Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Inhibition of K562 leukemia angiogenesis and growth by expression of antisense vascular endothelial growth factor (VEGF) sequence

Cancer Gene Therapy volume 10, pages 879–886 (2003)Cite this article

Abstract

Vascular endothelial growth factor (VEGF), a major angiogenic factor, plays a key role in the growth of solid tumor. Recently, expression of VEGF and its receptors has been found on leukemic cells as well as on endothelial cells. VEGF may fulfill a fundamental role in promoting tumor angiogenesis and proliferation by stimulating both endothelial cells and leukemic cells. To investigate the role of VEGF in the angiogenesis and growth of leukemic cell, we used an antisense strategy to downregulate VEGF expression in K562 cells, a human erythroleukemia cell line. Expression of antisense-VEGF in K562 cells reduced the secretion of VEGF protein and inhibited cell survival. The proliferation and migration of human umbilical vein endothelial cells were decreased in response to the conditioned medium (CM) from K562 cells expressed antisense-VEGF, compared to CM from K562 cells transfected with vector control. Moreover, subcutaneous injection of nude mice with antisense-VEGF K562 cells inhibited tumor growth with a reduction of the density of microvessels and an increased apoptosis in those tumors, compared to vector control K562 cells. These results suggest that the efficient downregulation of the VEGF production in leukemic cells using antisense-VEGF may constitute a novel strategy of treatment in leukemia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig 1
Fig 2
Fig 3
Fig 4
Fig 5
Fig 6

Similar content being viewed by others

References

  1. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW . The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991;5:1806–1814.

    Article  CAS  PubMed  Google Scholar 

  2. Kim KJ, Li B, Armanin M, Gillett N, Phillip HS, Ferrara N . Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature. 1993;362:841–844.

    Article  CAS  PubMed  Google Scholar 

  3. Toi M, Hosshina, Takayanagi T, Tominaga T . Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res. 1994;85:1045–1049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Drake CJ, Little CD. VEGF and vascular fusion: implication for normal and pathological vessels. J Histochem Cytochem. 1999;47:1351–1356.

    Article  CAS  PubMed  Google Scholar 

  5. Weider N, Semple JP, Welch WR, Folkman J . Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.

    Article  Google Scholar 

  6. O'Brien T, Cranston D, Fuggle S, Bicknell R, Harris AL . Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res. 1995;55:510–513.

    CAS  PubMed  Google Scholar 

  7. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM . Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995;55:3964–3968.

    CAS  PubMed  Google Scholar 

  8. Salven P, Ruotsalainen T, Mattson K, Joensuu H . High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer. 1998;79:144–146.

    Article  CAS  PubMed  Google Scholar 

  9. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N . Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309.

    Article  CAS  PubMed  Google Scholar 

  10. Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y . Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 1995;55:5687–5692.

    CAS  PubMed  Google Scholar 

  11. Shalaby F, Ho J, Stanford WL, et al. A requirement for Flk-1 in primitive and definitive hematopoiesis and vasculogenesis. Cell. 1997;89:981–990.

    Article  CAS  PubMed  Google Scholar 

  12. Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001;193:1005–1014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bellamy WT, Richter L, Frutiger Y, Grogan TM . Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res. 1999;59:728–733.

    CAS  PubMed  Google Scholar 

  14. Aguayo A, Estey E, Kantarjian H, et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood. 1999;94:3717–3721

    CAS  PubMed  Google Scholar 

  15. Aguayo A, O'Brien S, Keating M, et al. Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia. Blood. 2000;96:768–770.

    CAS  PubMed  Google Scholar 

  16. Aguayo A, Kantarjian H, Manshouri T, et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood. 2000;96:2240–2245.

    CAS  PubMed  Google Scholar 

  17. Brogi E, Schatteman G, Wu T, et al. Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest. 1996;97:469–476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fiedler W, Graeven U, Ergun S, et al. Vascular endothelial growth factor, a possible paracrine factor in human acute myeloid leukemia. Blood. 1997;89:1870–1875.

    CAS  PubMed  Google Scholar 

  19. Dias S, Hattori K, Zhou Z, et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest. 2000; 106: 511–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. List AF . Vascular endothelial growth factor signaling pathway as an emerging target in hematologic malignancies. Oncologist. 2001;6(Suppl 1):24–31.

    Article  CAS  PubMed  Google Scholar 

  21. Gerber H-P, Malik AK, Solar GP, et al. VEGF regulates hematopoitic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–958.

    Article  CAS  PubMed  Google Scholar 

  22. Nakashima T, Hudson JM, Clayman GL . Antisense inhibition of vascular endothelial growth factor in human head and neck squamous cell carcinoma. Head Neck. 2000;22:483–488.

    Article  CAS  PubMed  Google Scholar 

  23. Mordenti J, Thomsen K, Licko V, Chen H, Meng YG, Ferrara N . Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to human. Toxicol Pathol. 1999;27:14–21.

    Article  CAS  PubMed  Google Scholar 

  24. Lin P, Sankar S, Shan S, et al. Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ. 1998;9:49–58.

    CAS  PubMed  Google Scholar 

  25. Prewett M, Huber J, Yiwen Li, et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 1999;59:5209–5218.

    CAS  PubMed  Google Scholar 

  26. Dias S, Hattori K, Heissig B, et al. Inhibition of both paracrine and autocrine VEGF/VEGFR2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA. 2001;10857–10862.

    Article  CAS  Google Scholar 

  27. Kang MA, Kim KY, Seol JY, Kim KC, Nam MJ . The growth inhibition of hepatoma by gene transfer of antisense vascular endothelial growth factor. J Gene Med. 2000;2:289–296.

    Article  CAS  PubMed  Google Scholar 

  28. Nguyen JT, Wu P, Clouse ME, Hlatky L, Terwilliger EF . Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy. Cancer Res. 1998;58:5673–5677.

    CAS  PubMed  Google Scholar 

  29. Fusetti L, Pruneri G, Gobbi A, et al. Human myeloid and lymphoid malignancies in the non-obese diabetic/severe combined immunodeficiency mouse model: frequency of apoptotic cells in vascular endothelial growth factor production. Cancer Res. 2000;60:2527–2534.

    CAS  PubMed  Google Scholar 

  30. Dias S, Shmelkov SV, Lam G, Rafii S . VEGF165 promotes survival of leukemic cells by Hsp-90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood. 2002;99:2532–2540.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the grants from the China National Foundation of Natural Science (39725014), the CMB-funded programs, the Ministry of Science & Technology of China, and the Tianjin Commission of Science and Technology (39725014).

Author information

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union of Medical College, Tianjin, 300020, China

    Rui He, Bin Liu, Chen Yang, Ren Chi Yang & Zhong Chao Han

  2. Institut des Vaisseaux et du Sang, Hopital Lariboisiere, Paris, France

    Gerard Tobelem

Authors
  1. Rui He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ren Chi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerard Tobelem
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhong Chao Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhong Chao Han.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, R., Liu, B., Yang, C. et al. Inhibition of K562 leukemia angiogenesis and growth by expression of antisense vascular endothelial growth factor (VEGF) sequence. Cancer Gene Ther 10, 879–886 (2003). https://doi.org/10.1038/sj.cgt.7700645

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700645

Keywords

This article is cited by

Search

Advanced search

Quick links