Inhibition of angiogenesis has progressed from a theoretical and esoteric discipline scrutinized in but a few laboratories far removed from the clinic, to mainstream experimental clinical cancer therapeutics. Dramatic progress in this field represents a triumph of the concept of translational biomedical research. Growth of knowledge in this discipline has brought to light a bewildering yet tantalizing array of interacting enzymatic algorithms that participate in the highly orchestrated process of new blood vessel formation critical for tumor growth and dissemination. It is clear that pathways of blood coagulation (in broad context) and angiogenesis are inextricably linked. The facts that much is already known about many components of these pathways and that stalling of tumor growth has already been demonstrated for several interventions aimed at participants in these reactions send a clear signal that more effective and less toxic cancer therapy may be at hand in the near future. There is no lack of candidate targets for intervention brought to light by preclinical scientists. Numerous well-characterized investigational agents are on hand for testing. The challenge is clearly in the hands of the clinical investigators to proceed with human intervention studies while armed with knowledge of opportunities and pitfalls that should guide insightful clinical trial design. A particularly compelling feature of this treatment paradigm is that it is not aimed directly at distruction of tumor through inhibition of the DNA replication machinery of the cell. Rather it is aimed at restoring the normal state by modulating the dysregulated interaction of tumor cells with their environment that is characteristic of cancer.
KEYWORDS
Cancer - hemostasis - angiogenesis - cancer therapy - angiogenesis inhibitors
REFERENCES
-
1
Folkman J.
Tumor angiogenesis: therapeutic implications.
N Engl J Med.
1971;
285
1182-1186
-
2
Folkman J, Browder T, Palmblad J.
Angiogenesis research: guidelines for translation to the clinic.
Thromb Haemost.
2001;
86
23-33
-
3
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
-
4
Dvorak H F.
Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.
J Clin Oncol.
2002;
20
4368-4380
-
5
Lyden D, Hattori K, Dias S et al..
Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.
Nat Med.
2001;
7
1194-1201
-
6
Rak J W, St Croix B D, Kerbel R S.
Consequences of angiogenesis for tumor progression, metastasis and cancer therapy.
Anticancer Drugs.
1995;
6
3-18
-
7
Wojtukiewicz M Z, Sierko E, Klement P, Rak J.
The hemostatic system and angiogenesis in malignancy.
Neoplasia.
2001;
3
371-384
-
8
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
-
9
O'Reilly M S, Boehm T, Shing Y et al..
Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
Cell.
1997;
88
277-285
-
10
Dameron K M, Volpert O V, Tainsky M A, Bouck N.
Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1.
Science.
1994;
265
1582-1584
-
11
Kerbel R S.
Inhibition of tumor angiogenesis as a strategy to circumvent resistance to anticancer therapeutic agents.
Bioessays.
1991;
13
31-36
-
12
Boehm T, Folkman J, Browder T, O'Reilly M S.
Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.
Nature.
1997;
390
404-407
-
13
Yang J C, Haworth L, Sherry R M et al..
A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.
N Engl J Med.
2003;
349
427-434
-
14
Kuenen B C, Tabernero J, Baselga J et al..
Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma.
Clin Cancer Res.
2003;
9
1648-1655
-
15
Albanell J, Codony J, Rovira A et al..
Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4.
Adv Exp Med Biol.
2003;
532
253-268
-
16 Hurwitz H, Fehrenbacher L, Cartwright T et al.. Bevacizumab (Avastin, a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. In: Program and abstracts of the 39th Annual Meeting of the American Society of Clinical Oncology; May 31-June 3, 2003; Chicago, IL;
-
17 Burstein H J, Parker L M, Savoie J et al.. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. In: Program and abstracts of the 25th Annual San Antonio Breast Cancer Symposium; December 11-14, 2002; San Antonio, TX;
-
18
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
-
19
Relf M, LeJeune S, Scott P A et al..
Expression of the angiogenic factors vascular endothelial growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.
Cancer Res.
1997;
57
963-969
-
20
Yu J L, Rak J W, Carmeliet P, Nagy A, Kerbel R S, Coomber B L.
