Archives of Virology

, Volume 164, Issue 1, pp 69–82 | Cite as

Suppression of angiogenesis and tumor growth by recombinant T4 phages displaying extracellular domain of vascular endothelial growth factor receptor 2

  • Shuguang ZuoEmail author
  • Gongpeng Dai
  • Liping Wang
  • Yuqing Wen
  • Zhiang Huang
  • Wenyi Yang
  • Wanli Ma
  • Xuequn RenEmail author
Original Article


Tumor growth, invasion and metastasis are dependent on angiogenesis. The Vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway plays a pivotal role in tumor angiogenesis and therefore represents a reasonable target for anti-angiogenesis/anti-tumor therapy. In the present study, we generated T4 recombinant phages expressing the extracellular domain of VEGFR2 (T4-VEGFR2) and investigated their anti-angiogenic activity. The T4-VEGFR2 phages were able to bind to VEGF specifically and inhibit VEGF-mediated phosphorylation of VEGFR2 and its downstream kinases such as extracellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase (MAPK). The in vitro experiments showed that the T4-VEGFR2 phages could inhibit VEGF-stimulated cell proliferation and migration of endothelial cells. Finally, administration of T4-VEGFR2 phages was able to suppress tumor growth and decrease microvascular density in murine models of Lewis lung carcinoma and colon carcinoma, and prolong the survival of tumor bearing mice. In conclusion, this study reveals that the recombinant T4-VEGFR2 phages generated using T4-based phage display system can inhibit VEGF-mediated tumor angiogenesis and the T4 phage display technology can therefore be used for the development of novel anti-cancer strategies.



Analysis of variance


American Type Culture Collection


Base pair


Bovine serum albumin


Colon carcinoma


Swine fever virus


Dimethyl sulfoxide


Deoxyribonucleic acid


Endothelial cell growth supplement


Enzyme-linked immunosorbent assay


Extracellular-signal-regulated kinase


Fetal bovine serum


Fetal liver kinase 1


fms-like tyrosine kinase-1


fms-like tyrosine kinase-4


Foot and mouth disease virus


Human immunodeficiency virus


Highly antigenic outer protein capsid


Horseradish peroxidase


Human umbilical vein endothelial cell






Kinase insert domain receptor


Lewis lung carcinoma


Mitogen-activated protein kinase


Mean fluorescence intensity


Multiplicity of infection


Methylthiazolyldiphenyl-tetrazolium bromide


Microvascular density


Optical density


Phosphate-buffered saline


Polymerase chain reaction


Phospho-extracellular-signal-regulated kinase




Protein kinase B


Placental growth factor


Phospho-vascular endothelial growth factor receptor 2


Standard deviation


Small outer capsid


Statistical Package for Social Sciences


Wild-type T4


Vascular endothelial growth factor


Vascular endothelial growth factor receptor



We thank Dr. Zhaojun Ren (VersatileBio LLC, MD, USA) for providing the pJKS plasmid and the T4-e-phage. We also thank MogoEdit ( for its linguistic assistance during the preparation of this manuscript.

Author contributions

SZ, GD and LW contributed equally to this work. SZ and XR designed the study. SZ analyzed the data, and wrote the manuscript. GD, LW and YW performed the experiments. ZH and WY provided critical review and comments. WM supervised the study.


This work was supported by Science and Technology Development Program of Henan Province (No. 132300410274), National Natural Science Foundation of China (No. 81301963), Natural Science Foundation of Henan Province (No. 162300410040) and Outstanding Youth Science Foundation of Henan University (No. yqpy20140036).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for Translational MedicineHuaihe Hospital of Henan UniversityKaifengChina
  2. 2.Institute of Infection and ImmunityHuaihe Hospital of Henan UniversityKaifengChina
  3. 3.Department of General SurgeryHuaihe Hospital of Henan UniversityKaifengChina
  4. 4.Department of Respiratory MedicineThe First Affiliated Hospital of Henan UniversityKaifengChina
  5. 5.Department of GastroenterologyThe First Affiliated Hospital of Henan UniversityKaifengChina

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