The Role of Tissue Factor Pathway Inhibitor in Tumor Growth and Metastasis

Abstract

Clotting activation occurs frequently in cancer. Tissue factor (TF), the most potent initiator of coagulation, is expressed aberrantly in many types of malignancy and is involved not only in tumor-associated hypercoagulability but also in promoting tumor angiogenesis and metastasis via coagulation-dependent and coagulation-independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) is the natural inhibitor of TF coagulant and signaling activities. Studies have shown that TFPI exhibits antiangiogenic and antimetastatic effects in vitro and in vivo. In animal models of experimental metastasis, both circulating and tumor cell-associated TFPI are shown to significantly reduce tumor cell-induced coagulation activation and lung metastasis. Heparins and heparin derivatives, which induce the release of TFPI from the vascular endothelium, also exhibit antitumor effects, and TFPI may contribute significantly to those effects. Indeed, a non-anticoagulant low-molecular-weight heparin with intact TFPI-releasing capacity has been shown to have significant antimetastatic effect in a similar experimental mouse model. The evidence supporting the dual inhibitory functions on TF-driven coagulation and signaling strengthen the rationale for considering TFPI as a potential anticancer agent. This article primarily summarizes the evidence for antiangiogenic and antimetastatic effects of TFPI and describes its potential mechanisms of action. The possible application of TFPI and other inhibitors of TF as potential anticancer agents is described, and information regarding potential antitumor properties of TFPI-2 (which has structural similarities to TFPI) is also included.

Keywords

Tissue factor pathway inhibitor - cancer - metastasis - angiogenesis - tissue factor

Publikationsverlauf

Publikationsdatum:
14. November 2007 (online)

