Oncogenes as Regulators of Tissue Factor Expression in Cancer: Implications for Tumor Angiogenesis and Anti-Cancer Therapy

Up-regulation of tissue factor (TF) is often observed in cancer. TF is a cell-associated receptor for coagulation factor VII/VIIa, an interaction known to activate the coagulation cascade. At the same time, TF is also known as a mediator of intracellular signaling events that can alter gene expression patterns and cell behavior. Both aspects of TF activity are of possible relevance to tumor growth, metastasis, and angiogenesis, including up-regulation of vascular endothelial growth factor (VEGF). TF up-regulation is often observed on the surfaces of tumor-associated endothelial cells, inflammatory cells, and particularly on cancer cells themselves. In the last case, high TF levels may be associated with poor prognosis and parallel clinical (and genetic) tumor progression. We have proposed elsewhere that TF may be a target of oncogenic events in cancer. Here we discuss our observations suggesting that oncogene-targeting agents may down-regulate TF expression. Such is the effect of treatment with the neutralizing monoclonal antibody (C225) raised against the epidermal growth factor receptor (EGFR) in EGFR-dependent squamous cell carcinoma cells (A431). This two- to threefold TF down-regulation by C225 treatment is paralleled by a decrease in expression of VEGF. It is conceivable that TF participates in signals that regulate VEGF and angiogenesis triggered by activated oncogenic pathways. Therefore, direct targeting of TF in cancer should be considered in combination with other treatment modalities such as oncogene-directed therapies, antiangiogenic agents (e.g., VEGF antagonists), and anti-cancer chemotherapy.

Tissue factor - cancer - angiogenesis - oncogenes - EGFR

REFERENCES

• 1 Fearon E R, Vogelstein B. A genetic model for colorectal tumorigenesis.  Cell. 1990;  61 759-767
• 2 Done S, Squire J A. Genetic basis of cancer progression. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 3-18
• 3 McCormick F. Signal transduction networks. Ras as a paradigm. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 35-46
• 4 Holland E C. The interplay between tumor suppressor genes and oncogenes in tumorigenesis. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 101-112
• 5 Hahn W C, Counter C M, Lundberg A S, Beijersbergen R L, Brooks M W, Weinberg R A. Creation of human tumour cells with defined genetic elements.  Nature. 1999;  400 464-468
• 6 Hanahan D, Weinberg R A. The hallmarks of cancer.  Cell. 2000;  100 57-70
• 7 Folkman J. Tumor angiogenesis. In: Holland JF, Bast RC, Morton DL, Frei E, Kufe DW, Weichselbaum RR Cancer Medicine. Baltimore; Williams & Wilkins 1997: 181-204
• 8 Trousseau A. Phlegmasia alba dolens. In: Clinique Medicale de l'Hôtel-Dieu de Paris. London; The New Sydenham Society 1865: 94-96
• 9 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem. 2000;  275 1521-1524
• 10 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy.  Neoplasia. 2001;  3 371-384
• 11 Folkman J. What is the evidence that tumors are angiogenesis-dependent?.  J Natl Cancer Inst. 1990;  82 4-6
• 12 Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease.  Cancer Cell. 2002;  1 219-227
• 13 Rak J, Filmus J, Kerbel R S. Reciprocal paracrine interactions between tumor cells and endothelial cells. The “angiogenesis progression” hypothesis.  Eur J Cancer. 1996;  32A 2438-2450
• 14 Hamada J, Cavanaugh P G, Miki K, Nicolson G L. A paracrine migration-stimulating factor for metastatic tumor cells secreted by mouse hepatic sinusoidal endothelial cells: identification as complement component C3b.  Cancer Res. 1993;  53 4418-4423
• 15 Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig N E. Halting angiogenesis suppresses carcinoma cell invasion.  Nat Med. 1997;  3 1222-1227
• 16 Brooks P C, Stromblad S, Klemke R, Visscher D, Sarkar F H, Cheresh D A. Antiintegrin αbβ3 blocks human breast cancer growth and angiogenesis in human skin.  J Clin Invest. 1995;  96 1815-1822
