A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion

Abstract

Human tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase-type plasminogen activator, tissue plasminogen activator, or thrombin. Preliminary ®ndings in our laboratory suggested that the expression of TFPI-2 is downregulated or lost during tumor progression in human gliomas. To investigate the role of TFPI-2 in the invasiveness of brain tumors, we stably transfected the human high-grade glioma cell line SNB19 and the human low-grade glioma cell line Hs683 with a vector capable of expressing a transcript complementary to the full-length TFPI-2 mRNA in either sense (0.7 kb) or antisense (1 kb) orientations. Parental cells and stably transfected cell lines were analysed for TFPI-2 protein by Western blotting and for TFPI-2 mRNA by Northern blotting. The levels of TFPI-2 protein and mRNA were higher in the sense clones (SNB19) and decreased in the antisense (Hs683) clones than in the corresponding parental and vector controls. In spheroid and matrigel invasion assays, the SNB19 parental cells were highly invasive, but the sense-transfected SNB-19 clones were much less invasive; the antisense-transfected Hs683 clones were more invasive than their parental and vector controls. After intracerebral injection in mice, the sensetransfected SNB19 clones were less able to form tumors than were their parental and vector controls, and the antisense-Hs683 clones but not the parental or vector controls formed small tumors. This is the ®rst study to demonstrate that down-or upregulation of TFPI-2 plays a signi®cant role in the invasive behavior of human gliomas. Oncogene (2001) 20, 6938 ± 6945.

Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

“…III and IV) of lung cancer. During tumour progression, malignant cells may invade adjacent tissues, particularly lymph nodes, and increased plasmin activity in the vicinity of malignant cells, with subsequent activation of MMPs and ECM CpG island of TFPI-2 gene promoter region degradation, enhances tumour invasion and metastases (Rao et al, 1999Konduri et al, 2000). Reduced synthesis in NSCLC of TFPI-2, a potent inhibitor of plasmin, might therefore contribute to tumour invasiveness and metastases in vivo.…”

Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis

“…injection with ketamine (50 mg/kg) zylazine (10mg/kg). Then, the mice were injected intracerebrally with a 10 ml aliquot (2 Â 10 5 cells/ml) with the aid of a stereotactic frame as described elsewhere (Konduri et al, 2001). After 10-12 days, mice were separated into three groups and mock (PBS), EV (150 mg) or pCM vector (150 mg) were injected into the brain using Alzet mini pumps at the rate of 0.25 ml/h (six mice/group).…”

“…Cryostat sections were screened for GFP fluorescence to examine tumor growth. The sections were evaluated by a neuropathologist who was blinded as to the treatment group and scored semiquantitatively for tumor size, as described previously (Konduri et al, 2001). In another set of experiments, after 10 days of GBM cells injected intracerebrally, the animals received pCM vector intraperitoneally (two injections at 10 and 13 days).…”

ADAMTS1 Interacts with, Cleaves, and Modifies the Extracellular Location of the Matrix Inhibitor Tissue Factor Pathway Inhibitor-2

“…In fact, altered levels of TFPI-2 have been associated with pathological conditions, such as atherosclerosis (14) and tumor growth, although its action in this second case appears paradoxical and dependent on the tumor model studied. For example, its expected inhibitory role was observed in models of glioma invasion (20) and fibrosarcoma growth and metastasis (21). In contrast, TFPI-2 exerts a pro-invasive effect on hepatocarcinoma (22).…”