title: Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer.
abstract: BACKGROUND
  Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment.
  
  
  METHODS
  The expression of phosphor VEGFR2 in gastric cancer cell lines was determined by real-time PCR, immunofluorescence, and Western blot. The gastric cancer cells were administrated with or without recombination human VEGF (rhVEGF), VEGFR2 neutralizing antibody, U73122, SU1498, and Apatinib. The nude mice were used for xenograft tumor model.
  
  
  RESULTS
  we found that autocrine VEGF induced high VEGFR2-expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells. The autocrine VEGF was self-sustained through increasing VEGF mRNA and protein expression. It exerted pro-proliferative effect through a PLC-ERK1/2 dependent pathway. Furthermore, we demonstrated that in VEGFR2 overexpressing gastric cancer cells, Apatinib inhibited cell proliferation in vitro and delayed xenograft tumor growth in vivo. However, these effects were not observed in VEGFR2 low expressing gastric cancer cells.
  
  
  CONCLUSIONS
  These results suggested that autocrine VEGF signaling promotes gastric cancer cell proliferation and enhances Apatinib treatment outcome in VEGFR2 overexpression gastric cancer cells both in vitro and in vivo. This study would enable better stratification of gastric cancer patients for clinical treatment decision.
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Ertao
authors.initials: E
authors.lastname: Zhai
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liao
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Sui
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Shirong
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China.
authors.forename: Minhu
authors.initials: M
authors.lastname: Chen
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C553458:apatinib
keywords: Apatinib; VEGF; autocrine; gastric cancer; proliferation