• 17 Nicosia R F, Tchao R, Leighton J. Angiogenesis-dependent tumor spread in reinforced fibrin clot culture.  Cancer Res. 1983;  43 2159-2166
• 18 Rak J W, Hegmann E J, Lu C, Kerbel R S. Progressive loss of sensitivity to endothelium-derived growth inhibitors expressed by human melanoma cells during disease progression.  J Cell Physiol. 1994;  159 245-255
• 19 Folkman J. Tumor angiogenesis.  Adv Cancer Res. 1985;  43 175-203
• 20 Holash J, Maisonpierre P C, Compton D et al.. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.  Science. 1999;  284 1994-1998
• 21 Rak J, Kerbel R S. Oncogenes and tumor angiogenesis. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 171-218
• 22 Bouck N, Stellmach V, Hsu S C. How tumors become angiogenic.  Adv Cancer Res. 1996;  69 135-174
• 23 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.  Cell. 1996;  86 353-364
• 24 Nash G F, Walsh D C, Kakkar A K. The role of the coagulation system in tumour angiogenesis.  Lancet Oncol. 2001;  2 608-613
• 25 O'Reilly M S, Pirie-Shepherd S, Lane W S, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin.  Science. 1999;  285 1926-1928
• 26 Cao Y. Endogenous angiogenesis inhibitors and their therapeutic implications.  Int J Biochem Cell Biol. 2001;  33 357-369
• 27 Gimbrone M, Leapman S, Cotran R, Folkman J. Tumor dormancy in vivo by prevention of neovascularization.  J Exp Med. 1972;  136 261-276
• 28 Holmgren L, O'Reilly M S, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.  Nat Med. 1995;  1 149-153
• 29 Hanahan D. Signaling vascular morphogenesis and maintenance.  Science. 1997;  277 48-50
• 30 Rak J, Kerbel R S. Prospects and progress in the development of anti-angiogenic agents. In: Rosenberg SA Principles and Practice of Biologic Therapy of Cancer-Updates 3[3]. New York; Lippincott, Williams & Wilkins 2002: 1-13
• 31 Yancopoulos G D, Davis S, Gale N W, Rudge J S, Wiegand S J, Holash J. Vascular-specific growth factors and blood vessel formation.  Nature. 2000;  407 242-248
• 32 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis.  Nat Med. 2000;  6 389-395
• 33 Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases.  Nature. 2000;  407 249-257
• 34 Folkman J, D'Amore P A. Blood vessel formation: what is its molecular basis?.  Cell. 1996;  87 1153-1155
• 35 LeCouter J, Kowalski J, Foster J et al.. Identification of an angiogenic mitogen selective for endocrine gland endothelium.  Nature. 2001;  412 877-884
• 36 Ferrara N, Gerber H P. The role of vascular endothelial growth factor in angiogenesis.  Acta Haematol. 2001;  106 148-156
• 37 LeCouter J, Lin R, Ferrara N. Endocrine gland-derived VEGF and the emerging hypothesis of organ-specific regulation of angiogenesis.  Nat Med. 2002;  8 913-917
• 38 Jones N, Iljin K, Dumont D J, Alitalo K. Tie receptors: new modulators of angiogenic and lymphangiogenic responses.  Nat Rev Mol Cell Biol. 2001;  2 257-267
• 39 Wang H U, Chen Z F, Anderson D J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4.  Cell. 1998;  93 741-753
• 40 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis [review].  Am J Pathol. 1995;  146 1029-1039
• 41 Ferrara N. VEGF and the quest for tumour angiogenesis factors.  Nat Rev Cancer. 2002;  2 795-803
• 42 Senger D R, Galli S, Dvorak A M, Perruzzi C A, Harvey V S, Dvorak H F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.  Science. 1983;  219 983-985
• 43 Leung D W, Cachianes G, Kuang W J, Goeddel D V, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen.  Science. 1989;  246 1306-1309
• 44 Ferrara N, Carver-Moore K, Chen H et al.. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.  Nature. 1996;  380 439-442
• 45 Carmeliet P, Ferreira V, Breier G et al.. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.  Nature. 1996;  380 435-439
• 46 Fong G H, Rossant J, Gertsenstein M, Breitman M L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.  Nature. 1995;  376 66-70
