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

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.

• Authors: Shakuntala Kondraganti, Christopher S Gondi, Meena Gujrati, Ian McCutcheon, Dzung H Dinh, Jasti S Rao, William C Olivero
• Journal: International journal of oncology (Int J Oncol) Vol. 29 Issue 1 Pg. 25-32 (Jul 2006) ISSN: 1019-6439 [Print] Greece
• PMID: 16773181 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Glycoproteins
• Laminin
• Lipoproteins
• Proteoglycans
• bcl-2-Associated X Protein
• lipoprotein-associated coagulation inhibitor
• tissue-factor-pathway inhibitor 2
• matrigel
• Collagen
• Cytochromes c
• Caspase 3

Topics

• Animals
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Movement
• Coculture Techniques
• Collagen
• Cytochromes c (metabolism)
• Drug Combinations
• Endothelial Cells (cytology)
• Female
• Glycoproteins (biosynthesis, genetics)
• Humans
• Laminin
• Lipoproteins (genetics, metabolism)
• Meningeal Neoplasms (metabolism, pathology)
• Meningioma (metabolism, pathology)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic (metabolism)
• Proteoglycans
• Skin (blood supply)
• Transfection
• bcl-2-Associated X Protein (metabolism)