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Departments of 1 Surgical Oncology, 2 Cancer Biology, and 3 Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; and 4 ImClone Systems, Inc., New York, New York
Requests for reprints: Lee M. Ellis, Department of Surgical Oncology, Unit 444, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402. Phone: 713-792-6926; Fax: 713-792-4689; E-mail: lellis{at}mdanderson.org.
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 ß-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and ß-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 ß-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)
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