Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line.
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.
Kondraganti
Shakuntala
S
Program of Cancer Biology, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, 61656, USA.
Gondi
Christopher S
CS
Gujrati
Meena
M
McCutcheon
Ian
I
Dinh
Dzung H
DH
Rao
Jasti S
JS
Olivero
William C
WC
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D003094:Collagen; D045304:Cytochromes c / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007797:Laminin; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008577:Meningeal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008579:Meningioma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011509:Proteoglycans; D012867:Skin / Q000098:blood supply; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004338:Drug Combinations; D006023:Glycoproteins; D007797:Laminin; D008074:Lipoproteins; D011509:Proteoglycans; D051028:bcl-2-Associated X Protein; C051928:lipoprotein-associated coagulation inhibitor; C021240:tissue-factor-pathway inhibitor 2; C059485:matrigel; D003094:Collagen; D045304:Cytochromes c; D053148:Caspase 3