Heterogeneous vascular dependence of tumor cell populations.
Am J Pathol.
2001;
158
1325-1334
-
21
Kerbel R S, Yu J, Tran J et al..
Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches.
Cancer Metastasis Rev.
2001;
20
79-86
-
22
Kerbel R S, Viloria-Petit A, Klement G, Rak J.
‘Accidental’ anti-angiogenic drugs, anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples.
Eur J Cancer.
2000;
36
1248-1257
-
23
Hahnfeldt P, Folkman J, Hlatky L.
Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis.
J Theor Biol.
2003;
220
545-554
-
24
Cao Y.
Endogenous angiogenesis inhibitors: angiostatin, endostatin and other proteolytic fragments.
Prog Mol Subcell Biol.
1998;
20
161-176
-
25
O'Reilly M S, Holmgren L, Shing Y et al..
Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by Lewis lung carcinoma.
Cell.
1994;
79
315-328
-
26
Jung S P, Siegrist B, Hornick C A et al..
Effect of human recombinant Endostatin protein on human angiogenesis.
Angiogenesis.
2002;
5
111-118
-
27
O'Reilly M S, Holmgreen L, Chen C, Folkman J.
Angiostatin induces and sustains dormancy of human primary tumors in mice.
Nat Med.
1996;
2
689-692
-
28
Soff G A, Hong J, Fishman D et al..
Angiostatin 4.5′: a naturally occurring human angiogenesis inhibitor.
Blood.
1998;
92(suppl)
174a
, (abst)
-
29
Cao R, Wu H L, Veitonmaki N et al..
Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis.
Proc Natl Acad Sci USA.
1999;
96
5728-5733
-
30
Cao Y.
Therapeutic potentials of angiostatin in the treatment of cancer.
Haematologica.
1999;
84
643-650
-
31
Prox D, Becker C, Pirie-Shepard S R, Celik I, Folkman J, Kisker O.
Treatment of human pancreatic cancer in mice with angiogenic inhibitors.
World J Surg.
2003;
27
405-411
-
32
Folkman J.
Role of angiogenesis in tumor and metastasis.
Semin Oncol.
2002;
29
15-18
-
33
Galaup A, Opolon P, Bouquet C et al..
Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model.
Mol Ther.
2003;
7
731-740
-
34
Mauceri H J, Seetharam S, Beckett M A et al..
Angiostatin potentiates cyclophosphamide treatment of metastatic disease.
Cancer Chemother Pharmacol.
2002;
50
412-418
-
35
Camhausen K, Moses M A, Beecken W D, Khan M K, Folkman J, O'Reilly M S.
Radiation therapy to a primary tumor accelerates metastatic growth in mice.
Cancer Res.
2001;
61
2207-2211
-
36
Mauceri H J, Hanna N N, Beckett M A et al..
Combined effects of angiostatin and ionizing radiation in antitumor therapy.
Nature.
1998;
394
287-291
-
37
Gorski D H, Mauceri H J, Salloum R M et al..
Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin.
Cancer Res.
1998;
58
5686-5689
-
38
Sim B KL, MacDonald N J, Gubish E R.
Angiostatin and endostatin: endogenous inhibitors of tumor growth.
Cancer Metastasis Rev.
2000;
19
181-190
-
39
Mundhenke C, Thomas J P, Wilding G et al..
Tissue examination to monitor antiangiogenic therapy: a phase I trial with endostatin.
Clin Cancer Res.
2001;
7
3366-3374
-
40
Eder Jr J P, Supko J G, Clark J W et al..
Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.
J Clin Oncol.
2002;
20
3772-3784
-
41
Feldman A L, Libutti S K.
Progress in antiangiogenic gene therapy of cancer.
Cancer.
2000;
89
1181-1194
-
42
Matsuda K M, Madoiwa S, Hasumi Y et al..
A novel strategy for the tumor angiogenesis-targeted gene therapy: generation of angiostatin from endogenous plasminogen by protease gene transfer.
Cancer Gene Ther.
2000;
7
589-596
-
43
Gorrin-Rivas M J, Arii S, Furutani M et al..
Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis.
