancies: recent progress and upcoming challenges. J Gastroenterol. 2011;46:1145–57.

    Article  PubMed  Google Scholar 

  22. Xu G, Su XL, Shen J, Bi LF, Ou Yang XH. Regulation of ACBP on cell cycle of human stomach cancer cell BGC-823. Chin J Cancer Prev Treat. 2007;14:1361–4.

    CAS  Google Scholar 

  23. Su XL, Ou Yang XH, Xu GH, Shen J, Wang ZY. Effect of ACBP-S on cell cycle and apoptosis in human gastric cancer cells. Zhonghua Zhong Liu Za Zhi. 2008;30:422–7.

    PubMed  CAS  Google Scholar 

  24. Su L, Xu G, Shen J, Tuo Y, Zhang X, Jia S, et al. Anticancer bioactive peptide suppresses human gastric cancer growth through modulation of apoptosis and the cell cycle. Oncol Rep. 2010;23:3–9.

    PubMed  CAS  Google Scholar 

  25. Rahman M, Deleyrolle L, Vedam-Mai V, Azari H, Abd-El-Barr M, Reynolds BA. The cancer stem cell hypothesis: failures and pitfalls. Neurosurgery. 2011;68:531–45.

    Article  PubMed  Google Scholar 

  26. Lee ER. Dynamic histology of the antral epithelium in the mouse stomach: I. Architecture of antral units. Am J Anat. 1985;172:187–204.

    Article  PubMed  CAS  Google Scholar 

  27. Lee ER, Leblond CP. Dynamic histology of the antral epithelium in the mouse stomach: II. Ultra-structure and renewal of isthmal cells. Am J Anat. 1985;172:205–24.

    Article  PubMed  CAS  Google Scholar 

  28. Lee ER. Dynamic histology of the antral epithelium in the mouse stomach: III. Ultrastructure and renewal of pit cells. Am J Anat. 1985;172:225–40.

    Article  PubMed  CAS  Google Scholar 

  29. Lee ER, Leblond CP. Dynamic histology of the antral epithelium in the mouse stomach: IV. Ultra-structure and renewal of gland cells. Am J Anat. 1985;172:241–59.

    Article  PubMed  CAS  Google Scholar 

  30. Saikawa Y, Fukuda K, Takahashi T, Nakamura R, Takeuchi H, Kitagawa Y. Gastric carcinogenesis and the cancer stem cell hypothesis. Gastric Cancer. 2010;13:11–24.

    Article  PubMed  Google Scholar 

  31. Bjerknes M, Cheng H. Multipotential stem cells in adult mouse gastric epithelium. Am J Physiol Gastrointest Liver Physiol. 2002;283:G767–77.

    PubMed  CAS  Google Scholar 

  32. Qiao XT, Ziel JW, McKimpson W, Madison BB, Todisco A, Merchant JL, et al. Prospective identification of a multi-lineage progenitor in murine stomach epithelium. Gastroenterology. 2007;133:1989–98.

    Article  PubMed  CAS  Google Scholar 

  33. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6:25–36.

    Article  PubMed  CAS  Google Scholar 

  34. Scoville DH, Sato T, He XC, Li L. Current view: intestinal stem cells and signaling. Gastroenterology. 2008;134:849–64.

    Article  PubMed  CAS  Google Scholar 

  35. Takaishi S, Okumura T, Wang TC. Gastric cancer stem cells. J Clin Oncol. 2008;26:2876–82.

    Article  PubMed  Google Scholar 

  36. Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med. 2002;8:1011–7.

    Article  PubMed  CAS  Google Scholar 

  37. Avital I, Moreira AL, Klimstra DS, Leversha M, Papadopoulos EB, Brennan M, et al. Donor derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation. Stem Cells. 2007;25:2903–9.

    Article  PubMed  Google Scholar 

  38. Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568–71.

    Article  PubMed  CAS  Google Scholar 

  39. Okumura T, Wang SS, Takaishi S, Tu SP, Ng V, Ericksen RE, et al. Identification of a bone marrow-derived mesenchymal progenitor cell subset that can contribute to the gastric epithelium. Lab Investig. 2009;89:1410–22.

