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DOI: 10.1055/s-2007-991532
The Role of Tissue Factor Pathway Inhibitor-2 in Cancer Biology
Publication History
Publication Date:
14 November 2007 (online)
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ABSTRACT
Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type serine proteinase inhibitor family, is a structural homologue of tissue factor pathway inhibitor (TFPI). The expression of TFPI-2 in tumors is inversely related to an increasing degree of malignancy, which may suggest a role for TFPI-2 in the maintenance of tumor stability and inhibition of the growth of neoplasms. TFPI-2 inhibits the tissue factor/factor VIIa (TF/VIIa) complex and a wide variety of serine proteinases including plasmin, plasma kallikrein, factor XIa, trypsin, and chymotrypsin. Aberrant methylation of TFPI-2 promoter cytosine-phosphorothioate-guanine (CpG) islands in human cancers and cancer cell lines was widely documented to be responsible for diminished expression of mRNA encoding TFPI-2 and decreased or inhibited synthesis of TFPI-2 protein during cancer progression. Furthermore, an aberrantly spliced variant of TFPI-2 mRNA (designated asTFPI-2) was detected, which represents an untranslated form of TFPI-2. The levels of asTFPI-2 were very low or undetectable in normal cells but markedly upregulated in neoplastic tissue. TFPI-2 functions in the maintenance of the stability of the tumor environment and inhibits invasiveness and growth of neoplasms, as well as metastases formation. TFPI-2 has also been shown to induce apoptosis and inhibit angiogenesis, which may contribute significantly to tumor growth inhibition. Restoration of TFPI-2 expression in tumor tissue inhibits invasion, tumor growth, and metastasis, which creates a novel possibility of cancer patient treatment. However, more information is still needed to define the precise role of TFPI-2 in human tumor biology.
KEYWORDS
Coagulation inhibitors - TFPI-2 - cancer
REFERENCES
- 1 Sprecher C A, Kisiel W, Mathews S, Foster D C. Molecular cloning, expression, and partial characterization of a second tissue-factor-pathway-inhibitor. Proc Natl Acad Sci USA. 1994; 91 3353-3357
- 2 Broze Jr G J. Tissue factor pathway inhibitor. Thromb Haemost. 1995; 74 90-93
- 3 Peterson L C, Sprecher C A, Foster D C, Blumberg H, Hamamoto T, Kisiel W. Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. Biochemistry. 1996; 35 266-272
- 4 Chand H S, Schmidt A E, Bajaj S P, Kisiel W. Structure-function analysis of the reactive site in the first Kunitz-type domain of human factor pathway inhibitor-2. J Biol Chem. 2004; 279 17500-17507
- 5 Kisiel W, Sprecher C A, Foster D C. Evidence that a second tissue factor pathway inhibitor (TFPI-2) and placental protein 5 are equivalent. Blood. 1994; 84 4384-4385
- 6 Bohn H, Winckler W. Isolierung und Charakterisierung des Plazenta-Proteins PP5. Arch Gynaek. 1977; 223 179-186
- 7 Rao C N, Liu Y Y, Peavey C L, Woodley D T. Novel extracellular matrix-associated serine proteinase inhibitors from human skin fibroblasts. Arch Biochem Biophys. 1995; 317 311-314
- 8 Rao C N, Peavey C L, Liu Y Y, Lapiere J C, Woodley D T. Partial characterization of matrix-associated serine protease inhibitors from human skin cells. J Invest Dermatol. 1995; 104 379-383
- 9 Rao C N, Reddy P, Liu Y et al.. Extracellular matrix-associated serine protease inhibitors (Mr 33,000, 31,000, 27,000) are single-gene products with differential glycosylation: cDNA cloning of the 33-kDa inhibitor reveals its identity to tissue factor pathway inhibitor-2. Arch Biochem Biophys. 1996; 335 82-92