Clin Cancer Res.
2000;
6
1647-1654
-
44
Browder T, Folkman J, Pirie-Shepherd S.
The hemostatic system as regulator of angiogenesis.
J Biol Chem.
2000;
275
1521-1524
-
45
Lee T H, RhimTH, Kim S S.
Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells.
J Biol Chem.
1998;
273
28805-28812
-
46
Rhim T H, Park C S, Kim E, Kim S S.
Human prothrombin fragment 1 and 2 inhibit bFGF-induced BCE cell growth.
Biochem Biophys Res Commun.
1998;
252
513-516
-
47
Gupta S K, Hassel T, Singh J P.
A potent inhibitor of endothelial cell proliferation is generated by proteolytic cleavage of the chemokine platelet factor 4.
Proc Natl Acad Sci USA.
1995;
92
7799-7803
-
48
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
-
49
Kisker O, Onizuka S, Banyard J et al..
Generation of multiple angiogenesis inhibitors by human pancreatic cancer.
Cancer Res.
2001;
61
7298-7304
-
50
Larsson H, Sjoblom T, Dixelius J et al..
Antiangiogenic effects of latent antithrombin through perturbated cell-matrix interactions and apoptosis of endothelial cells.
Cancer Res.
2000;
60
6723-6729
-
51
Larsson H, Akerud P, Nordling K, Rauh-Segall E, Claesson-Welsh L, Bjork I.
A novel anti-angiogenic form of antithrombin with retained proteinase binding ability and heparin affinity.
J Biol Chem.
2001;
276
11996-12002
-
52
Pahl M V, Vaziri N D, Oveisi F, Wang J, Ding Y.
Antithrombin III inhibits mesangial cell proliferation.
J Am Soc Nephrol.
1996;
7
2249-2253
-
53
Souter P J, Thomas S, Hubbard A R, Poole S, Römisch J, Gray E.
Antithrombin inhibits lipopolysaccharide-induced tissue factor and interleukin-6 production by mononuclear cells, human umbilical vein endothelial cells, and whole blood.
Crit Care Med.
2001;
29
134-139
-
54
Bombeli T, Mueller M, Haeberii A.
Anticoagulant properties of the vascular endothelium.
Thromb Haemost.
1997;
77
408-423
-
55
Sato Y, Shimada H, Takaki R.
Autocrinological role of basic fibroblast growth factor on tube formation of vascular endothelial cells in vitro.
Biochem Biophys Res Commun.
1991;
180
1098-1102
-
56
Pluda J M, Parkinson D R.
Clinical implications of tumor-associated neovascularisation and current antiangiogenic strategies for the treatment of malignancies of pancreas.
Cancer.
1996;
78(suppl)
680-687
-
57
Gengrinovitch S, Greenberg S M, Cohen T et al..
Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms.
J Biol Chem.
1995;
270
15059-15065
-
58
Perollet C, Han Z C, Savona C, Caen J P, Bikfalvi A.
Platelet factor-4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization.
Blood.
1998;
91
3289-3299
-
59
Hampl M, Tanaka T, Albert P S, Lee J, Ferrari N, Fine H A.
Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites.
Hum Gene Ther.
2001;
12
1713-1729
-
60
Callendar N S, Varki N, Rao L V.
Immunohistochemical identification of tissue factor in solid tumors.
Cancer.
1992;
70
1194-1201
-
61
Rao L VM.
Tissue factor as a tumor procoagulant.
Cancer Metastasis Rev.
1992;
11
249-266
-
62
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
-
63
Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H.
Binding of human factor VIIa to tissue factor induces Ca2+ signals in J82 cells, transfected COS-1 cells, MDCK cells and in human endothelial cells induced to synthesize tissue factor.
J Biol Chem.
1995;
270
4650-4660
-
64
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
-
65
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
-
66
Sorensen B B, Freskgard P O, Nielsen L S, Rao L V, Ezban M, Peterson L C.
Factor VIIa-induced p44/42 mitogen-activated protein activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain.
J Biol Chem.
1999;
274
21349-21354
-
67
Versteeg H H, Hoedemaeker I, Diks S H et al..