• 47 Shalaby F, Rossant J, Yamaguchi T P et al.. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.  Nature. 1995;  376 62-66
• 48 Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.  Nat Med. 1995;  1 1024-1028
• 49 Watanabe Y, Lee S W, Detmar M, Ajioka I, Dvorak H F. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells.  Oncogene. 1997;  14 2025-2032
• 50 Asahara T, Takahashi T, Masuda H et al.. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.  EMBO J. 1999;  18 3964-3972
• 51 Hattori K, Dias S, Heissig B et al.. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells.  J Exp Med. 2001;  193 1005-1014
• 52 Pettersson A, Nagy J A, Brown L F et al.. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor.  Lab Invest. 2000;  80 99-115
• 53 Jain R K. Transport of molecules in the tumor interstitium: a review.  Cancer Res. 1987;  47 3039-3051
• 54 Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications.  Semin Oncol. 2002;  29 10-14
• 55 Ollivier V, Chabbat J, Herbert J M, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa.  Arterioscler Thromb Vasc Biol. 2000;  20 1374-1381
• 56 Bergers G, Brekken R, McMahon G et al.. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.  Nat Cell Biol. 2000;  2 737-744
• 57 Rak J, Mitsuhashi Y, Bayko L, Filmus J, Sasazuki T, Kerbel R S. Mutant ras oncogenes up-regulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.  Cancer Res. 1995;  55 4575-4580
• 58 Viloria-Petit A M, Rak J, Hung M-C, Rockwell P, Goldstein N, Kerbel R S. Neutralizing antibodies against EGF and ErbB-2/neu receptor tyrosine kinases down-regulate VEGF production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.  Am J Pathol. 1997;  151 1523-1530
• 59 Feldkamp M M, Lau N, Rak J, Kerbel R S, Guha A. Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras.  Int J Cancer. 1999;  81 118-124
• 60 Rak J, Mitsuhashi Y, Sheehan C et al.. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts.  Cancer Res. 2000;  60 490-498
• 61 Viloria-Petit A, Crombet T, Jothy S et al.. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis.  Cancer Res. 2001;  61 5090-5101
• 62 Rak J, Yu J L, Klement G, Kerbel R S. Oncogenes and angiogenesis: signaling three-dimensional tumor growth.  J Investig Dermatol Symp Proc. 2000;  5 24-33
• 63 Mazure N M, Chen E Y, Laderoute K R, Giaccia A J. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element.  Blood. 1997;  90 3322-3331
• 64 Sodhi A, Montaner S, Miyazaki H, Gutkind J S. MAPK and Akt act cooperatively but independently on hypoxia inducible factor-1 alpha in rasV12 up-regulation of VEGF.  Biochem Biophys Res Commun. 2001;  287 292-300
• 65 Maity A, Pore N, Lee J, Solomon D, O'Rourke D M. Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3′-kinase and distinct from that induced by hypoxia.  Cancer Res. 2000;  60 5879-5886
• 66 Semenza G L. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression.  Crit Rev Biochem Mol Biol. 2000;  35 71-103
• 67 Dvorak H F, Dvorak A M, Manseau E J, Wiberg L, Churchill W H. Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression.  J Natl Cancer Inst. 1979;  62 1459-1472
• 68 Palumbo J S, Kombrinck K W, Drew A F et al.. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.  Blood. 2000;  96 3302-3309
• 69 Dvorak F H. Abnormalities of hemostasis in malignant disease. In: Coleman RB, Hirsh J, Marder VJ, Salzman JB Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia; Lippincott Co 1994: 1238-1254
• 70 Rickles F R, Shoji M, Abe K. The role of the hemostatic system in tumor growth, metastasis, and angiogenesis: tissue factor is a bifunctional molecule capable of inducing both fibrin deposition and angiogenesis in cancer.  Int J Hematol. 2001;  73 145-150
• 71 Mackman N. Gene targeting in hemostasis. Tissue factor.  Front Biosci. 2001;  6 D208-D215
• 72 Fernandez P M, Rickles F R. Tissue factor and angiogenesis in cancer.  Curr Opin Hematol. 2002;  9 401-406