- 10 Siiteri J E, Koistinen H AT, Salem H AT, Bohn H, Seppaelae M. Placental protein 5 is related to blood coagulation and fibrinolytic systems. Life Sci. 1982; 30 1885-1891
- 11 Meisser A, Bischof P, Bohn H. Placental protein 5 (PP5) inhibits thrombin-induced coagulation of fibrinogen. Arch Gynecol. 1985; 236 197-201
- 12 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
- 13 Miyagi Y, Yasumitsu H, Eki T et al.. Assignment of the human PP5/TFPI-2 gene to 7q22 by FISH and PCR-based human/rodent cell hybrid mapping panel analysis. Genomics. 1996; 35 267-268
- 14 Kamei S, Kazama Y, Foster D C, Kisiel W. Genomic structure and promoter activity of the human tissue factor pathway inhibitor-2 gene. Biochim Biophys Acta. 2001; 1517 430-435
- 15 Hubé F, Reverdiau P, Iochmann S, Cherpi-Antar C, Gruel Y. Characterization and functional analysis of TFPI-2 gene promoter in a human choriocarcinoma cell line. Thromb Res. 2003; 109 207-215
- 16 Iino M, Foster D C, Kisiel W. Quantification and characterization of human endothelial cell-derived tissue factor pathway inhibitor-2. Arterioscler Thromb Vasc Biol. 1998; 18 40-46
- 17 Ortego J, Escribano J, Coca-Prados M. Gene expression of proteases and proteases inhibitors in the human ciliary epithelium and ODM-2 cells. Exp Eye Res. 1997; 65 289-299
- 18 Udagawa K, Miyagi Y, Hirahara F et al.. Specific expression of PP5/TFPI-2 mRNA by syncytiotrophoblasts in human placenta as revealed by in situ hybridization. Placenta. 1998; 19 217-223
- 19 Buetzow R, Virtanen I, Seppaelae M et al.. Monoclonal antibodies reacting with placental protein 5: use in radioimmunoassay, Western blot analysis, and immunohistochemistry. J Lab Clin Med. 1988; 111 249-256
- 20 Wahlstroem T, Bohn H, Seppaelae M. Immunohistochemical demonstration of placental protein 5 (PP5) - like material in the seminal vesicles and the ampullar part of vas deferens. Life Sci. 1982; 31 2723-2725
- 21 Wojtukiewicz M Z, Sierko E, Zimnoch L, Kozłowski L, Sulkowski S, Kisiel W. Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue. Thromb Haemost. 2003; 90 140-146
- 22 Ranta T, Siiteri J E, Koistinen R et al.. Human seminal plasma contains a protein that shares physiochemical and immunochemical properties with placental protein 5 from the human placenta. J Clin Endocrinol Metab. 1981; 53 1087-1089
- 23 Seppaelae M, Tenhunen A, Koskimies A I, Wahlstroem T, Koistinen R, Stenmam U H. Hyperstimulated human preovulatory follicular fluid contains placental protein 5 (PP5). Fertil Steril. 1984; 41 62-65
- 24 Rao C N, Lakka S S, 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
- 25 Izumi H, Takahashi C, Oh J, Noda M. Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring activated ras oncogene. FEBS Lett. 2000; 481 31-36
- 26 Rollin J, Régina S, Vourc'h P et al.. Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer. Lung Cancer. 2007; 56 273-280
- 27 Rollin J, Iochmann S, Bléchet C et al.. Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer. Br J Cancer. 2005; 92 775-783
- 28 Sato N, Parker A R, Fukushima N et al.. Epigenetic inactivation of TFPI-2 as a mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene. 2005; 24 850-858
- 29 Wong C M, Ng Y L, Lee J M et al.. Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma. Hepatology. 2007; 45 1129-1138
- 30 Osella P, Carlson A, Wyandt H, Milunsky A. Cytogenetic studies of eight squamous cell carcinomas of the head and neck. Deletion of 7q, a possible primary chromosomal event. Cancer Genet Cytogenet. 1992; 59 73-78
- 31 Atkin N B, Baker M C. Chromosome 7q deletions: observations on 13 malignant tumors. Cancer Genet Cytogenet. 1993; 67 123-125
