This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koizume, S. Articles by Miyagi, Y. Search for Related Content PubMed PubMed Citation Articles by Koizume, S. Articles by Miyagi, Y.

Activation of Cancer Cell Migration and Invasion by Ectopic Synthesis of Coagulation Factor VII

¹ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute; ² Department of Obstetrics, Gynecology and Molecular Reproductive Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan; ³ Department of Neurosurgery, Hirakata Hospital, Kansai Medical University, Osaka, Japan; and ⁴ Department of Immunology, The Scripps Research Institute, La Jolla, California

Requests for reprints: Yohei Miyagi, Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan. Phone: 81-45-391-5761; Fax: 81-45-366-3157; E-mail: miyagi{at}gancen.asahi.yokohama.jp.

Blood coagulation factor VII (fVII) is physiologically synthesized in the liver and released into the blood. Binding of fVII to tissue factor (TF) at sites of vascular injury triggers coagulation and hemostasis. TF/fVIIa complex formation on the surface of cancer cells plays important roles in cancer biology. Although fVII is synthesized by hepatocellular carcinoma, it remained unclear how TF/fVIIa complex formation and promigratory signaling can occur for most other cancers in extravascular locations. Here, we show by reverse transcription-PCR analysis that nonhepatic cancer cell lines constitutively express fVII mRNA and that endogenously synthesized fVIIa triggers coagulation activation on these cells. fVIIa expression in cancer cells is inducible under hypoxic conditions and hypoxia-inducible factor-2 bound the promoter region of the FVII gene in chromatin immunoprecipitation analyses. Constitutive fVII expression in an ovarian cancer cell line enhanced both migration and invasion. Enhanced motility was blocked by anti-TF antibodies, factor Xa inhibition, and anti–protease-activated receptor-1 antibody treatment, confirming that TF/fVIIa stimulated migration by triggering cell signaling. This study shows that ectopic synthesis of fVII by cancer cells is sufficient to support proinvasive factor Xa–mediated protease-activated receptor-1 signaling and that this pathway is inducible under hypoxia. (Cancer Res 2006; 66(19): 9453-60)

This article has been cited by other articles:

				H. H. Versteeg, F. Schaffner, M. Kerver, L. G. Ellies, P. Andrade-Gordon, B. M. Mueller, and W. Ruf Protease-Activated Receptor (PAR) 2, but not PAR1, Signaling Promotes the Development of Mammary Adenocarcinoma in Polyoma Middle T Mice Cancer Res., September 1, 2008; 68(17): 7219 - 7227. [Abstract] [Full Text] [PDF]

				H. H. Versteeg, F. Schaffner, M. Kerver, H. H. Petersen, J. Ahamed, B. Felding-Habermann, Y. Takada, B. M. Mueller, and W. Ruf Inhibition of tissue factor signaling suppresses tumor growth Blood, January 1, 2008; 111(1): 190 - 199. [Abstract] [Full Text] [PDF]

				H. Uusitalo-Jarvinen, T. Kurokawa, B. M. Mueller, P. Andrade-Gordon, M. Friedlander, and W. Ruf Role of Protease Activated Receptor 1 and 2 Signaling in Hypoxia-Induced Angiogenesis Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1456 - 1462. [Abstract] [Full Text] [PDF]

				P. Arora, T. K. Ricks, and J. Trejo Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer J. Cell Sci., March 15, 2007; 120(6): 921 - 928. [Abstract] [Full Text] [PDF]