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Gastroenterology. 2014 Feb;146(2):461-72.e6. doi: 10.1053/j.gastro.2013.10.011. Epub 2013 Oct 9.

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

Author information

1
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.
2
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; Division of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
3
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas.
4
Department of Research and Development, VA North Texas Heath Care System, Dallas, Texas.
5
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; Department of Pediatrics, Children's Medical Center, Dallas, Texas.
6
Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas.
7
Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas.
8
Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Research and Development, VA North Texas Heath Care System, Dallas, Texas.
9
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; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
10
Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas.
11
Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Miraca Life Sciences, Inc., Irving, Texas.
12
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; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: rhonda.souza@utsouthwestern.edu.

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; BAR-T; BrdU; ERK; Esophageal Cancer; Mouse Model; PKC; PLC; PLCG1; VEGF; VEGF-NA; VEGFR; Vascular Endothelial Growth Factor Receptor 2; bromodeoxyuridine; extracellular signal-regulated kinase; mRNA; messenger RNA; non-neoplastic, telomerase-immortalized Barrett's epithelial cell; phospholipase C; phospholipase Cγ1; protein kinase C; recombinant human vascular endothelial growth factor; rhVEGF; shRNA; short-hairpin RNA; siRNA; small interfering RNA; vascular endothelial growth factor; vascular endothelial growth factor neutralization antibody; vascular endothelial growth factor receptor

PMID:
24120473
PMCID:
PMC3899829
DOI:
10.1053/j.gastro.2013.10.011
[Indexed for MEDLINE]
Free PMC Article
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