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

Abstract

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.