Oncotarget

Research Papers:

Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer

Yi Lin _, Ertao Zhai, Bing Liao, Lixia Xu, Xinhua Zhang, Sui Peng, Yulong He, Shirong Cai, Zhirong Zeng and Minhu Chen

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Oncotarget. 2017; 8:11990-12002. https://doi.org/10.18632/oncotarget.14467

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Abstract

Yi Lin1,*, Ertao Zhai2,*, Bing Liao3,*, Lixia Xu1, Xinhua Zhang2, Sui Peng1, Yulong He2, Shirong Cai2, Zhirong Zeng1, Minhu Chen1

1Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China

2Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China

3Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R.China

*These authors have contributed equally to this work

Correspondence to:

Shirong Cai, email: [email protected]

Zhirong Zeng, email: [email protected]

Keywords: autocrine, VEGF, proliferation, Apatinib, gastric cancer

Received: December 16, 2015     Accepted: December 25, 2016     Published: January 03, 2017

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.

Conclusion: 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.


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