    Article  PubMed  Google Scholar 

  40. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19:257–72.

    Article  PubMed  CAS  Google Scholar 

  41. Shibata W, Ariyama H, Westphalen CB, Worthley DL, Muthupalani S, Asfaha S, et al. Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors. Gut 2012 [Epub ahead of print].

  42. Varon C, Dubus P, Mazurier F, Asencio C, Chambonnier L, Ferrand J, et al. Helicobacter pylori infection recruits bone marrow-derived cells that participate in gastric preneoplasia in mice. Gastroenterology. 2012;142:281–91.

    Article  PubMed  Google Scholar 

  43. Marhaba R, Zoller M. CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol. 2004;35:211–31.

    Article  PubMed  CAS  Google Scholar 

  44. Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011;11:254–67.

    Article  PubMed  CAS  Google Scholar 

  45. Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27:1006–20.

    Article  PubMed  CAS  Google Scholar 

  46. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.

    Article  PubMed  CAS  Google Scholar 

  47. Zhang C, Li C, He F, Cai Y, Yang H. Identification of CD44+CD24+ gastric cancer stem cells. J Cancer Res Clin Oncol. 2011;137:1679–86.

    Article  PubMed  CAS  Google Scholar 

  48. Chen T, Yang K, Yu J, Meng W, Yuan D, Bi F, et al. Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients. Cell Res. 2012;22:248–58.

    Article  PubMed  CAS  Google Scholar 

  49. Han ME, Jeon TY, Hwang SH, Lee YS, Kim HJ, Shim HE, et al. Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research. Cell Mol Life Sci. 2011;68:3589–605.

    Article  PubMed  CAS  Google Scholar 

  50. Jiang J, Zhang Y, Chuai S, Wang Z, Zheng D, Xu F, et al. Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype. Oncogene. 2012;31:671–82.

    Article  PubMed  CAS  Google Scholar 

  51. Katsuno Y, Ehata S, Yashiro M, Yanagihara K, Hirakawa K, Miyazono K. Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-β. J Pathol. 2012;228(3):391–404.

    Article  PubMed  CAS  Google Scholar 

  52. Ohkuma M, Haraguchi N, Ishii H, Mimori K, Tanaka F, Kim HM, et al. Absence of CD71 transferrin receptor characterizes human gastric adenosquamous carcinoma stem cells. Ann Surg Oncol. 2012;19:1357–64.

    Article  PubMed  Google Scholar 

  53. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature. 2008;456:593–8.

    Article  PubMed  CAS  Google Scholar 

  54. Rocco A, Liguori E, Pirozzi G, Tirino V, Compare D, Franco R, et al. CD133 and CD44 cell surface markers do not identify cancer stem cells in primary human gastric tumors. J Cell Physiol. 2012;227:2686–93.

    Article  PubMed  CAS  Google Scholar 

  55. Moserle L, Ghisi M, Amadori A, Indraccolo S. Side population and cancer stem cells: therapeutic implications. Cancer Lett. 2010;288:1–9.

    Article  PubMed  CAS  Google Scholar 

  56. Golebiewska A, Brons NH, Bjerkvig R, Niclou SP. Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell. 2011;8:136–47.

    Article  PubMed  CAS  Google Scholar 

  57. Hadnagy A, Gaboury L, Beaulieu R, Balicki D. SP analysis may be used to identify cancer stem cell populations. Exp Cell Res. 2006;312:3701–10.

    Article  PubMed  CAS  Google Scholar 

  58. Wu C, Alman BA. Side population cells in human cancers. Cancer Lett. 2008;268:1–9.

    Article  PubMed  CAS  Google Scholar 

  59. Haraguchi N, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Sasaki A, et al. Cancer stem cells in human gastrointestinal cancers. Hum Cell. 2006;19:24–9.

    Article  PubMed  Google Scholar 

  60. Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006;24:506–13.

    Article  PubMed  CAS  Google Scholar 

  61. Schmuck R, Warneke V, Behrens HM, Simon E, Weichert W, Röcken C. Genotypic and phenotypic characterization of side population of gastric cancer cell lines. Am J Pathol. 2011;178:1792–804.