-
32 Rowley J D, Mitelman F.
Principles of molecular cell biology of cancer: chromosome abnormalities in human cancer and leukemia . In: DeVita VT, Hellman S, Rosenberg SA Cancer. Principles and Practice of Oncology. 4th ed. Philadelphia, PA; JB Lippincott 1993: 67-91 - 33 Saito E, Okamoto A, Saito M et al.. Genes associated with the genesis of leiomyoma of the uterus in a commonly deleted chromosomal region at 7q22. Oncol Rep. 2005; 13 2386-2397
- 34 Dong J T. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev. 2001; 20 171-193
- 35 Sell S M, Tullis C, Stracner D, Song C Y, Gewin J. Minimal interwal defined on 7q in uterine leiomyoma. Cancer Genet Cytogenet. 2005; 157 67-69
- 36 Konduri S D, Osman F A, Rao C N et al.. Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas. Oncogene. 2002; 21 921-928
- 37 Konduri S D, Yanamandra N, Dinh D H et al.. Physiological and chemical inducers of tissue factor pathway inhibitor-2 in human glioma cells. Int J Oncol. 2003; 22 1277-1283
- 38 Nobeyama Y, Okochi-Takada E, Furuta J et al.. Silencing of tissue factor pathway inhibitor-2 gene in malignant melanomas. Int J Cancer. 2007; 121 301-307
- 39 Steiner F A, Hong J A, Fischette M R et al.. Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells. Oncogene. 2005; 23 2386-2397
- 40 Konduri S D, Srivenugopal K S, Yanamandra N et al.. Promoter methylation and silencind of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human gliomas cells. Oncogene. 2003; 22 4509-4516
- 41 Jiang P, Watanabe H, Okada G et al.. Diagnostic utility of aberrant methylation of tissue factor pathway inhibitor 2 in pure pancreatic carcinoma. Cancer Sci. 2006; 97 1267-1272
- 42 Rao C N, Segawa T, Navari J R et al.. Methylation of TFPI-2 gene is not the sole cause of its silencing. Int J Oncol. 2003; 22 843-848
- 43 Kast C, Wang M, Whiteway M. The ERK/MAPK pathway regulates the activity of the human tissue factor pathway inhibitor-2 promoter. J Biol Chem. 2003; 278 6787-6794
- 44 Khosravi-Far R, Campbell S, Rossman K L, Der C J. Increasing complexity of Ras signal transduction: involvement of Rho family proteins. Adv Cancer Res. 1998; 72 57-107
- 45 Shapiro P. Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy. Crit Rev Clin Lab Sci. 2002; 39 285-330
- 46 Sivaraman V S, Wang H, Nuovo G J, Malbon C C. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest. 1997; 99 1478-1483
- 47 Oka H, Chatani Y, Hoshino R et al.. Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res. 1995; 55 4182-4187
- 48 Kempaiah P, Chand H S, Kisiel W. Identification of a human TFPI-2 slice variant that is upregulated in human tumor tissue. Mol Cancer. 2007; 6 20-31
- 49 Torres-Collado A X, Kisiel W, Iruela-Arispe M L, Rodriguez-Manzaneque J C. ADAMTS1 interacts with, cleaves, and modifies the extracellular location of the matrix inhibitor tissue factor pathway inhibitor-2. J Biol Chem. 2006; 28 17827-17837
- 50 Mochizuki S, Okada Y. ADAMs in cancer cell proliferation and progression. Cancer Sci. 2007; 98 621-628
- 51 Jin M, Udagawa K, Miyagi E et al.. Expression of serine proteinase inhibitor PP5/TFPI-2/MSPI decreases the invasive potential of human choriocarcinoma cells in vitro and in vivo. Gynecol Oncol. 2001; 83 325-333
- 52 Lakka S S, Konduri S D, Mohanam S, Nicolson G L, Rao J S. 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