Factor VIIa/tissue factor-induced signaling via the activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac.
J Biol Chem.
2000;
275
28750-28756
-
68
Ollivier V, Bentolila S, Chabbat J, Hakim J, Prost D.
Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.
Blood.
1998;
91
2698-2703
-
69
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
-
70
Abe K, Shoji M, Chen J et al..
Regulation of vascular endothelial growth production and angiogenesis by the cytoplasmic tail of tissue factor.
Proc Natl Acad Sci USA.
1999;
96
8663-8668
-
71
Zioncheck T F, Roy S, Vehar G A.
The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism.
J Biol Chem.
1992;
267
3561-3564
-
72
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
-
73
Shoji M, Abe K, Nawroth P P, Rickles R.
Molecular mechanisms linking thrombosis and angiogenesis in cancer.
Trends Cardiovasc Med.
1997;
7
52-59
-
74
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
-
75
Takano S, Tsuboi K, Tomono Y, Mitsui Y, Nose T.
Tissue factor, osteopontin, αvβ3 integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression.
Br J Cancer.
2000;
82
1967-1973
-
76
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
-
77
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
-
78
Bajaj M S, Bajaj S P.
Tissue factor pathway inhibitor: potential therapeutic applications.
Thromb Haemost.
1997;
78
471-477
-
79
Bromberg M E, Capello M.
Cancer and blood coagulation: molecular aspects.
Cancer J.
1999;
5
132-138
-
80
Preissner K T.
Hemostatic protease receptors and endothelial cell function: insights from gene targeting in mice.
Semin Thromb Hemost.
2000;
26
451-461
-
81
Fernandez Pujol B, Lucibello F C, Gehling U M.
Endothelial-like cells derived from human CD14 positive monocytes.
Differentiation.
2000;
65
287-300
-
82
Gude R P, Binda M M, Boquete A L, Bonfil R D.
Inhibition of endothelial cell proliferation and tumor-induced angiogenesis by pentoxifylline.
J Cancer Res Clin Oncol.
2001;
127
625-630
-
83
Amirkhosravi A, Meyer T, Warnes G et al..
Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor.
Thromb Haemost.
1998;
80
598-602
-
84
Vincent L, Chen W, Hong L et al..
Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect.
FEBS Lett.
2001;
495
159-166
-
85
Kureishi Y, Luo Z, Shiojima I et al..
The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.
Nat Med.
2000;
6
1004-1010
-
86
Brouet A, Sonveaux P, Dessy C, Moniotte S, Balligand J L, Feron O.
Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins.
Circ Res.
2001;
89
866-873
-
87
Weis M, Heeschen C, Glassford A J, Cooke J P.
Statins have biphasic effects on angiogenesis.
Circulation.
2002;
105
739-745
-
88
Fenton 2nd J W, Shen G X, Minnear F L et al..
Statins induce hypothrombotic states?.
Clin Appl Thromb Hemost.
2000;
6
18-21
-
89
Golino P, Ragini M, Cirillo P et al..
Antithrombotic effects of recombinant human active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.
Circ Res.
1998;
82
39-46
-
90
Clauss M.
Molecular biology of the VEGF and the VEGF receptor family [review].
Semin Thromb Hemost.
2000;
26
561-569
-
91
Rosen L.
Antiangiogenic strategies and agents in clinical trials [review].
Oncologist.
2000;
5(suppl 1)
20-27
-
92
Svidhar S S, Shepherd F A.
Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer.
Lung Cancer.
2003;
42(suppl 1)
581-591
-
93
Rapaport S I, Rao L VM.
The tissue factor pathway: how it become a “Prima Ballerina”.
Thromb Haemost.
1995;
74
7-17
-
94
Mousa S A, Mohamed S.
Anti-angiogenesis efficacy of the low molecular weight heparin (LMWH) tinzaparin and tissue factor pathway inhibitor (TFPI).
Blood.
1999;
94(suppl)
, 22a, 82-I (Abst)
-
95
Amirkhosravi A, Francis J, Mousa S A.