    Article  PubMed  Google Scholar 

  62. Nishii T, Yashiro M, Shinto O, Sawada T, Ohira M, Hirakawa K. Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma. Cancer Sci. 2009;100:1397–402.

    Article  PubMed  CAS  Google Scholar 

  63. Fukuda K, Saikawa Y, Ohashi M, Kumagai K, Kitajima M, Okano H, et al. Tumor initiating potential of side population cells in human gastric cancer. Int J Oncol. 2009;34:1201–7.

    PubMed  CAS  Google Scholar 

  64. Ehata S, Johansson E, Katayama R, Koike S, Watanabe A, Hoshino Y, et al. Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Oncogene. 2011;30:1693–705.

    Article  PubMed  CAS  Google Scholar 

  65. Burkert J, Otto WR, Wright NA. Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol. 2008;214:564–73.

    Article  PubMed  CAS  Google Scholar 

  66. Zhang H, Xi H, Cai A, Xia Q, Wang XX, Lu C, et al. Not all side population cells contain cancer stem-like cells in human gastric cancer cell lines. Dig Dis Sci. 2012 [Epub ahead of print].

  67. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21:283–96.

    Article  PubMed  CAS  Google Scholar 

  68. Tsujimoto H, Hagiwara A, Shimotsuma M, Sakakura C, Osaki K, Sasaki S, et al. Role of milky spots as selective implantation sites for malignant cells in peritoneal dissemination in mice. J Cancer Res Clin Oncol. 1996;122:590–5.

    Article  PubMed  CAS  Google Scholar 

  69. Berberich S, Dähne S, Schippers A, Peters T, Müller W, Kremmer E, et al. Differential molecular and anatomical basis for B cell migration into the peritoneal cavity and omental milky spots. J Immunol. 2008;180:2196–203.

    PubMed  CAS  Google Scholar 

  70. Cui L, Johkura K, Liang Y, Teng R, Ogiwara N, Okouchi Y, et al. Biodefense function of omental milky spots through cell adhesion molecules and leukocyte proliferation. Cell Tissue Res. 2002;310:321–30.

    Article  PubMed  CAS  Google Scholar 

  71. Oosterling SJ, van der Bij GJ, Bögels M, van der Sijp JR, Beelen RH, Meijer S, et al. Insufficient ability of omental milky spots to prevent peritoneal tumor outgrowth supports omentectomy in minimal residual disease. Cancer Immunol Immunother. 2006;55:1043–51.

    Article  PubMed  CAS  Google Scholar 

  72. Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, Frelinger JG, et al. Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol. 2006;169:1739–52.

    Article  PubMed  CAS  Google Scholar 

  73. Sorensen EW, Gerber SA, Sedlacek AL, Rybalko VY, Chan WM, Lord EM. Omental immune aggregates and tumor metastasis within the peritoneal cavity. Immunol Res. 2009;45:185–94.

    Article  PubMed  CAS  Google Scholar 

  74. Cao L, Hu X, Zhang Y. Omental milky spots—highly efficient “natural filter” for screening gastric cancer stem cells. Med Hypotheses. 2009;73:1017–8.

    Article  PubMed  Google Scholar 

  75. Cao L, Hu X, Zhang Y, Sun XT. Omental milky spots in screening gastric cancer stem cells. Neoplasma. 2011;58:20–6.

    Article  PubMed  CAS  Google Scholar 

  76. Winquist RJ, Boucher DM, Wood M, Furey BF. Targeting cancer stem cells for more effective therapies: taking out cancer’s locomotive engine. Biochem Pharmacol. 2009;78:326–34.

    Article  PubMed  CAS  Google Scholar 

  77. Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 2011;8:97–106.

    Article  PubMed  CAS  Google Scholar 

  78. Katoh M. Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol Ther. 2007;6:832–9.

    Article  PubMed  CAS  Google Scholar 

  79. Eaves CJ, Humphries RK. Acute myeloid leukemia and the Wnt pathway. N Engl J Med. 2010;362:2326–7.

    Article  PubMed  CAS  Google Scholar 

  80. Nusse R, Fuerer C, Ching W, Harnish K, Logan C, Zeng A, et al. Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol. 2008;73:59–66.

