Activated STAT3 is a mediator and biomarker of VEGF endothelial activation

Abstract

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.

Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

“…However, endothelial signaling through ERK and STAT3 are known to be induced by factors other than VEGF (e.g., basic FGF) and are unlikely to be specific indicators of VEGF action. 18,25 That this may be the case in Colo-205 tumors is supported by the observation that neither p-STAT3 nor p-ERK is reduced to basal levels by VEGF Trap therapy, suggesting that factors not neutralized by this agent induce signaling through these intermediates. On the other hand, the fact that therapy reduced both p-STAT3 and p-ERK in K1735 tumor endothelial cells to levels found in normal quiescent vessels suggests that VEGF may be the predominant or sole inducer of endothelial signaling through these intermediates in these tumors.…”

“…Notably, the reduction in endothelial p-STAT3 occurs quickly, is significant at the first time point examined (day 3) following therapy initiation and may directly reflect inhibition of VEGF-VEGFR signaling. 18 By comparison, the reduction in p-ERK is delayed, taking 7 days in K1735 tumors and 14 days in Colo-205 tumors to become significant. This lag The tumors were excised after, 3 days, 7 days and 14 days.…”

“…9,10 In response to ligand binding, VEGFR2 initiates signaling through the Raf-MEK-ERK and PI3K-AKT kinase cascades 11,[13][14][15][16][17] and through STAT3. 18,19 Signaling through these pathways promotes proliferation, survival and chemotaxis in endothelial cells and ultimately, produces the characteristic effects of VEGF on vessels, such as increased vascular permeability and angiogenesis. [20][21][22][23] These signaling pathways in endothelial cells can be activated not only by VEGF-VEGFR2 but also by other angiogenesis promoters (e.g., basic FGF) interacting with their cognate receptors and therefore, [24][25][26] may function as general indicators of angiogenic vessel activation.…”

The effects of recombinant human GH on promoting tumor growth depend on the expression of GH receptor in vivo

“…rhGH exerts its effect when rhGH binds to GHR on the tumor cell surface, and then JAK-2 is activated, which leads to serial signal cascade reaction and cell biological reactions including proliferation, differentiate, migration, inhibition of apoptosis, remodeling of cystoskeleton, and regulation of metabolic pathways. Chen et al (2008) found that pSTAT3 was a biomarker of endothelial activation that reported VEGF-VEGFR2 activity and also a key activating transcription factor on angiogenesis. The Jak-2-STAT3 pathway is one of the three classical STAT3 activating pathways, which accomplish signal transduction from extracellular to intracellular immediately.…”

Biochemical Effects of Exercise on a Fasciocutaneous Flap in a Rat Model

“…9 In response to VEGF binding, the VEGF receptor (VEGFR) undergoes autophosphorylation and transmits metabolic signals via phosphatidylinositol 3-kinase (PI3K)/protein kinase B (also known as Akt), a signal transducer and activator of transcription 3 (STAT3), Src family kinases (SFKs), nitric oxide synthase (NOS), phospholipase C-γ (PLC-γ), mitogen-activated protein kinase (MAPK), and other signaling pathways. [10][11][12][13] Activation of these signaling cascades inhibits cell death, promotes cell cycle progression with DNA synthesis, and stimulates cell motility. These cascades also induce angiogenesis, increase vascular permeability, and enhance autocrine VEGF production.…”