Anti-metastatic effect of the low molecular weight heparin (LMWH) tinzaparin and tissue factor pathway inhibitor (TFPI).
Thromb Haemost.
2001;
15
149,-A118
, (Abst)
-
96
Bajaj M S, Bajaj S P.
Tissue factor pathway inhibitor: potential therapeutic applications.
Thromb Haemost.
1997;
78
471-477
-
97
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
-
98
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
-
99
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
-
100
Wojtukiewicz M Z, Sierko E, Zimnoch L, Kozlowski L, Kisiel W.
Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue.
Thromb Haemost.
2003;
90
140-146
-
101
Zacharski L R, Costantini V, Wojtukiewicz M Z, Memoli V A, Kudryk B J.
Anticoagulants as cancer therapy.
Semin Oncol.
1990;
17
217-227
-
102
Tsopanoglou N E, Pipili-Synestos E, Maragoudakis M E.
Thrombin promotes angiogenesis by a mechanism independent of fibrin formation.
Am J Physiol.
1993;
264
1302-1307
-
103
Möhle R, Green D, Moore M AS, Nachman R L, Rafii S.
Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets.
Proc Natl Acad Sci USA.
1997;
94
663-668
-
104
Wojtukiewicz M Z, Tang D 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
-
105
Ukropec J A, Hollinger M K, Salva S M, Woolkalis M J.
SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin.
J Biol Chem.
2000;
275
5983-5986
-
106
Belloni P N, Carney D H, Nicolson G L.
Organ-derived microvessel endothelial cells exhibit differential responsiveness to thrombin and other growth factors.
Microvasc Res.
1992;
43
20-45
-
107
Wojtukiewicz M Z, Tang D G, Nelson K K, Walz D A, Diglio C A, Honn K V.
Thrombin enhances tumor cell adhesive and metastatic properties via increased αIIbβ3 expression on the cell surface.
Thromb Res.
1992;
68
233-245
-
108
BenEzra M, Vlodavsky I, Ishai-Michaeli R, Neufeld G, Bar-Shavit R.
Thrombin-induced release of active basic fibroblast growth factor-heparan sulfate complexes from subendothelial extracellular matrix.
Blood.
1993;
81
3324-3331
-
109
Tsopanoglou N E, Maragoudakis M E.
On the mechanism of thrombin-induced angiogenesis.
J Biol Chem.
1999;
274
23969-23976
-
110
Markwardt F.
Development of direct thrombin inhibitors in comparison with glycosaminoglycans.
Semin Thromb Hemost.
2001;
27
523-530
-
111
Hassan A AK, Amenta S, Schmaier A H.
Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of α-thrombin-induced platelet activation.
Circulation.
1996;
94
517-528
-
112
Hassan A A, Warnock M, Srikanth S, Schmaier A H.
Developing peptide inhibitors to thrombin activation of platelets from bradykinin analogs.
Thromb Res.
2001;
104
451-465
-
113
Bahou W F, Coller B S, Potter C L, Norton K J, Kutok J L, Goligorsky M S.
The thrombin receptor extracellular domain contains sites crucial for peptide ligand-induced activation.
J Clin Invest.
1993;
91
1405-1413
-
114
Cook J J, Sitko G R, Bednar B et al..
An antibody against the exo-site of the cloned thrombin receptor inhibits experimental arterial thrombosis in the African green monkey.
Circulation.
1995;
91
2961-2971
-
115
Derian C K, Maryanoff B E, Zhang H-C, Andrade-Gordon P.
Therapeutic potential of protease-activated receptor-1 antagonists.
Expert Opin Investig Drugs.
2003;
12
209-221
-
116
Engelberg H.
Action of heparin that may affect the malignant process.
Cancer.
1999;
85
257-272
-
117
Hull R D, Raskob G E, Pineo G F et al..
Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.
N Engl J Med.
1992;
326
975-982
-
118
Prandoni P, Lensing A WA, Büller H R et al..
Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis.
Lancet.
1992;
339
441-445
-
119
Hirsh J, Siragusa S, Cosmi B, Ginsberg J S.