    Article  PubMed  CAS  Google Scholar 

  81. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.

    Article  PubMed  CAS  Google Scholar 

  82. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.

    Article  PubMed  CAS  Google Scholar 

  83. Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature. 2008;452:650–3.

    Article  PubMed  CAS  Google Scholar 

  84. Oshima H, Matsunaga A, Fujimura T, Tsukamoto T, Taketo MM, Oshima M. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway. Gastroenterology. 2006;131:1086–95.

    Article  PubMed  CAS  Google Scholar 

  85. Ishimoto T, Oshima H, Oshima M, Kai K, Torii R, Masuko T, et al. CD44+ slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis. Cancer Sci. 2010;101:673–8.

    Article  PubMed  CAS  Google Scholar 

  86. Byun T, Karimi M, Marsh JL, Milovanovic T, Lin F, Holcombe RF. Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis. J Clin Pathol. 2005;58:515–9.

    Article  PubMed  CAS  Google Scholar 

  87. Cai C, Zhu X. The Wnt/β-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer. Mol Med Rep. 2012;5:1191–6.

    PubMed  CAS  Google Scholar 

  88. Merchant JL. Hedgehog signalling in gut development, physiology and cancer. J Physiol. 2012;590(Pt 3):421–32.

    PubMed  CAS  Google Scholar 

  89. van den Brink GR, Hardwick JC, Tytgat GN, Brink MA, Ten Kate FJ, Van Deventer SJ, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 2001;121:317–8.

    Article  PubMed  Google Scholar 

  90. Dimmler A, Brabletz T, Hlubek F, Hafner M, Rau T, Kirchner T, et al. Transcription of sonic hedgehog, a potential factor for gastric morphogenesis and gastric mucosa maintenance, is up-regulated in acidic conditions. Lab Investig. 2003;83:1829–37.

    Article  PubMed  CAS  Google Scholar 

  91. Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumors. Nature. 2003;425:846–51.

    Article  PubMed  CAS  Google Scholar 

  92. Ma X, Chen K, Huang S, Zhang X, Adegboyega PA, Evers BM, et al. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 2005;26:1698–705.

    Article  PubMed  CAS  Google Scholar 

  93. Martin J, Donnelly JM, Houghton J, Zavros Y. The role of sonic hedgehog reemergence during gastric cancer. Dig Dis Sci. 2010;55:1516–24.

    Article  PubMed  Google Scholar 

  94. Ohta M, Tateishi K, Kanai F, Watabe H, Kondo S, Guleng B, et al. p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells. Cancer Res. 2005;65:10822–9.

    Article  PubMed  CAS  Google Scholar 

  95. Fukaya M, Isohata N, Ohta H, Aoyagi K, Ochiya T, Saeki N, et al. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology. 2006;131:14–29.

    Article  PubMed  CAS  Google Scholar 

  96. Lee SY, Han HS, Lee KY, Hwang TS, Kim JH, Sung IK, et al. Sonic hedgehog expression in gastric cancer and gastric adenoma. Oncol Rep. 2007;17:1051–5.

    PubMed  Google Scholar 

  97. Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5–Smad 3 pathway. Carcinogenesis. 2008;29:480–90.

    Article  PubMed  CAS  Google Scholar 

  98. Lee KM, Lee JS, Jung HS, Park DK, Park HS, Hahm KB. Late reactivation of sonic hedgehog by Helicobacter pylori results in population of gastric epithelial cells that are resistant to apoptosis: implication for gastric carcinogenesis. Cancer Lett. 2010;287:44–53.

    Article  PubMed  CAS  Google Scholar 

  99. Song Z, Yue W, Wei B, Wang N, Li T, Guan L, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS ONE. 2011;6:e17687.

    Article  PubMed  CAS  Google Scholar 

  100. Lai EC. Notch signaling: control of cell communication and cell fate. Development. 2004;131:965–73.

    Article  PubMed  CAS  Google Scholar 

  101. Katoh M, Katoh M. Notch signaling in gastrointestinal tract (review). Int J Oncol. 2007;30:247–51.

    PubMed  CAS  Google Scholar 

  102. Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, et al. Targeting Notch to target cancer stem cells. Clin Cancer Res. 2010;16:3141–52.

