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Blood, 1 February 2004, Vol. 103, No. 3, pp. 1069-1077. Prepublished online as a Blood First Edition Paper on October 2, 2003; DOI 10.1182/blood-2003-06-1930. This Article Full Text (PDF) All Versions of this Article: 2003-06-1930v1 103/3/1069    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chand, H. S. Articles by Kisiel, W. Search for Related Content PubMed PubMed Citation Articles by Chand, H. S. Articles by Kisiel, W. Social Bookmarking                   What's this? Submitted June 16, 2003 Accepted September 25, 2003 The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice Hitendra Singh Chand, Xin Du, Duan Ma, Hector David Inzunza, Shintaro Kamei, Donald Foster, Steven Brodie, and Walter Kisiel* Department of Pathology, University of New Mexico, Albuquerque, NM, USA Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA ZymoGenetics Inc., Seattle, WA, USA * Corresponding author; email: wkisiel{at}salud.unm.edu. Human tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits the plasmin and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion and metastasis. To directly assess its role in tumor growth and metastasis in-vivo, we stably-transfected HT-1080 fibrosarcoma cells expressing either fully active wild-type human TFPI-2 (WT) or inactive R24Q TFPI-2 (QT), and examined their ability to form tumors and metastasize in athymic mice in comparison to mock-transfected cells (MT). MT and QT fibrosarcoma tumors grew 2-3 times larger than WT tumors. Tumor metastasis was confined to the lung and was observed in 75% of mice treated with either MT- or QT-cells whereas only 42% of mice treated with WT-cells developed lung metastases. Real time quantitative RT-PCR analyses of each tumor group revealed 3-6-fold lower levels of murine vascular endothelial growth factor gene expression in WT tumors in relation to either MT or QT tumors. Comparative tumor gene-expression analysis revealed that several human genes implicated in oncogenesis, invasion and metastasis, apoptosis and angiogenesis had significantly altered levels of expression in WT-tumors. Our collective data demonstrate that secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis in-vivo by regulating pericellular ECM remodeling and angiogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Zhao, G. Aguilar, S. Palencia, E. Newton, and A. Abo rNAPc2 Inhibits Colorectal Cancer in Mice through Tissue Factor Clin. Cancer Res., January 1, 2009; 15(1): 208 - 216. [Abstract] [Full Text] [PDF] J. George, C. S. Gondi, D. H. Dinh, M. Gujrati, and J. S. Rao Restoration of Tissue Factor Pathway Inhibitor-2 in a Human Glioblastoma Cell Line Triggers Caspase-Mediated Pathway and Apoptosis Clin. Cancer Res., June 15, 2007; 13(12): 3507 - 3517. [Abstract] [Full Text] [PDF] L. Ivanciu, R. D. Gerard, H. Tang, F. Lupu, and C. Lupu Adenovirus-Mediated Expression of Tissue Factor Pathway Inhibitor-2 Inhibits Endothelial Cell Migration and Angiogenesis Arterioscler Thromb Vasc Biol, February 1, 2007; 27(2): 310 - 316. [Abstract] [Full Text] [PDF] Z. Xu, D. Maiti, W. Kisiel, and E. J. Duh Tissue Factor Pathway Inhibitor-2 Is Upregulated by Vascular Endothelial Growth Factor and Suppresses Growth Factor-Induced Proliferation of Endothelial Cells Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2819 - 2825. [Abstract] [Full Text] [PDF] A. X. Torres-Collado, W. Kisiel, M. L. Iruela-Arispe, and J. C. Rodriguez-Manzaneque ADAMTS1 Interacts with, Cleaves, and Modifies the Extracellular Location of the Matrix Inhibitor Tissue Factor Pathway Inhibitor-2 J. Biol. Chem., June 30, 2006; 281(26): 17827 - 17837. [Abstract] [Full Text] [PDF] A. E. Schmidt, H. S. Chand, D. Cascio, W. Kisiel, and S. P. Bajaj Crystal Structure of Kunitz Domain 1 (KD1) of Tissue Factor Pathway Inhibitor-2 in Complex with Trypsin: IMPLICATIONS FOR KD1 SPECIFICITY OF INHIBITION J. Biol. Chem., July 29, 2005; 280(30): 27832 - 27838. [Abstract] [Full Text] [PDF] H. S. Chand, A. E. Schmidt, S. P. Bajaj, and W. Kisiel Structure-Function Analysis of the Reactive Site in the First Kunitz-type Domain of Human Tissue Factor Pathway Inhibitor-2 J. Biol. Chem., April 23, 2004; 279(17): 17500 - 17507. [Abstract] [Full Text] [PDF]

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