• REFERENCES

• 1 Dvorak HF. Thrombosis and cancer. Hum Pathol 1987; 18: 275-284
• 2 Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol 2001; 106: 6-12
• 3 Hillen HF. Thrombosis in cancer patients. Ann Oncol 2000; 11 (Suppl. 03) 273-276
• 4 Wojtukiewicz MZ, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy. Neoplasia 2001; 3: 371-384
• 5 Bogdanov VY, Balasubramanian V, Hathcock J. et al. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003; 9: 458-462
• 6 Giesen PL, Rauch U, Bohrmann B. et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-2315
• 7 Yu JL, Rak JW. Sheddign tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the main source of TF activity released from human cancer cells. J Thromb Haemost 2004; 2: 2065-2067
• 8 Hron G, Kollars M, Weber H. et al. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007; 97: 119-123
• 9 Langer F, Chunk FK, Amirkhosravi A. et al. Plasma tissue factor antigen in localized prostate cancer: distribution, clinical significance and correlation with haemostatic activation. Thromb Haemost 2007; 97: 464-470
• 10 Del Conde I, Bharwani LD, Dietzen DJ. et al. Microvesicle-associated tissue factor and Trousseau's syndrome. J Thromb Haemost 2007; 5: 70-74
• 11 Zwicker I, Furie BC, Furie B. Cancer-associated thrombosis. Crit Rev Oncol Hematol 2007; 62: 126-136
• 12 Nemerson Y, Repke D. Tissue factor accelerates the activation of coagulation factor VII: the role of a bifunctional coagulation cofactor. Thromb Res 1985; 40: 351-358
• 13 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744
• 14 Gemmell CH, Broze GJ, Turitto VT, Nemerson Y. Utilization of a continuous flow reactor to study the lipoprotein-associated coagulation inhibitor (LACI) that inhibits tissue factor. Blood 1990; 76: 2266-2271
• 15 Bajaj MS, Birktoft, Steer SA, Bajaj SP. Structure and biology of tissue factor pathway inhibitor. Thromb Haemost 2001; 86: 959-972
• 16 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of synthesis. Proc Natl Acad Sci USA 1990; 87: 8869-8873
• 17 Werling RW, Zacharski LR, Kiesiel W, Bajaj SP, Memoli VA, Rouseau SM. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69: 366-369
• 18 Novotny WF, Girard TJ, Miletich JP, Broze Jr GJ. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988; 72: 2020-2025
• 19 Novotny WF, Girard TJ, Miletich JP, Broze Jr GJ. Purification and characterization of the lipoprotein-associated coagulation inhibitor from human plasma. J Biol Chem 1989; 264: 18832-18837
• 20 Zhang J, Piro O, Lu L, Broze Jr GJ. Glycosyl phosphatidylinositol anchorage of tissue factor pathway inhibitor. Circulation 2003; 108: 623-627
• 21 Lupu C, Poulsen E, Roquefeuil S. et al. Cellular effects of heparin on the production and release of tissue factor pathway inhibitor in human endothelial cells in culture. Arterioscler Thromb Vasc Biol 1999; 19: 2251-2262
• 22 Hansen JB, Svenson B, Olsen R. Heparin induces synthesis and secretion of tissue factor pathway inhibitor from endothelial cells in vitro . Thromb Haemost 2000; 83: 937-943
• 23 Lindahl AK, Sandset PM, Abildgaard U. et al. High plasma levels of extrinsic pathway inhibitor and low levels of other coagulation inhibitors in advanced cancer. Acta Chir Scand 1989; 155: 389-393
• 24 Lindahl AK, Abildgaard U, Stokke G. Release of extrinsic pathway inhibitor after heparin injection: increased response in cancer patients. Thromb Res 1990; 59: 651-656
• 25 Piro O, Broze Jr GJ. Comparison of cell-surface TFPIα and β. Thromb Haemost 2005; 3: 2677-2683
• 26 Bai H, Ma D, Zhang YG. et al. Molecular design and characterization of recombinant long half-life mutants of human tissue factor pathway inhibitor. Thromb Haemost 2005; 93: 1055-1060
• 27 Chang JY, Monroe DM, Oliver JA, Roberts HR. TFPIbeta, a second product from the mouse tissue factor pathway inhibitor TFPI gene. Thromb Haemost 1999; 81: 45-49
• 28 Wun TC, Kretzmer KK, Girard TJ, Miletich JP, Broze Jr GJ. Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains. J Biol Chem 1988; 263: 6001-6004
• 29 Girard TJ, Warren LA, Novotny WF. et al. Functional significance of the kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 1989; 338: 518-520
• 30 Petersen LC, Bijorn SE, Olsen OH. et al. Inhibitory properties of separate recombinant Kunitz-type protease inhibitor domains from tissue factor-pathway inhibitor. Eur J Biochem 1996; 235: 310-316
• 31 Piro O, Broze Jr GJ. Role of the Kunitz-3 domain of tissue factor pathway inhibitor-alpha in cell surface binding. Circulation 2004; 110: 3567-3572
• 32 Ettelaie C, Adam JM, James NJ. et al. The role of C-terminal domain in the inhibitory functions of tissue factor pathway inhibitor. FEBS Lett 1999; 463: 341-344
• 33 Nakasaki T, Wada H, Shigemori C. et al. Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer. Am J Hematol 2002; 69: 247-254
• 34 Ueda C, Hirohata Y, Kihara Y. et al. Pancreatic cancer complicated by disseminated intravascular coagulation associated with production of tissue factor. J Gastroenterol 2001; 36: 848-850
• 35 Guan M, Jin J, Su B. et al. Tissue factor expression and angiogenesis in human glioma. Clin Biochem 2002; 35: 321-325
• 36 Ueno T, Toi M, Koike M. et al. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer 2000; 83: 164-170
• 37 Swada M, Miyakes S, Ohdama S. et al. Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis. Br J Cancer 1999; 79: 472-477
• 38 Hamada K, Kuratsu J, Saitoh Y. et al. Expression of tissue factor in glioma. Noshuyo Byori 1996; 13: 115-118
• 39 Zhang Y, Deng Y, Luther T. et al. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 1994; 94: 1320-1327
• 40 Shoji M, Abe K, Nawroth PP. et al. Molecular mechanisms linking thrombosis and angiogenesis in cancer. Trends Cardiovasc Med 1997; 7: 52-59
• 41 Abe K, Shoji M, Chen J. et al. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999; 96: 8663-8668
• 42 Ott I, Fischer EG, Miyagi Y. et al. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol 1998; 140: 1241-1253
• 43 Belting M, Dorrell MI, Sandgren S. et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 2004; 10: 502-509
• 44 Ahamed J, Versteeg HH, Kerver M. et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci USA 2006; 103: 13932-13937