    Article  PubMed  CAS  Google Scholar 

  103. Kim TH, Shivdasani RA. Notch signaling in stomach epithelial stem cell homeostasis. J Exp Med. 2011;208:677–88.

    Article  PubMed  CAS  Google Scholar 

  104. Purow B. Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol. 2012;727:305–19.

    Article  PubMed  CAS  Google Scholar 

  105. Ji Q, Hao X, Meng Y, Zhang M, Desano J, Fan D, et al. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer. 2008;8:266.

    Article  PubMed  CAS  Google Scholar 

  106. Yeh TS, Wu CW, Hsu KW, Liao WJ, Yang MC, Li AF, et al. The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2. Cancer Res. 2009;69:5039–48.

    Article  PubMed  CAS  Google Scholar 

  107. Wu WK, Cho CH, Lee CW, Fan D, Wu K, Yu J, et al. Dysregulation of cellular signaling in gastric cancer. Cancer Lett. 2010;295:144–53.

    Article  PubMed  CAS  Google Scholar 

  108. Piazzi G, Fini L, Selgrad M, Garcia M, Daoud Y, Wex T, et al. Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer. Oncotarget. 2011;2:1291–301.

    PubMed  Google Scholar 

  109. Tseng YC, Tsai YH, Tseng MJ, Hsu KW, Yang MC, Huang KH, et al. Notch2-induced COX-2 expression enhancing gastric cancer progression. Mol Carcinog. 2011;51(12):939–51.

    Article  PubMed  CAS  Google Scholar 

  110. Hsu KW, Hsieh RH, Huang KH, Li AF, Chi CW, Wang TY, et al. Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression. Carcinogenesis. 2012;33(8):1459–67.

    Article  PubMed  CAS  Google Scholar 

  111. Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M, et al. p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells. 2007;25:807–15.

    Article  PubMed  CAS  Google Scholar 

  112. Sikandar SS, Pate KT, Anderson S, Dizon D, Edwards RA, Waterman ML, et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 2010;70:1469–78.

    Article  PubMed  CAS  Google Scholar 

  113. Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006;66:7445–52.

    Article  PubMed  CAS  Google Scholar 

  114. Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, et al. Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells. 2010;28:5–16.

    PubMed  CAS  Google Scholar 

  115. Auclair BA, Benoit YD, Rivard N, Mishina Y, Perreault N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology. 2007;133:887–96.

    Article  PubMed  CAS  Google Scholar 

  116. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–beta-catenin signaling. Nat Genet. 2004;36:1117–21.

    Article  PubMed  CAS  Google Scholar 

  117. Shinohara M, Mao M, Keeley TM, El-Zaatari M, Lee HJ, Eaton KA, Samuelson LC, et al. Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice. Gastroenterology. 2010;139(205060):e2.

    PubMed  Google Scholar 

  118. Maloum F, Allaire JM, Gagné-Sansfaçon J, Roy E, Belleville K, Sarret P, et al. Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells. Am J Physiol Gastrointest Liver Physiol. 2011;300:G1065–79.

    Article  PubMed  CAS  Google Scholar 

  119. Wen XZ, Akiyama Y, Baylin SB, Yuasa Y. Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas. Oncogene. 2006;25:2666–73.

    Article  PubMed  CAS  Google Scholar 

  120. Hohenstein P, Molenaar L, Elsinga J, Morreau H, van der Klift H, Struijk A, et al. Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene. Genes Chromosomes Cancer. 2003;36:273–82.

    Article  PubMed  CAS  Google Scholar 

  121. Bleuming SA, He XC, Kodach LL, Hardwick JC, Koopman FA, Ten Kate FJ, et al. Bone morphogenetic protein signaling suppresses tumorigenesis at gastric epithelial transition zones in mice. Cancer Res. 2007;67:8149–55.

    Article  PubMed  CAS  Google Scholar 

  122. Wen XZ, Miyake S, Akiyama Y, Yuasa Y. BMP-2 modulates the proliferation and differentiation of normal and cancerous gastric cells. Biochem Biophys Res Commun. 2004;316:100–6.

