Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells

Anthony D. Yang, E. Ramsay Camp, Fan Fan, Lanlan Shen, Michael J. Gray, Wenbiao Liu, Ray Somcio, Todd W. Bauer, Yan Wu, Daniel J. Hicklin, Lee M. Ellis

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212 Scopus citations

Abstract

Our laboratory has shown that vascular endothelial growth factor receptor-1 (VEGFR-1) expression on human pancreatic cancer cell lines mediates cell migration and invasion. Because epithelial to mesenchymal transition (EMT) also plays a role in cell motility by altering the cell phenotype and morphology, we hypothesized that VEGFR-1 activation induces molecular alterations that mediate EMT. Our treatment of the human pancreatic cancer cell line L3.6pl with the VEGFR-1 ligands VEGF-A and VEGF-B led to morphologic changes characteristic of EMT, including loss of polarity, increased intercellular separation, and the presence of pseudopodia. Immunofluorescent staining with antibodies to E-cadherin and β-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and β-catenin from their usual cell membrane-bound location to the cytoplasm and nucleus, respectively. Western blotting showed that VEGFR-1 activation led to decreased expression of the epithelial markers E-cadherin and plakoglobin, increased expression of the mesenchymal markers vimentin and N-cadherin, and increased nuclear expression of β-catenin. Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced immunohistochemical and molecular changes in E-cadherin. VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug. The changes mediated by VEGFR-1 in this pancreatic carcinoma cell line are highly consistent with the changes characteristic of EMT. Given our previous finding of VEGFR-1-mediated tumor cell invasion and migration in pancreatic carcinoma cells, we hypothesize that VEGFR-1 plays a role in tumor progression in pancreatic cancer through the induction of EMT.

Original languageEnglish (US)
Pages (from-to)46-51
Number of pages6
JournalCancer Research
Volume66
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yang, A. D., Camp, E. R., Fan, F., Shen, L., Gray, M. J., Liu, W., Somcio, R., Bauer, T. W., Wu, Y., Hicklin, D. J., & Ellis, L. M. (2006). Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Research, 66(1), 46-51. https://doi.org/10.1158/0008-5472.CAN-05-3086