Skip to main content
SpringerLink
Log in

Absence of CD71 Transferrin Receptor Characterizes Human Gastric Adenosquamous Carcinoma Stem Cells

Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Although the importance of cancer stem cells (CSCs) in overcoming resistance to therapy and metastasis has recently been reported, the role of CSCs in gastric cancer remains to be elucidated.

Methods

MKN-1 cells were used to study markers of CSCs in gastric adenosquamous carcinoma, as these cells are suitable for determining multidifferentiation ability. Changes in expression of CD44, CD49f, CD133, and CD71 following 5-fluorouracil (5-FU) treatment were assessed.

Results

After 5-FU treatment, only the CD71− fraction was significantly increased. Investigation of CD71 indicated that the CD71− cell fraction was present in the G1/G0 cell cycle phase and showed high resistance to the anticancer agent 5-FU. Limiting dilution and serial transplantation assays revealed the CD71− cell fraction to have higher tumorigenicity than the CD71+ cell fraction. The CD71− cell fraction showed multipotency to adenocarcinoma and squamous cell carcinoma. A three-dimensional (3D) invasion assay and immunohistochemical analysis showed CD71− cells to be highly invasive and to exist in the invasive fronts of cancer foci.

Conclusion

The present study suggests that use of CD71− as a marker for adenosquamous carcinoma may provide a useful model for studying CSCs.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.

    Article  PubMed  CAS  Google Scholar 

  2. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902.

    Article  PubMed  CAS  Google Scholar 

  3. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432(7015):324–31.

    Article  PubMed  CAS  Google Scholar 

  4. Polyak K, Hahn WC. Roots and stems: stem cells in cancer. Nat Med. 2006;12(3):296–300.

    Article  PubMed  CAS  Google Scholar 

  5. Tanaka K, Kiyohara Y, Kubo M, et al. Secular trends in the incidence, mortality, and survival rate of gastric cancer in a general Japanese population: the Hisayama study. Cancer Causes Control. 2005;16(5):573–8.

    Article  PubMed  Google Scholar 

  6. Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27(5):1006–20.

    Article  PubMed  CAS  Google Scholar 

  7. 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(8):1397–402.

    Article  PubMed  CAS  Google Scholar 

  8. Boku N. Chemotherapy for metastatic gastric cancer in Japan. Int J Clin Oncol. 2008;13(6):483–7.

    Article  PubMed  CAS  Google Scholar 

  9. Boku N. Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group. Chemotherapy for metastatic disease: review from JCOG trials. Int J Clin Oncol. 2008;13(3):196–200.

    Google Scholar 

  10. 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(7):3983–8.

    Article  PubMed  CAS  Google Scholar 

  11. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

    Article  PubMed  CAS  Google Scholar 

  12. 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(7123):106–10.

    Article  PubMed  Google Scholar 

  13. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.

    Article  PubMed  CAS  Google Scholar 

  14. Joshi PA, Jackson HW, Beristain AG, et al. Progesterone induces adult mammary stem cell expansion. Nature. 2010;465(7299):803–7.

    Article  PubMed  CAS  Google Scholar 

  15. Lathia JD, Gallagher J, Heddleston JM, et al. Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell. 2010;6(5):421–32.

    Article  PubMed  CAS  Google Scholar 

  16. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61.

    Article  PubMed  CAS  Google Scholar 

  17. Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood. 2003;101(8):3142–9.

    Article  PubMed  CAS  Google Scholar 

  18. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94(6):2056–64.

    PubMed  CAS  Google Scholar 

  19. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.

    Article  PubMed  CAS  Google Scholar 

  20. Hogge DE, Lansdorp PM, Reid D, Gerhard B, Eaves CJ. Enhanced detection, maintenance, and differentiation of primitive human hematopoietic cells in cultures containing murine fibroblasts engineered to produce human steel factor, interleukin-3, and granulocyte colony-stimulating factor. Blood. 1996;88(10):3765–73.

    PubMed  CAS  Google Scholar 

  21. Yang G, Hisha H, Cui Y, et al. A new assay method for late CFU-S formation and long-term reconstituting activity using a small number of pluripotent hemopoietic stem cells. Stem Cells. 2002;20(3):241–8.