    Article  PubMed  CAS  Google Scholar 

  123. Zhang J, Ge Y, Sun L, Cao J, Wu Q, Guo L, et al. Effect of bone morphogenetic protein-2 on proliferation and apoptosis of gastric cancer cells. Int J Med Sci. 2012;9:184–92.

    Article  PubMed  CAS  Google Scholar 

  124. Shirai YT, Ehata S, Yashiro M, Yanagihara K, Hirakawa K, Miyazono K. Bone morphogenetic protein-2 and -4 play tumor suppressive roles in human diffuse-type gastric carcinoma. Am J Pathol. 2011;179:2920–30.

    Article  PubMed  CAS  Google Scholar 

  125. Ivanova T, Zouridis H, Wu Y, Cheng LL, Tan IB, Gopalakrishnan V, et al. Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut 2012 [Epub ahead of print].

  126. Park Y, Kim JW, Kim DS, Kim EB, Park SJ, Park JY, et al. The bone morphogenesis protein-2 (BMP-2) is associated with progression to metastatic disease in gastric cancer. Cancer Res Treat. 2008;40:127–32.

    Article  PubMed  Google Scholar 

  127. Park Y, Kang MH, Seo HY, Park JM, Choi CW, Kim YH, et al. Bone morphogenetic protein-2 levels are elevated in the patients with gastric cancer and correlate with disease progression. Med Oncol. 2010;27:1192–9.

    Article  PubMed  CAS  Google Scholar 

  128. Kang MH, Kim JS, Seo JE, Oh SC, Yoo YA. BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Exp Cell Res. 2010;316:24–37.

    Article  PubMed  CAS  Google Scholar 

  129. Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS, et al. Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expression. Exp Cell Res. 2011;317:1746–62.

    Article  PubMed  CAS  Google Scholar 

  130. Aoki M, Ishigami S, Uenosono Y, Arigami T, Uchikado Y, Kita Y, et al. Expression of BMP-7 in human gastric cancer and its clinical significance. Br J Cancer. 2011;104:714–8.

    Article  PubMed  CAS  Google Scholar 

  131. Caja L, Kahata K, Moustakas A. Context-dependent action of transforming growth factor β family members on normal and cancer stem cells. Curr Pharm Des. 2012 [Epub ahead of print].

  132. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011;208:2641–55.

    Article  PubMed  CAS  Google Scholar 

  133. Buijs JT, van der Horst G, van den Hoogen C, Cheung H, de Rooij B, Kroon J, et al. The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene. 2012;31:2164–74.

    Article  PubMed  CAS  Google Scholar 

  134. McLean K, Gong Y, Choi Y, Deng N, Yang K, Bai S, et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J Clin Investig. 2011;121:3206–19.

    Article  PubMed  CAS  Google Scholar 

  135. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444:761–5.

    Article  PubMed  CAS  Google Scholar 

  136. Voog J, Jones DL. Stem cells and the niche: a dynamic duo. Cell Stem Cell. 2010;6:103–15.

    Article  PubMed  CAS  Google Scholar 

  137. Borovski T, De Sousa E, Melo F, Vermeulen L, Medema JP. Cancer stem cell niche: the place to be. Cancer Res. 2011;71:634–9.

    Article  PubMed  CAS  Google Scholar 

  138. Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H, et al. Inhibition of Notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells. 2010;28:1019–29.

    Article  PubMed  CAS  Google Scholar 

  139. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007;67:3560–4.

    Article  PubMed  CAS  Google Scholar 

  140. Guo X, Oshima H, Kitmura T, Taketo MM, Oshima M. Stromal fibroblasts activated by tumor cells promote angiogenesis in mouse gastric cancer. J Biol Chem. 2008;283:19864–71.

    Article  PubMed  CAS  Google Scholar 

  141. Worthley DL, Ruszkiewicz A, Davies R, Moore S, Nivison-Smith I, Bik To L, et al. Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation. Stem Cells. 2009;27:1463–8.

    Article  PubMed  CAS  Google Scholar 

  142. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 2009;28:3949–59.

    Article  PubMed  CAS  Google Scholar 

  143. Seidel S, Garvalov BK, Wirta V, von Stechow L, Schänzer A, Meletis K, et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain. 2010;133(Pt 4):983–95.

