Intracellular autocrine VEGF signaling promotes EBDC cell proliferation, which can be inhibited by Apatinib

Cancer Letters
Sui PengMing Kuang

Abstract

Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a pr...Continue Reading

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Citations

Aug 16, 2018·Cancer Medicine·Chaoxu Yang, Shukui Qin
Dec 18, 2018·Endocrine Connections·Shan WuZai Wang
Jul 6, 2017·Oncotarget·Yong ZhouChongqi Tu
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Jan 23, 2021·Biomolecules·Sophie Wiszniak, Quenten Schwarz
Nov 18, 2020·World Journal of Hepatology·Xi-Hao ZhangTi Zhang

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