Low molecular weight heparins (LMWH) in the treatment of patients with acute venous thromboembolism.
Thromb Haemost.
1995;
74
360-363
-
120
Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg J S.
Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis.
Am J Med.
1996;
100
269-277
-
121
Norrby K.
Heparin and angiogenesis: a low-molecular-weight-fraction inhibits and a high-molecular-weight fraction stimulates angiogenesis systemically.
Haemostasis.
1993;
23(suppl 1)
141-149
-
122
Norrby K, Østergaard P.
A 5.0-kD heparin fraction systemically suppresses VEGF165-mediated angiogenesis.
Int J Microcirc Clin Exp.
1997;
17
314-321
-
123
Norrby K, Østergaard P.
Basic fibroblast growth factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin.
Int J Microcirc Clin Exp.
1996;
16
8-15
-
124
Lepri A, Benelli U, Bernardini N et al..
Effect of low molecular weight heparan sulphate on angiogenesis in the rat cornea after chemical cauterization.
J Ocul Pharmacol.
1994;
10
273-280
-
125
Folkman J, Langer R, Linhardt R J, Haudenschild C, Taylor S.
Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone.
Science.
1983;
221
719-725
-
126
Jacobson A M, Hahnenberger R.
Antiangiogenic effect of heparin and other sulphated glycosaminoglycans in the chick chorioallantoic membrane.
Pharmacol Toxicol.
1991;
69
122-126
-
127
Norrby K.
2.5 kD and 5 kD heparin fragments specifically inhibit microvessel sprouting and network formation in VEGF165-mediated mammalian angiogenesis.
Int J Exp Pathol.
2000;
81
191-198
-
128
Sasisekharan R, Ernst S, Venkataraman G.
On the regulation of fibroblast growth factor activity by heparin-like glycosaminoglycans.
Angiogenesis.
1997;
1
45-54
-
129
Colin S, Jeanny J C, Mascarelli F et al..
In vivo involvement of heparan sulfate proteoglycan in the bioavailability, internalization, and catabolism of exogenous basic fibroblast growth factor.
Mol Pharmacol.
1999;
55
74-82
-
130
Saksela O, Moscatelli D, Sommer A, Rifkin D B.
Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation.
J Cell Biol.
1988;
107
743-751
-
131
Rusnati M, Presta M.
Interaction of angiogenic basic fibroblast growth factor with endothelial cell heparan sulfate proteoglycans. Biological implications in neovascularization.
Int J Clin Lab Res.
1996;
26
15-23
-
132
Presta M, Maier J A, Rusnati M, Ragnotti G.
Basic fibroblast growth factor is released from endothelial extracellular matrix in a biologically active form.
J Cell Physiol.
1989;
140
68-74
-
133
Ishai-Michaeli R, Eldor A, Vlodavsky I.
Heparanase activity expressed by platelets, neutrophils, and lymphoma cells releases active fibroblast growth factor from extracellular matrix.
Cell Regul.
1990;
1
833-842
-
134
Vlodavsky I, Ishai-Michaeli R, Mohsen M et al..
Modulation of neovascularization and metastasis by species of heparin.
Adv Exp Med Biol.
1992;
313
317-327
-
135
Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I.
A heparin-binding angiogenic protein-basic fibroblast growth factor-is stored within basement membrane.
Am J Pathol.
1988;
130
393-400
-
136
D'Amore P A.
Heparin-endothelial cell interactions.
Haemostasis.
1990;
20(suppl 1)
159-165
-
137
Taniguchi T, Toi M, Tominaga T.
Rapid induction of hepatocyte growth factor by heparin.
Lancet.
1994;
344
470
-
138
Yamazaki H, Oi H, Matsushita M et al..
Heparin induces rapid and remarkable elevation of hepatocyte growth factor/scatter factor during trans arterial embolization of renal cell carcinoma.
Anticancer Res.
1997;
17
1435-1437
-
139
Mason I J.
The ins and outs of fibroblast growth factors.
Cell.
1994;
78
547-552
-
140
Tessler S, Rockwell P, Hicklin D et al..
Heparin modulates the interaction of VEGF165 with soluble and cell associated flk-1 receptors.