• 73 Morrissey J H. Tissue factor: an enzyme cofactor and a true receptor.  Thromb Haemost. 2001;  86 66-74
• 74 Kaplan R, DeLa Cadena R A. Mechanism of the coagulopathy associated with acute promyelocytic leukemia-clinical conference.  Am J Hematol. 1998;  59 234-237
• 75 Lee A Y. Cancer and thromboembolic disease: pathogenic mechanisms.  Cancer Treat Rev. 2002;  28 137-140
• 76 Rickles F R, Levine M N. Epidemiology of thrombosis in cancer.  Acta Haematol. 2001;  106 6-12
• 77 Levine M. Thromboembolic risk of tamoxifen in patients with stage II breast cancer.  J Clin Oncol. 1989;  7 1579-1580
• 78 Levine M N, Gent M, Hirsh J et al.. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer.  N Engl J Med. 1988;  318 404-407
• 79 Kuenen B C, Levi M, Meijers J C et al.. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients.  Arterioscler Thromb Vasc Biol. 2002;  22 1500-1505
• 80 Kuenen B C, Rosen L, Smit E F et al.. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.  J Clin Oncol. 2002;  20 1657-1667
• 81 Zacharski L R, Costantini V, Wojtukiewicz M Z, Memoli V A, Kudryk B J. Anticoagulants as cancer therapy.  Semin Oncol. 1990;  17 217-227
• 82 Thodiyil P, Kakkar A K. Can low-molecular-weight heparins improve outcome in patients with cancer?.  Cancer Treat Rev. 2002;  28 151-155
• 83 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease.  Nat Med. 1996;  2 209-215
• 84 Shoji M, Hancock W W, Abe K et al.. Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.  Am J Pathol. 1998;  152 399-411
• 85 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
• 86 Ruf W, Mueller B M. Tissue factor in cancer angiogenesis and metastasis.  Curr Opin Hematol. 1996;  3 379-384
• 87 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
• 88 Chen J, Bierhaus A, Schiekofer S et al.. Tissue factor-a receptor involved in the control of cellular properties, including angiogenesis.  Thromb Haemost. 2001;  86 334-345
• 89 Mackman N, Morrissey J H, Fowler B, Edgington T S. Complete sequence of the human tissue factor gene, a highly regulated cellular receptor that initiates the coagulation protease cascade.  Biochemistry. 1989;  28 1755-1762
• 90 Giesen P L, Rauch U, Bohrmann B et al.. Blood-borne tissue factor: another view of thrombosis.  Proc Natl Acad Sci USA. 1999;  96 2311-2315
• 91 Colman R W, Marder V J, Salzman E W, Hirsh J. Overview of Hemostasis. In: Coleman RB, Hirsh J, Marder VJ, Salzman JB Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia; Lippincott Co 1994: 3-18
• 92 Rak J, Klement G. Impact of oncogenes and tumor suppressor genes on deregulation of hemostasis and angiogenesis in cancer.  Cancer Metastasis Rev. 2000;  19 93-96
• 93 Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration.  Br J Cancer. 2000;  83 164-170
• 94 Sawada M, Miyake 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
• 95 Kakkar A K, Lemoine N R, Scully M F, Tebbutt S, Williamson R C. Tissue factor expression correlates with histological grade in human pancreatic cancer.  Br J Surg. 1995;  82 1101-1104
• 96 Koomagi R, Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis.  Int J Cancer. 1998;  79 19-22
• 97 Seto S, Onodera H, Kaido T et al.. Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis.  Cancer. 2000;  88 295-301
• 98 Shigemori C, Wada H, Matsumoto K, Shiku H, Nakamura S, Suzuki H. Tissue factor expression and metastatic potential of colorectal cancer.  Thromb Haemost. 1998;  80 894-898
• 99 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
• 100 Mueller B M, Reisfeld R A, Edgington T S, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis.  Proc Natl Acad Sci USA. 1992;  89 11832-11836
• 101 Francis J L, Amirkhosravi A. Effect of antihemostatic agents on experimental tumor dissemination.  Semin Thromb Hemost. 2002;  28 29-38
• 102 Bromberg M E, Sundaram R, Homer R J, Garen A, Konigsberg W H. Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule.  Thromb Haemost. 1999;  82 88-92
