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

Proc Amer Assoc Cancer Res, Volume 45, 2004

1820 

Malignant meningiomas constitute 10%-15% of all meningiomas. Tissue factor pathway inhibitor (TFPI-2) is a serine protease inhibitor with broad inhibitory effects, including certain matrix metalloproteinases, plasmin, tissue factor, etc. Our previous studies have revealed that TFPI-2 expression is lost during the progression of malignant gliomas and meningiomas. To investigate the role of TFPI-2 in the invasiveness of meningiomas, we stably transfected the human malignant meningioma cell line IOMM with a vector capable of expressing a transcript complimentary to the full-length of TFPI-2 mRNA in a sense orientation. Restoration of TFPI-2 led to decreased invasive behavior of IOMM cells when compared to parental and vector controls in Matrigel and spheroid invasion assays. During in vitro angiogenesis, IOMM cells co-cultured with human umbilical vascular endothelial cells (HUVEC) showed vascular network formation after 48-72 h. In contrast, this capillary-like structure formation was inhibited when HUVEC cells were co-cultured with sense TFPI-2 stable IOMM cells. Similar findings were observed using the dorsal skin fold assay, an in vivo angiogenesis model. Western blot analysis showed that increased expression of TFPI-2 leads to increased expression of BAX, caspase-3 and cytochrome C as compared to the controls. In contrast, decreased expression of XIAP, a X-linked inhibitor of apoptosis, was observed. Finally, TFPI-2 overexpression inhibited tumor formation in nude mice. Our data substantiate our previous observations that TFPI-2 plays an important role in tumor progression and has potential as a target for anticancer therapy.