Journal of Gastroenterology

, Volume 47, Issue 9, pp 1057–1060 | Cite as

Human gastric cancer organizes neighboring lymphatic vessels via recruitment of bone marrow-derived lymphatic endothelial progenitor cells

  • Masahiro Tawada
  • Shin-ichiro HayashiEmail author
  • Shinji Osada
  • Shigeru Nakashima
  • Kazuhiro Yoshida
Rapid Communication



Lymphatic metastasis is a critical determinant of prognosis in human gastrointestinal cancers. Studies suggest that lymphatic metastasis has been linked to lymphangiogenesis, the growth of lymphatic vessels, while the mechanisms of tumor lymphangiogenesis remain poorly characterized.


Human gastric cancer cells, MKN45, were implanted under the gastric submucosa of nude mice receiving green fluorescent protein-positive bone marrow (BM) transplants. In addition, MKN45 cells were subcutaneously injected into the back of each mouse as a model of human tumor xenografts. The tumor tissue was analyzed 3 weeks after implantation.


The mice with MKN45 cells represent recruitment and incorporation of BM-derived lymphatic endothelial progenitor cells (LEPC) into gastric lymphatics. Moreover, in a xenograft model, MKN45 cells induced lymphangiogenesis as well as recruitment of BM-derived LEPC in tumor lymphatics in a xenograft model.


These findings of this study suggest that human gastric adenocarcinoma induces tumor lymphangiogenesis via recruitment of LEPC from BM.


Human gastric cancer Lymphatic endothelial progenitor cells Lymphangiogenesis Bone marrow 



Green fluorescence protein


Bone marrow


Lymphatic endothelial progenitor cells



This study was supported by a NaSNeLC research grant from Gifu University Graduate School of Medicine to S. Hayashi and M. Tawada, and the grants-in-aid from the Japan Society for the Promotion of Science, the Ministry of Education, Culture, Sports, Science and Technology to S. Hayashi. We wish to thank Dr. Yosuke Osawa, Dr. Genzo Takemura, and Dr. Shinya Minatoguchi for technical support with the murine radiation systems.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell. 2005;7:121–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999;144:789–801.PubMedCrossRefGoogle Scholar
  3. 3.
    Alitaro K, Tammela T, Petrova TV. Lymphoangiogenesis in development and human disease. Nature. 2005;438:946–53.CrossRefGoogle Scholar
  4. 4.
    Kerjaschki D, Huttary N, Raab I, Regele H, Bojarshi-Nagy K, Bartel G, et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med. 2006;12:230–4.PubMedCrossRefGoogle Scholar
  5. 5.
    He Y, Rajantie I, Ilmonen M, Maikinen T, Karkkainen MJ, Haiko P, et al. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res. 2004;64:3737–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85:221–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001;7:1194–201.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Masahiro Tawada
    • 1
  • Shin-ichiro Hayashi
    • 2
    • 3
    Email author
  • Shinji Osada
    • 1
  • Shigeru Nakashima
    • 2
  • Kazuhiro Yoshida
    • 1
  1. 1.Departments of Surgical OncologyGifu University Graduate School of MedicineGifuJapan
  2. 2.Department of Cell SignalingGifu University Graduate School of MedicineGifuJapan
  3. 3.Division of Hypertension and NephrologyNational Cerebral and Cardiovascular CenterSuitaJapan

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