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

Sui Peng, Yanyan Zhang, Hong Peng, Zunfu Ke, Lixia Xu, Tianhong Su, Allan Tsung, Samer Tohme, Hai Huang, Qiuyang Zhang, Riccardo Lencioni, Zhirong Zeng, Baogang Peng, Minhu Chen, Ming Kuang

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


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 predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC.

Original languageEnglish (US)
Pages (from-to)193-202
Number of pages10
JournalCancer Letters
Issue number2
StatePublished - Apr 10 2016


  • Apatinib
  • Extrahepatic bile duct cancer
  • Proliferation
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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