• Qiuyang Zhang, Chunhua Yu, Sui Peng, Hao Xu, Ellen Wright, Xi Zhang, Xiaofang Huo, Edaire Cheng, Thai H Pham, Kiyotaka Asanuma, Kimmo J Hatanpaa, Davood Rezai, David H Wang, Venetia Sarode, Shelby Melton, Robert M Genta, Stuart J Spechler, and Rhonda F Souza.
• Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas.
• Gastroenterology. 2014 Feb 1;146(2):461-72.e6.

Background & AimsTumor cells express vascular endothelial growth factor (VEGF), which induces angiogenesis. VEGF also activates VEGF receptors (VEGFRs) on or within tumor cells to promote their proliferation in an autocrine fashion. We studied the mechanisms of autocrine VEGF signaling in Barrett's esophagus cells.MethodsUsing Barrett's epithelial cell lines, we measured VEGF and VEGFR messenger RNA and protein, and studied the effects of VEGF signaling on cell proliferation and VEGF secretion. We studied the effects of inhibiting factors in this pathway on levels of phosphorylated phospholipase Cγ1 (PLCG1), protein kinase C, and extracellular signal-regulated kinases (ERK)1/2. We performed immunohistochemical analysis of phosphorylated VEGFR2 on esophageal adenocarcinoma tissues. We studied effects of sunitinib, a VEGFR2 inhibitor, on proliferation of neoplastic cells and growth of xenograft tumors in mice.ResultsNeoplastic and non-neoplastic Barrett's cells expressed VEGF and VEGFR2 messenger RNA and protein, with higher levels in neoplastic cells. Incubation with recombinant human VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the recombinant human VEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells. Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2. Sunitinib inhibited VEGF signaling in neoplastic cells and reduced weight and volume of xenograft tumors in mice.ConclusionsNeoplastic and non-neoplastic Barrett's epithelial cells have autocrine VEGF signaling. In neoplastic Barrett's cells, VEGF activation of VEGFR2 initiates a PLCG1-protein kinase C-ERK pathway that promotes proliferation and is self-sustaining (by causing more VEGF production). Strategies to reduce autocrine VEGF signaling (eg, with sunitinib) might be used to prevent or treat cancer in patients with Barrett's esophagus.Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

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