Activated STAT3 is a mediator and biomarker of VEGF endothelial activation.
STAT3 plays important roles in cell proliferation and survival signaling and is often constitutively activated in transformed cells. In this study, we examined STAT3 activation in endothelial cells (EC) during angiogenic activation and therapeutic angiogenesis inhibition. VEGF stimulation of cultured EC induced STAT3 phosphorylation by a VEGFR2- and Src-dependent mechanism. FGF2 but not PlGF also induced EC STAT3 activation in vitro. Activated STAT3 mediated VEGF induction of EC Bcl-2 and contributed to VEGF protection of EC from apoptosis. In vivo, p-STAT3 was absent by immunohistological staining in the vascular EC of most normal mouse organs but was present in the vessels of mouse and human tumors. Tumor vascular p-STAT3 increased as tumors were induced to overexpress VEGF, indicating that VEGF is an activator of EC p-STAT3 in vivo. Tumor vascular p-STAT3 decreased during angiogenesis inhibition by antagonists of VEGF-VEGFR signaling, VEGF Trap and SU5416, indicating that VEGF contributed to the EC STAT3 activation seen in the tumors prior to treatment and that p-STAT3 may be used to monitor therapy. These studies show that p-STAT3 is a mediator and biomarker of endothelial activation that reports VEGF-VEGFR2 activity and may be useful for studying the pharmacodynamics of targeted angiogenesis inhibitors.
Chen
Shao-Hua
SH
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Murphy
Danielle A
DA
Lassoued
Wiem
W
Thurston
Gavin
G
Feldman
Michael D
MD
Lee
William M F
WM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2