J Biol Chem.
1994;
269
12456-12461
-
141
Schlessinger J, Lax I, Lemmon M.
Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors?.
Cell.
1995;
83
357-360
-
142
Soker S, Goldstaub D, Svahn C M, Vlodavsky I, Levi B Z, Neufeld G.
Variations in the size and sulfation of heparin modulate the effect of heparin on the binding of VEGF165 to its receptors.
Biochem Biophys Res Commun.
1994;
203
1339-1347
-
143
Jayson G C, Gallagher J T.
Heparin oligosaccharides: Inhibitors of the biological activity of bFGF on Caco-2 cells.
Br J Cancer.
1997;
75
9-16
-
144
Pinedo H M, Verheul H MW, D'Amato R J, Folkman J.
Involvement of platelets in tumor angiogenesis?.
Lancet.
1998;
352
1775-1777
-
145
Verheul H MW, Hoekman K, Lupu F et al..
Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas.
Clin Cancer Res.
2000;
6
166-171
-
146
Edwards R L, Rickles F R, Moritz T E et al..
Abnormalities of blood coagulation tests in patients with cancer.
Am J Clin Pathol.
1987;
88
596-602
-
147
Verheul H MW, Hoekman K, Luykx-de Bakker S et al..
Platelet transporter of vascular endothelial growth factor.
Clin Cancer Res.
1997;
3
2187-2190
-
148
Brunner G, Nguyen H, Gabrilove J et al..
Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells.
Blood.
1993;
81
631-638
-
149
Nakamura T, Teramoto H, Ichihara A.
Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary culture.
Proc Natl Acad Sci USA.
1986;
83
6489-6493
-
150
Griffiths L, Stratford I J.
Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumor growth and response to therapy.
Br J Cancer.
1997;
76
689-693
-
151
Good D J, Polverini P J, Rastinejad F et al..
A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistiguishable from a fragment of thrombospondin.
Proc Natl Acad Sci USA.
1990;
87
6624-6628
-
152
Taylor S, Folkman J.
Protamine is an inhibitor of angiogenesis.
Nature.
1982;
297
307-312
-
153
Selheim F, Holmsen H, Vassbotn F S.
Identification of functional VEGF receptors on human platelets.
FEBS Lett.
2002;
512
107-110
-
154
Sawicki G, Salas E, Murat J et al..
Release of gelatinase A during platelet activation mediates aggregation.
Nature.
1997;
386
616-619
-
155
Menashi S, He L, Soria C et al..
Modulation of endothelial cells fibrinolytic activity by platelets.
Thromb Haemost.
1991;
65
77-81
-
156
Belloc C, Lu H, Soria C et al..
The effect of platelets on invasiveness and protease production of human mammary tumor cells.
Int J Cancer.
1995;
60
413-417
-
157
Mandriota S J, Seghezzi G, Vassali J D et al..
Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells.
J Biol Chem.
1995;
270
9709-9716
-
158
Friesel R E, Maciag T.
Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling.
Thromb Haemost.
1999;
82
748-754
-
159
Honn K V, Tang G T, Chen Y Q.
Platelets and cancer metastasis: more than an epiphenomenon.
Semin Thromb Hemost.
1992;
18
392-415
-
160
Felding-Habermann B, O'Toole T E, Smith J W et al..
Integrin activation controls metastasis in human breast cancer.
Proc Natl Acad Sci USA.
2001;
98
1853-1858
-
161
Coller B S, Peerschke E L, Scudder L E, Sullivan C A.
A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa.
J Clin Invest.
1983;
72
325-328
-
162
Coller B S.
Anti-GpIIb/IIIa drugs: current strategies and future directions.
Thromb Haemost.
2001;
86
427-443
-
163
Nierodzik M L, Klepfish A, Karpatkin S.
Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo.
Thromb Haemost.
1995;
74
282-290
-
164
Amirkhosravi A, Amaya M, Siddiqui F et al..
Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor-cell-activated platelets and experimental metastasis.
Platelets.
1999;
10
285-292
-
165
Trikha M, Zhou Z, Jordan J, Nakada M T.
