Vascular Endothelial Growth Factor Receptor-1 Activation Mediates Epithelial to Mesenchymal Transition in Human Pancreatic Carcinoma Cells

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 B-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and B-catenin from their usual cell membranebound 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 B-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. (Cancer Res 2006; 66(1): 46-51)

High Motility of Triple-negative Breast Cancer Cells Is Due to Repression of Plakoglobin Gene by Metastasis Modulator Protein SLUG

“…Our research established that SLUG induction knocks down plakoglobin gene expression and thus increases the motility of the cells, thus contributing toward the understanding of how extracellular signals influence the metastatic behavior of aggressive breast cancer cells. Because SLUG and plakoglobin levels are inversely related in other cancers including pancreatic and colorectal cancers as well (39,40), our findings will also help in the mechanistic evaluation of metastatic progression of other cancers.…”

“…This inverse relationship between SLUG and plakoglobin led to our hypothesis that negative regulation of plakoglobin by SLUG increases the motility of the SLUG-high breast cancer cells. Although causal relationship was not established, inverse relationship between SLUG and plakoglobin was also reported in other cancer cells including human pancreatic (39) and colon cancer (40).…”

Identification of the high-risk group for metastasis of gastric cancer cases by vascular endothelial growth factor receptor-1 overexpression in peripheral blood

“…In general, the metastatic pathway in gastric cancer is not haematogenous, and therefore, the responsible cells expressing VEGFR1 may be monocytes and not HPCs and CECs. A last possibility is that VEGFR1 originates from circulating cancer cells in the bone marrow or peripheral blood (Fan et al, 2005;Yang et al, 2006). However, the number of circulating cancer cells is very low, which allow us to ignore the possibility that cancer cell are the origin of VEGFR1 expression.…”

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…The most important inducer of EMT is the cytokine transforming growth factor-β (TGF-β), acting through its transducers, the SMAD proteins [42]. Most of the factors that promote EMT (i.e., epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), hepatic growth factor (HGF), vascular and endothelial growth factor VEGF) act through specific receptors that show intrinsic tyrosinekinase activity (RTK) [43][44][45][46][47].…”