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Tissue Factor Regulation by Epidermal Growth Factor Receptor and Epithelial-to-Mesenchymal Transitions: Effect on Tumor Initiation and Angiogenesis

¹ Henderson Research Centre, McMaster University, Hamilton, Ontario, Canada; ² The Hospital for Sick Children, ³ University of Toronto, Toronto, Ontario, Canada; ⁴ Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ⁵ Centocor, Inc., Radnor, Pennsylvania; and ⁶ Montreal Children's Hospital, McGill University, Quebec, Canada

Requests for reprints: Janusz Rak, McGill University, Montreal Children's Hospital Research Institute, Place Toulon, 4060 Ste. Catherine West, PT-232, Montreal, Quebec, Canada H3Z 2Z3. Phone: 514-412-4400, ext. 22342; Fax: 514-412-4331; E-mail: janusz.rak{at}mcgill.ca.

Key Words: EGFR • E-cadherin • tissue factor • EMT • tumor angiogenesis

ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies. [Cancer Res 2008;68(24):10068–76]

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