Autocrine VEGF signaling promotes proliferation of neoplastic barrett's epithelial cells through a PLC-dependent pathway

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background & Aims Tumor 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. Methods Using 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. Results Neoplastic 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. Conclusions Neoplastic 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.

Original languageEnglish (US)
JournalGastroenterology
Volume146
Issue number2
DOIs
StatePublished - Feb 2014

Fingerprint

Vascular Endothelial Growth Factor A
Epithelial Cells
Vascular Endothelial Growth Factor Receptor
Barrett Esophagus
Heterografts
Protein Kinase C
Neoplasms
Adenocarcinoma
Cell Proliferation
Messenger RNA
Proteins
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Tumor Burden
Cell Count
Weights and Measures
Cell Line

Keywords

  • Apoptosis
  • Esophageal Cancer
  • Mouse Model
  • Vascular Endothelial Growth Factor Receptor 2

ASJC Scopus subject areas

  • Gastroenterology

Cite this

@article{1de7584f5b2c4575839f9af22299ea88,
title = "Autocrine VEGF signaling promotes proliferation of neoplastic barrett's epithelial cells through a PLC-dependent pathway",
abstract = "Background & Aims Tumor 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. Methods Using 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. Results Neoplastic 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. Conclusions Neoplastic 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.",
keywords = "Apoptosis, Esophageal Cancer, Mouse Model, Vascular Endothelial Growth Factor Receptor 2",
author = "Zhang, {Qiuyang D} and Chunhua Yu and Sui Peng and Hao Xu and Ellen Wright and Xi Zhang and Xiaofang Huo and Edaire Cheng and Pham, {Thai H} and Kiyotaka Asanuma and Hatanpaa, {Kimmo J} and Davood Rezai and Wang, {David H} and Sarode, {Venetia R} and Melton, {Shelby D} and Genta, {Robert M} and Spechler, {Stuart J} and Souza, {Rhonda F}",
year = "2014",
month = "2",
doi = "10.1053/j.gastro.2013.10.011",
language = "English (US)",
volume = "146",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

TY - JOUR

T1 - Autocrine VEGF signaling promotes proliferation of neoplastic barrett's epithelial cells through a PLC-dependent pathway

AU - Zhang, Qiuyang D

AU - Yu, Chunhua

AU - Peng, Sui

AU - Xu, Hao

AU - Wright, Ellen

AU - Zhang, Xi

AU - Huo, Xiaofang

AU - Cheng, Edaire

AU - Pham, Thai H

AU - Asanuma, Kiyotaka

AU - Hatanpaa, Kimmo J

AU - Rezai, Davood

AU - Wang, David H

AU - Sarode, Venetia R

AU - Melton, Shelby D

AU - Genta, Robert M

AU - Spechler, Stuart J

AU - Souza, Rhonda F

PY - 2014/2

Y1 - 2014/2

N2 - Background & Aims Tumor 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. Methods Using 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. Results Neoplastic 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. Conclusions Neoplastic 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.

AB - Background & Aims Tumor 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. Methods Using 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. Results Neoplastic 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. Conclusions Neoplastic 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.

KW - Apoptosis

KW - Esophageal Cancer

KW - Mouse Model

KW - Vascular Endothelial Growth Factor Receptor 2

UR - http://www.scopus.com/inward/record.url?scp=84890090885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890090885&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2013.10.011

DO - 10.1053/j.gastro.2013.10.011

M3 - Article

VL - 146

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -