Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line

Shakuntala Kondraganti, Christopher S. Gondi, Meena Gujrati, Ian McCutcheon, Dzung H. Dinh, Jasti S. Rao, William C. Olivero

Research output: Contribution to journalArticle

Abstract

Tissue factor pathway inhibitor 2 (TFPI-2) is a 32-kDa extracellular matrix-associated kunitz-type serine proteinase inhibitor. It is secreted by all vascular cells and plays a role in tumor invasion and metastasis, presumably by plasmin-mediated matrix remodeling. Previous studies have shown high expression of TFPI-2 by benign tumors and low or absent expression in highly malignant tumors. Malignant meningiomas constitute 10-15% of all meningiomas and our previous studies revealed loss of expression of TFPI-2 in malignant gliomas. To investigate the role of TFPI-2 in the invasiveness of malignant meningiomas, we stably transfected the human meningioma cell line, IOMM-Lee, with a vector capable of expressing a transcript complementary to the full length of TFPI-2 mRNA in a sense orientation. Restoration of TFPI-2 led to decreased invasiveness of transfected cells compared to parental and vector controls in Matrigel and spheroid assays and inhibition of angiogenesis in in vitro co-cultures with human umbilical vein endothelial cells (HUVEC) and in vivo dorsal skin assay studies. As assessed by Western blotting, we also observed increased expression of BAX, cytochrome c and caspase 3 as well as decreased expression of XIAP (X-linked inhibitor of apoptosis). Finally, TFPI-2 overexpression inhibited intracranial tumor formation in nude mice. Our data substantiate our previous observation that TFPI-2 plays an important role in tumor progression and has potential in anti-cancer therapy.

Original languageEnglish (US)
Pages (from-to)25-32
Number of pages8
JournalInternational journal of oncology
Volume29
Issue number1
DOIs
StatePublished - Jul 2006

Keywords

  • Angiogenesis
  • Invasion
  • TFPI-2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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