    Article  PubMed  Google Scholar 

  144. Liang D, Ma Y, Liu J, Trope CG, Holm R, Nesland JM, et al. The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells. BMC Cancer. 2012;12:201.

    Article  PubMed  CAS  Google Scholar 

  145. Ma Y, Liang D, Liu J, Axcrona K, Kvalheim G, Stokke T, et al. Prostate cancer cell lines under hypoxia exhibit greater stem-like properties. PLoS ONE. 2011;6:e29170.

    Article  PubMed  CAS  Google Scholar 

  146. Yeung TM, Gandhi SC, Bodmer WF. Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci USA. 2011;108:4382–7.

    Article  PubMed  CAS  Google Scholar 

  147. Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C, et al. Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 2008;99:121–8.

    PubMed  CAS  Google Scholar 

  148. Kato Y, Yashiro M, Fuyuhiro Y, Kashiwagi S, Matsuoka J, Hirakawa T, et al. Effects of acute and chronic hypoxia on the radiosensitivity of gastric and esophageal cancer cells. Anticancer Res. 2011;31:3369–75.

    PubMed  CAS  Google Scholar 

  149. Matsumoto K, Arao T, Tanaka K, Kaneda H, Kudo K, Fujita Y, et al. mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res. 2009;69:7160–4.

    Article  PubMed  CAS  Google Scholar 

  150. Komuro A, Yashiro M, Iwata C, Morishita Y, Johansson E, Matsumoto Y, et al. Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor beta signaling. J Natl Cancer Inst. 2009;101:592–604.

    Article  PubMed  CAS  Google Scholar 

  151. Johansson E, Komuro A, Iwata C, Hagiwara A, Fuse Y, Watanabe A, et al. Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma. Cancer Sci. 2010;101:2398–403.

    Article  PubMed  CAS  Google Scholar 

  152. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11:69–82.

    Article  PubMed  CAS  Google Scholar 

  153. Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature. 2011;478:399–403.

    Article  PubMed  CAS  Google Scholar 

  154. Zhao Y, Bao Q, Renner A, Camaj P, Eichhorn M, Ischenko I, et al. Cancer stem cells and angiogenesis. Int J Dev Biol. 2011;55:477–82.

    Article  PubMed  CAS  Google Scholar 

  155. Ping YF, Bian XW. Concise review: contribution of cancer stem cells to neovascularization. Stem Cells. 2011;29:888–94.

    Article  PubMed  CAS  Google Scholar 

  156. Zhao HC, Qin R, Chen XX, Sheng X, Wu JF, Wang DB, et al. Microvessel density is a prognostic marker of human gastric cancer. World J Gastroenterol. 2006;12:7598–603.

    PubMed  Google Scholar 

  157. Kolev Y, Uetake H, Iida S, Ishikawa T, Kawano T, Sugihara K. Prognostic significance of VEGF expression in correlation with COX-2, microvessel density, and clinicopathological characteristics in human gastric carcinoma. Ann Surg Oncol. 2007;14:2738–47.

    Article  PubMed  Google Scholar 

  158. Lieto E, Ferraraccio F, Orditura M, Castellano P, Mura AL, Pinto M, et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol. 2008;15:69–79.

    Article  PubMed  Google Scholar 

  159. Yang Q, Ye ZY, Zhang JX, Tao HQ, Li SG, Zhao ZS. Expression of matrix metalloproteinase-9 mRNA and vascular endothelial growth factor protein in gastric carcinoma and its relationship to its pathological features and prognosis. Anat Rec (Hoboken). 2010;293:2012–9.

    Article  CAS  Google Scholar 

  160. Suzuki S, Dobashi Y, Hatakeyama Y, Tajiri R, Fujimura T, Heldin CH, et al. Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer. BMC Cancer. 2010;10:659.

    Article  PubMed  CAS  Google Scholar 

  161. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968–76.

    Article  PubMed  CAS  Google Scholar 

  162. Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, Peng Yong W, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30:2119–27.