    Article  PubMed  Google Scholar 

  22. Tani H, Morris RJ, Kaur P. Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci USA. 2000;97(20):10960–5.

    Article  PubMed  CAS  Google Scholar 

  23. Calenic B, Ishkitiev N, Yaegaki K, et al. Magnetic separation and characterization of keratinocyte stem cells from human gingiva. J Periodontal Res. 2010;45(6):703–8.

    Google Scholar 

  24. Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest. 2006;116(1):249–60.

    Article  PubMed  CAS  Google Scholar 

  25. Yamazaki J, Mizukami T, Takizawa K, et al. Identification of cancer stem cells in a Tax-transgenic (Tax-Tg) mouse model of adult T-cell leukemia/lymphoma. Blood. 2009;114(13):2709–20.

    Article  PubMed  CAS  Google Scholar 

  26. Yalcintepe L, Frankel AE, Hogge DE. Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice. Blood. 2006;108(10):3530–7.

    Article  PubMed  CAS  Google Scholar 

  27. Holyoake TL, Jiang X, Jorgensen HG, et al. Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood. 2001;97(3):720–8.

    Article  PubMed  CAS  Google Scholar 

  28. Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR−. Blood. 1998;92(11):4325–35.

    PubMed  CAS  Google Scholar 

  29. Kalabis J, Oyama K, Okawa T, et al. A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. Clin Invest. 2008;118(12):3860–9.

    CAS  Google Scholar 

  30. Croagh D, Phillips WA, Redvers R, Thomas RJ, Kaur P. Identification of candidate murine esophageal stem cells using a combination of cell kinetic studies and cell surface markers. Stem Cells. 2007;25(2):313–8.

    Article  PubMed  CAS  Google Scholar 

  31. Meng S, Tripathy D, Frenkel EP, et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004;10(24):8152–62.

    Article  PubMed  Google Scholar 

  32. Terpstra W, Ploemacher RE, Prins A, et al. Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. Blood. 1996;88(6):1944–50.

    PubMed  CAS  Google Scholar 

  33. Chung SW, Chen H, Wong PM. Activation of quiescent ABL-transduced hemopoietic stem cells. Oncogene. 1996;13(11):2397–405.

    PubMed  CAS  Google Scholar 

  34. Sutherland R, Delia D, Schneider C, Newman R, Kemshead J, Greaves M. Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc Natl Acad Sci USA. 1981;78(7):4515–9.

    Article  PubMed  CAS  Google Scholar 

  35. Haraguchi N, Ishii H, Mimori K, et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010;120(9):3326–39.

    Article  PubMed  CAS  Google Scholar 

  36. Yoshida K, Manabe T, Tsunoda T, Kimoto M, Tadaoka Y, Shimizu M. Early gastric cancer of adenosquamous carcinoma type: report of a case and review of literature. Jpn J Clin Oncol. 1996;26(4):252–7.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We thank T. Shimooka for excellent technical assistance. This work was supported in part by a grant from Core Research for Evolutional Science and Technology, and grants-in-aid for scientific research on priority areas (20012039) and for scientific research (S) (21229015) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Disclosure

There is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

    Masahisa Ohkuma MD, Naotsugu Haraguchi MD, PhD, Hideshi Ishii MD, PhD, Ho Min Kim MD, Miho Shimomura MD, Hajime Hirose MD & Masaki Mori MD, PhD

  2. Department of Surgery, Jikei University School of Medicine, Tokyo, Japan

    Masahisa Ohkuma MD & Katsuhiko Yanaga MD, PhD

  3. Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Oita, Japan

    Hideshi Ishii MD, PhD, Koshi Mimori MD, PhD & Fumiaki Tanaka MD, PhD

Authors
  1. Masahisa Ohkuma MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naotsugu Haraguchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideshi Ishii MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koshi Mimori MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fumiaki Tanaka MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ho Min Kim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miho Shimomura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hajime Hirose MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Katsuhiko Yanaga MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masaki Mori MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hideshi Ishii MD, PhD or Masaki Mori MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohkuma, M., Haraguchi, N., Ishii, H. et al. Absence of CD71 Transferrin Receptor Characterizes Human Gastric Adenosquamous Carcinoma Stem Cells. Ann Surg Oncol 19, 1357–1364 (2012). https://doi.org/10.1245/s10434-011-1739-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-1739-7

Keywords

search

Navigation