- 53 Konduri S D, Rao C N, Chandrasekar N et al.. A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion. Oncogene. 2001; 20 6938-6945
- 54 Rao C N, 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
- 55 Konduri S D, Tasiou A, Chandrasekar N, Rao J S. Overexpression of tissue factor pathway inhibitor-2 (TFPI-2) decreases the invasiveness of prostate cancer cells in vitro. Int J Cancer. 2001; 18 127-131
- 56 Konduri S D, Tasiou A, Chandrasekar N, Nicolson G L, Rao J S. Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion. Clin Exp Metastasis. 2000; 18 303-308
- 57 Carroll V, Binder B. The role of the plasminogen activation system in cancer. Semin Thromb Hemost. 1999; 25 183-197
- 58 Siiteri J E, Koistinen H AT, Salem H AT, Bohn H, Seppaelae M. Placental protein 5 is related to blood coagulation and fibrinolytic systems. Life Sci. 1982; 30 1885-1891
- 59 Rao C N, Mohanam S, Puppala A, Rao J S. Regulation of pro-MMP-1 and pro-MMP-3 activation by tissue factor pathway inhibitor-2/matrix associated serine protease inhibitor. Biochem Biophys Res Commun. 1999; 255 94-98
- 60 Herman M P, Sukhova G K, Kisiel W et al.. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. J Clin Invest. 2001; 107 1117-1126
- 61 Du X, Chand H S, Kisiel W. Human tissue factor pathway inhibitor-2 does not bind or inhibit activated matrix metalloproteinase-1. Biochim Biophys Acta. 2003; 162 242-245
- 62 Kondraganti S, Gondi C S, Gujrati M et al.. Restoration of tissue factor patway inhibitor inhibits invasion and trumor growth in vitro and in vivo a malignant meningioma cell line. Int J Oncol. 2006; 29 25-32
- 63 Sun Y, Xie M, Liu M, Jin D, Li P. Growth suppression of human laryngeal squamous cell carcinoma by adenovirus-mediated tissue factor pathway inhibitor gene 2. Laryngoscope. 2006; 116 596-601
- 64 Neaud V, Hisaka T, Monvoisin A et al.. Paradoxical pro-invasive effect of the serine proteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells. J Biol Chem. 2000; 275 35565-35569
- 65 Tasiou A, Konduri S D, Yanamandra N et al.. A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas. Int J Cancer. 2001; 19 591-597
- 66 George J, Gondi C S, Dinh D H, Gujrati M, Rao J S. Restoration of tissue factor patway inhibitor-2 in a human glioblastoma cell line triggers caspase-mediated pathway and apoptosis. Clin Cancer Res. 2007; 13 3507-3517
- 67 Zacharski L R, Wojtukiewicz M Z, Costantini V, Ornstein D L, Memoli V A. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost. 1992; 18 104-116
- 68 Hillen H FP. Thrombosis in cancer patients. Ann Oncol. 2000; 11(Suppl. 3) 273-276
- 69 Wojtukiewicz M Z, Rucinska M, Zacharski R R et al.. Localization of blood coagulation factors in situ in pancreatic carcinoma. Thromb Haemost. 2001; 86 1416-1420
- 70 Wojtukiewicz M Z, Rucińska M, Zimnoch L et al.. Expression of prothrombin fragment 1 + 2 in cancer tissue as an indicator of local activation of blood coagulation. Thromb Res. 2000; 97 335-342
- 71 Shoji M, Hancock W W, Abe K et al.. Activation of blood coagulation and angiogenesis in cancer. Am J Pathol. 1998; 152 399-411
- 72 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Indirect activation of blood coagulation in colon cancer. Thromb Haemost. 1989; 62 1062-1066
- 73 Wojtukiewicz M Z, Zacharski L R, Rucińska M et al.. Expression of tissue factor and tissue factor pathway inhibitor in situ in laryngeal carcinoma. Thromb Haemost. 1999; 82 1659-1662