• 103 Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca²⁺ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.  J Biol Chem. 1995;  270 4650-4660
• 104 Rottingen J A, Camerer E, Mathiesen I, Prydz H, Iversen J G. Synchronized Ca²⁺ oscillations induced in Madin Darby canine kidney cells by bradykinin and thrombin but not by ATP.  Cell Calcium. 1997;  21 195-211
• 105 Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression.  J Biol Chem. 2000;  275 6580-6585
• 106 Prydz H, Camerer E, Rottingen J A, Wiiger M T, Gjernes E. Cellular consequences of the initiation of blood coagulation.  Thromb Haemost. 1999;  82 183-192
• 107 Camerer E, Rottingen J A, Iversen J G, Prydz H. Coagulation factors VII and X induce Ca²⁺ oscillations in Madin-Darby canine kidney cells only when proteolytically active.  J Biol Chem. 1996;  271 29034-29042
• 108 Camerer E, Rottingen J A, Gjernes E et al.. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene.  J Biol Chem. 1999;  274 32225-32233
• 109 Herbert J M, de Prost D, Ollivier V, Melis E, Carmeliet P. Tissue factor is not involved in the mitogenic activity of factor VIIa.  Biochem Biophys Res Commun. 2001;  281 1074-1077
• 110 Contrino J, Goralnick S, Qi J, Hair G, Rickles F R, Kreutzer D L. Fibrin induction of tissue factor expression in human vascular endothelial cells.  Circulation. 1997;  96 605-613
• 111 Jahner D, Hunter T. The stimulation of quiescent rat fibroblasts by v-src and v-fps oncogenic protein-tyrosine kinases leads to the induction of a subset of immediate early genes.  Oncogene. 1991;  6 1259-1268
• 112 Mackman N. Regulation of the tissue factor gene.  Thromb Haemost. 1997;  78 747-754
• 113 Carson S D, Bromberg M E. Tissue factor encryption/de-encryption is not altered in the absence of the cytoplasmic domain.  Thromb Haemost. 2000;  84 657-663
• 114 Wolberg A S, Kon R H, Monroe D M, Ezban M, Roberts H R, Hoffman M. De-encryption of cellular tissue factor is independent of its cytoplasmic domain.  Biochem Biophys Res Commun. 2000;  272 332-336
• 115 Ollivier V, Bentolila S, Chabbat J, Hakim J, de Prost D. Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.  Blood. 1998;  91 2698-2703
• 116 Pandolfi P P. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia.  Hum Mol Genet. 2001;  10 769-775
• 117 Koyama T, Hirosawa S, Kawamata N, Tohda S, Aoki N. All-trans retinoic acid up-regulates thrombomodulin and down-regulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells.  Blood. 1994;  84 3001-3009
• 118 Lopez-Pedrera C, Dobado-Berrios P M, Ros R et al.. Signal transduction pathways underlying the expression of tissue factor and thrombomodulin in promyelocytic cells induced to differentiate by retinoid acid and dibutyryl cAMP.  Thromb Haemost. 2001;  85 1031-1036
• 119 Kini A R, Peterson L C, Tallman M S, Lingen M W. Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid.  Blood. 2001;  97 3919-3924
• 120 Fletcher L. Approval heralds new generation of kinase inhibitors?.  Nat Biotechnol. 2001;  19 599-600
• 121 Konecny G E, Arboleda J, Slamon D, Pegram M. Inhibition of the HER-2 oncogene: A translational research model for the development of future targeted therapies. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 331-352
• 122 Lin E H, Abbruzzese J. Clinical evaluation of agents targeting epidermal growth factor receptor (EGFR) in cancer. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 313-330
• 123 Cox A D. Farnesyltransferase inhibitors as anticancer agents. In: Rak J Oncogene-Directed Therapies. Totowa, NJ; Humana Press 2003: 353-362
• 124 Bykov V J, Issaeva N, Shilov A et al.. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.  Nat Med. 2002;  8 282-288
• 125 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 oncogenes.  FEBS Lett. 2000;  481 31-36
• 126 Lengyel E, Ried S, Heiss M M, Jager C, Schmitt M, Allgayer H. Ras regulation of urokinase-type plasminogen activator.  Methods Enzymol. 2001;  333 105-116