• 45 Hembrough TA, Swartz GM, Papathanassiu GP. et al. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a non-hemostatic mechanism. Cancer Res 2003; 63: 2997-3000
• 46 Hembrough TA, Ruiz JF, Papathanassiu AE. et al. Tissue factor pathway inhibitor inhibits endothelial cell proliferation via association with the very low density lipoprotein receptor. J Biol Chem 2001; 276: 12241-12248
• 47 Hembrough TA, Ruiz JF, Swerdlow BM. et al. Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity. Blood 2004; 103: 3374-3380
• 48 Amirkhosravi A, Meyer T, Desai H. et al. TFPI carboxy-terminal peptide exhibits anticoagulant activity and suppresses proliferation of melanoma and endothelial cells. Blood 2001; 98 (11) 66b
• 49 Ahamed J, Ruf W. Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain. J Biol Chem 2004; 279: 23038-23044
• 50 Riewald M, Kravchenko VV, Petrovan RJ. et al. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor1. Blood 2001; 97: 3109-3116
• 51 Hjortoe GM, Petersen LC, Albrektsen T. et al. Tissue factor-factor VIIa-specific upregulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration. Blood 2004; 103: 3029-3037
• 52 Ahamed J, Belting M, Ruf W. Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1. Blood 2005; 105: 2384-2391
• 53 Sevinsky JR, Rao LVM, Ruf W. Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue factor-dependent coagulation pathway. J Cell Biol 1996; 133: 293-304
• 54 Abraham E, Reinhart K, Opal S. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290: 238-247
• 55 Bromberg ME, Konigsberg WH, Madison JF. et al. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-8209
• 56 Mueller BM, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest 1998; 101: 1372-1378
• 57 Francis JL, Amirkhosravi A. Effect of anti-hemostatic agents on experimental tumor dissemination. Semin Thromb Hemost 2002; 28: 29-38
• 58 Henn V, Slupsky JR, Grafe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594
• 59 St Pierre J, Yang LY, Tamirisa K. et al. Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs. Arterioscler Thromb Vasc Biol 1999; 19: 2263-2268
• 60 Abraham E. tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000; 28: S31-S33
• 61 Nishida T, Ueno H, Atsuchi N. et al. Adenovirus-mediated local expression of tissue factor pathway inhibitor eliminates shear stress-induced recurrent thrombosis in the injured carotid artery of the rabbit. Circ Res 1999; 84: 1446-1452
• 62 Zoldhelyi P, Chen ZQ, Shelat HS. et al. Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries. Proc Natl Acad Sci USA 2001; 98: 4078-4083
• 63 Amirkhosravi A, Meyer T, Chang JY. et al. Tissue factor pathway inhibitor reduces experimental lung metastasis of B16 melanoma. Thromb Haemost 2002; 87: 930-936
• 64 Donnelly KM, Bromberg ME, Milstone A. et al. Ancylostoma caninum anticoagulant peptide blocks metastasis in vivo and inhibits factor Xa binding to melanoma cells in vitro . Thromb Haemost 1998; 79: 1041-1047
• 65 Amirkhosravi M, Francis JL. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation. Thromb Haemost 1995; 73: 59-65
• 66 Langer F, Amirkhosravi A, Ingersoll SB. et al. Experimental metastasis and primary tumor growth in mice with hemophilia A. J Thromb Haemost 2006; 4: 1056-1062
• 67 Palumbo JS, Kombrinick KW, Drew AF. et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 2000; 96: 3302-3309
• 68 Fischer EG, Riewald M, Huang HY. et al. Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J Clin Invest 1999; 104: 1213-1221
• 69 Lorenzet R, Donati MB. Blood clotting activation, angiogenesis and tumor metastasis: any role for TFPI?. Thromb Haemost 2002; 87: 928-929
• 70 Zacharski LR, Ornstein DL, Mamourian AC. Low-molecular-weight heparin and cancer. Semin Thromb Hemost 2000; 26 (Suppl. 01) 69-77
• 71 Lee AYY, Rickles FR, Julian JA. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-2129
• 72 Mousa SA. Low molecular weight heparins in thrombosis and cancer: emerging links. Cardiovasc Drug Rev 2004; 22: 121-134
• 73 Mousa SA, Linhardt R, Francis J, Amirkhosravi A. Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin. Thromb Haemost 2006; 96: 816-821
• 74 Mousa SA, Mohamed S. Inhibition of endothelial tube formation by the low molecular weight heparin, Tinzaparin, is mediated by tissue factor pathway inhibitor. Thromb Haemost 2004; 92: 627-633
• 75 Miyagi Y, Koshikawa N, Yasumitsu H. et al. cDNA cloning and mRNA expression of a serine proteinase inhibitor secreted by cancer cells: identification as placental protein 5 and tissue factor pathway inhibitor-2. J Biochem (Tokyo) 1994; 116: 939-942
• 76 Sprecher CA, Kisiel W, Mathewes S, Foster DC. Molecular cloning, expression, and partial characterization of a second human tissue factor pathway inhibitor. Proc Natl Acad Sci USA 1994; 91: 3353-3357
• 77 Rao CN, Cook B, Liu Y. et al. HT-1080 fibrosarcoma cell matrix degradation and invasion are inhibited by the matrix-associated serine protease inhibitor TFPI-2/33 kDa MSPI. Int J Cancer 1998; 76: 749-756
• 78 Petersen LC, Spercher CA, Foster DC. et al. Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. Biochemistry 1996; 35: 266-272
• 79 Chand HS, Du X, Ma D. et al. The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice. Blood 2004; 103: 1069-1077
• 80 Ivanciu L, Gerard RD, Tang H. et al. Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesis. Arterioscler Thromb Vasc Biol 2007; 27: 310-316
• 81 Tasiou A, Konduri SD, Yanamandra N. et al. A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignanthuman gliomas. Int J Oncol 2001; 19: 591-597
• 82 Rao CN, Lakka SS, Kin Y. et al. Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. Clin Cancer Res 2001; 7: 570-576
• 83 Konduri SD, Rao CN, Chandrasekar N. et al. A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion. Oncogene 2001; 20: 6938-6945
• 84 Lakka SS, Konduri SD, Mohanam S. et al. In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2. Clin Exp Metastasis 2000; 18: 239-244
• 85 Konduri SD, Tasiou A, Chandrasekar N, Rao JS. Overexpression of tissue factor pathway inhibitor-2 (TFPI-2), decreases the invasiveness of prostate cancer cells in vitro . Int J Oncol 2001; 18: 127-131
• 86 Kondraganti S, Gondi CS, Gujrati M. et al. Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line. Int J Oncol 2006; 29: 25-32