- 74 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Fibrinogen-fibrin transformation in situ in renal cell carcinoma. Anticancer Res. 1990; 10 579-582
- 75 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer. 1990; 65 481-485
- 76 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ. Am J Clin Pathol. 1990; 93 516-521
- 77 Wojtukiewicz M Z, Tang T G, Ben-Josef E, Renaud C, Walz D A, Honn K V. Solid tumor cells express functional “tethered ligand” thrombin receptor. Cancer Res. 1995; 55 698-704
- 78 Wojtukiewicz M Z, Tang T G, Ciarelli J J et al.. Thrombin increases the metastatic potential of tumor cell. Int J Cancer. 1993; 54 793-806
- 79 Wojtukiewicz M Z, Tang T G, Nelson K K, Walz D A, Diglio C A, Honn K V. Thrombin enhances tumor cell adhesive and metastatic properties via increased αIIbß3 expression on the cell surface. Thromb Res. 1992; 68 233-245
- 80 Even-Ram S, Uziely B. Cohen P met al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med. 1998; 4 909-914
- 81 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med. 1995; 1 27-31
- 82 Rao L VM. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev. 1992; 11 249-266
- 83 Tsopanoglou N E, Maragoudakis M E. On the mechanism of thrombin-induced angiogenesis. J Biol Chem. 1999; 274 23969-23976
- 84 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
- 85 Neaud V, Duplantier J G, Mazzocco C, Kisiel W. Thrombin up-regulates tissue factor pathway inhibitor-2 synthesis through a cyclogenase-2-dependent, epidermal growth factor receptor-independent mechanism. J Biol Chem. 2004; 279 5200-5206
- 86 Yanamandra N, Kondraganti S, Gondi C S et al.. Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line. Int J Cancer. 2005; 115 998-1005
- 87 Ivanciu L, Gerard R D, Tang H, Lupu F, Lupu C. Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesis. Arterioscler Thromb Vasc Biol. 2007; 27 310-316
- 88 Xu Z, Maiti D, Kisiel W, Duh E L. Tissue factor pathway inhibitor-2 is up-regulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells. Arterioscler Thromb Vasc Biol. 2006; 26 2819-2825
- 89 Ruf W, Seftor E, Petrovan R J et al.. Differential role of tissue factor pathway inhibitor 1 and 2 in melanoma vasculogenic mimicry. Cancer Res. 2003; 63 5381-5389
- 90 Liu C, Huang H, Donate F et al.. Prostate-specific membrane antigen directed selective thrombotic infarction of tumors. Cancer Res. 2002; 62 560-566
- 91 Shirakawa K, Tsuda H, Heike Y et al.. Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res. 2001; 61 445-451
- 92 Pezzella F. Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Lancet. 2000; 355 1787-1800
- 93 Sood A K, Seftor E A, Fletcher M S et al.. Molecular determinants of ovarian cancer plasticity. Am J Pathol. 2001; 158 1279-1288
- 94 Sharma N, Seftor R EB, Seftor E A et al.. Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate. 2002; 50 189-201
- 95 Passalidou E, Trivella M, Singh N et al.. Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br J Cancer. 2002; 86 244-249
- 96 Ruf W, Seftor E A, Petrovan R J et al.. Differential role of tissue factor pathway inhibitors 1 and 2 in melanoma vasculogenic mimicry. Cancer Res. 2003; 63 5381-5389
- 97 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient. Semin Thromb Hemost. 1999; 25 173-182
Dr. Marek Z Wojtukiewicz
Department of Oncology, Medical University
12 Ogrodowa St., 15-027 Bialystok, Poland
Email: m.wojtukiewicz@neostrada.pl