    Article  PubMed  CAS  Google Scholar 

  163. Petrillo M, Scambia G, Ferrandina G. Novel targets for VEGF-independent anti-angiogenic drugs. Expert Opin Investig Drugs. 2012;21:451–72.

    Article  PubMed  CAS  Google Scholar 

  164. Yao XH, Ping YF, Bian XW. Contribution of cancer stem cells to tumor vasculogenic mimicry. Protein Cell. 2011;2:266–72.

    Article  PubMed  Google Scholar 

  165. Mirshahi P, Rafii A, Vincent L, Berthaut A, Varin R, Kalantar G, et al. Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia. 2009;23:1039–48.

    Article  PubMed  CAS  Google Scholar 

  166. Chiao MT, Yang YC, Cheng WY, Shen CC, Ko JL. CD133+ glioblastoma stem-like cells induce vascular mimicry in vivo. Curr Neurovasc Res. 2011;8:210–9.

    Article  PubMed  CAS  Google Scholar 

  167. Liu TJ, Sun BC, Zhao XL, Zhao XM, Sun T, Gu Q, et al. CD133(+) cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene 2012 [Epub ahead of print].

  168. Li M, Gu Y, Zhang Z, Zhang S, Zhang D, Saleem AF, et al. Vasculogenic mimicry: a new prognostic sign of gastric adenocarcinoma. Pathol Oncol Res. 2010;16:259–66.

    Article  PubMed  Google Scholar 

  169. Jiang J, Liu W, Guo X, Zhang R, Zhi Q, Ji J, Zhang J, et al. IRX1 influences peritoneal spreading and metastasis via inhibiting BDKRB2-dependent neovascularization on gastric cancer. Oncogene. 2011;30:4498–508.

    Article  PubMed  CAS  Google Scholar 

  170. Li L, Bhatia R. Stem cell quiescence. Clin Cancer Res. 2011;17:4936–41.

    Article  PubMed  CAS  Google Scholar 

  171. Deonarain MP, Kousparou CA, Epenetos AA. Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs. 2009;1:12–25.

    Article  PubMed  Google Scholar 

  172. Beug H. Breast cancer stem cells: eradication by differentiation therapy? Cell. 2009;138:623–5.

    Article  PubMed  CAS  Google Scholar 

  173. Chen C, Wei Y, Hummel M, Hoffmann TK, Gross M, Kaufmann AM, et al. Evidence for epithelial–mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS ONE. 2011;6:e16466.

    Article  PubMed  CAS  Google Scholar 

  174. Nakamura K, Iinuma H, Aoyagi Y, Shibuya H, Watanabe T. Predictive value of cancer stem-like cells and cancer-associated genetic markers for peritoneal recurrence of colorectal cancer in patients after curative surgery. Oncology. 2010;78:309–15.

    Article  PubMed  CAS  Google Scholar 

  175. Watanabe T, Kobunai T, Yamamoto Y, Ikeuchi H, Matsuda K, Ishihara S, et al. Predicting ulcerative colitis-associated colorectal cancer using reverse-transcription polymerase chain reaction analysis. Clin Colorectal Cancer. 2011;10:134–41.

    Article  PubMed  CAS  Google Scholar 

  176. Shien K, Toyooka S, Ichimura K, Soh J, Furukawa M, Maki Y, et al. Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy. Lung Cancer. 2012;77:162–7.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81160254, China).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Clinical Medicine Research Center, Inner Mongolia Medical University, No. 1 Tongdao North Street, Hohhot, 010050, Inner Mongolia, China

    Guihua Xu & Xiulan Su

  2. Department of Neurology, Inner Mongolia Hospital, Hohhot, China

    Jie Shen

  3. Department of General Surgery, Inner Mongolia Hospital, Hohhot, Inner Mongolia, China

    Xiaohui Ou Yang

  4. Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Masakiyo Sasahara

Authors
  1. Guihua Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaohui Ou Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masakiyo Sasahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiulan Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiulan Su.

Additional information

G. Xu and J. Shen contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, G., Shen, J., Ou Yang, X. et al. Cancer stem cells: the ‘heartbeat’ of gastric cancer. J Gastroenterol 48, 781–797 (2013). https://doi.org/10.1007/s00535-012-0712-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0712-y

Keywords

Search

Navigation