ReoPro and m7E3 F(ab′)2 inhibit β3 integrin mediated tumor growth and angiogenesis.
Proc Am Assoc Cancer Res.
2000;
42
824,-A3678
-
166
Butenas S, Cawthern K, Veer C et al..
Antiplatelet agents in tissue factor-induced blood coagulation.
Blood.
2001;
97
2314-2322
-
167
Waltermann A, Wolzt M, Petersmann K et al..
Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo.
Arterioscler Thromb Vasc Biol.
1999;
19
1757-1760
-
168
Borsig L, Wong R, Feramisco J et al..
Heparin and cancer revised: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis.
Proc Natl Acad Sci USA.
2001;
98
3352-3357
-
169
Ma L, Elliott S N, Ciriano G et al..
Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release.
Proc Natl Acad Sci USA.
2001;
98
6470-6475
-
170
Foekens J A, Peters H A, Look M P et al..
The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients.
Cancer Res.
2000;
60
636-643
-
171
Kuhn W, Schmalfeld B, Reuning U et al..
Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIC.
Br J Cancer.
1999;
79
1746-1751
-
172
Witte J H, Sweep C GJ, Klijn J GM et al..
Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer.
Br J Cancer.
1999;
80
286-294
-
173
Schleef R R, Loskutoff D J.
Fibrinolytic system of vascular endothelial cells. Role of plasminogen activator inhibitors.
Haemostasis.
1988;
18
328-341
-
174
Kroon M E, Koolwijk P, van Goor H et al..
Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices.
Am J Pathol.
1999;
154
1731-1742
-
175
Blasi F.
Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system.
Thromb Haemost.
1999;
82
298-304
-
176
Bajou K, Noel A, Gerard R D et al..
Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularisation.
Nat Med.
1998;
4
923-927
-
177
Carmeliet P, Moons L, Dewerchin A et al..
Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and plasminogen system.
Ann NY Acad Sci.
1997;
811
191-206
-
178
Heymans S, Luttun A, Nuyens D et al..
Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.
Nat Med.
1999;
5
1135-1142
-
179
Overall C M, Lopez-Otin C.
Strategies for MMP inhibition in cancer: innovations for the post-trial era.
Nat Rev Cancer.
2002;
2
657-672
-
180
Mandelli F, Diverio D, Avvisati G et al..
Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malottie Ematologiche Maligna dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups.
Blood.
1997;
90
1014-1021
-
181
Horne III M K, Figg W D, Arlen P et al..
Increased frequency of venous thromboembolism with the combination of docetaxel and thalidomide in patients with metastatic androgen-independent prostate cancer.
Pharmacotherapy.
2003;
23
315-318
-
182
Desai A A, Vogelzang N J, Rini B I, Ansari R, Krauss S, Stadler W M.
A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma.
Cancer.
2002;
95
1629-1636
-
183
Wun T, Law L, Harvey D, Sieracki B, Scudder S A, Ryu J K.
Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin.
Cancer.
2003;
98
1514-1520
-
184
Verso M, Agnelli G.
Venous thromboembolism associated with long-term use of central venous catheters in cancer patients.
J Clin Oncol.
2003;
21
3665-3675
-
185
Lee A Y, Levine M N.
The thrombophilic state induced by therapeutic agents in the cancer patient.
Semin Thromb Hemost.
1999;
25
137-145
-
186
Khushal A, Quinlan D, Alikhan R, Gardner J, Bailey C, Cohen A.
Thromboembolic disease in surgery for malignancy-rationale for prolonged thromboprophylaxis.
Semin Thromb Hemost.
2002;
28
569-576
-
187
Zacharski L R.
Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy.
Cancer Lett.
2002;
186
1-9
-
188
Zacharski L R.
Malignancy as a solid phase coagulopathy: implications for the etiology, pathogenesis, and treatment of cancer.
Semin Thromb Hemost.
2003;
29
239-246
Marek Z WojtukiewiczM.D.
Department of Oncology, Medical University
12 Ogrodowa St, 15-027 Bialystok, Poland
Email: mwojtuk@polbox.com