Clinical, laboratory, histopathological, and pharmacological evidence support the
notion that the coagulation system, which is activated in most cancer patients, plays
an important role in tumor biology. Our laboratory has provided evidence that thrombin
activates angiogenesis, a process which is essential in tumor growth and metastasis.
This event is independent of fibrin formation. At the cellular level many actions
of thrombin can contribute to activation of angiogenesis: (1) Thrombin decreases the
ability of endothelial cells to attach to basement membrane proteins. (2) Thrombin
greatly potentiates vascular endothelial growth factor- (VEGF-) induced endothelial
cell proliferation. This potentiation is accompanied by up-regulation of the expression
of VEGF receptors (kinase insert domain-containing receptor [KDR] and fms-like tyrosine
kinase [Flt-1]). (3) Thrombin increases the mRNA and protein levels of αvβ3 integrin and serves as a ligand to this receptor. Furthermore, thrombin increases
the secretion of VEGF and enhances the expression and protein synthesis of matrix
metalloprotease-9 and αvβ3 integrin in human prostate cancer PC-3 cells. These results could explain the angiogenic
and tumor-promoting effect of thrombin and provide the basis for development of thrombin
receptor mimetics or antagonists for therapeutic application.
KEYWORDS
Thrombin - angiogenesis - tumor - VEGF - integrin
REFERENCES
- 1
Dano K, Andreasen P A, Grondahl-Hansen J et al..
Plasminogen activators, tissue degradation, and cancer [review].
Adv Cancer Res.
1985;
44
139-266
- 2
Nash G F, Walsh D C, Kakkar A K.
The role of the coagulation system in tumor angiogenesis.
Lancet Oncol.
2001;
2
608-613
- 3
Rickles F R, Edwards R L.
Activation of blood coagulation in cancer: Trousseau's syndrome revisited.
Blood.
1983;
62
14-31
- 4
Del Rosso M, Fibbi G, Pucci M et al..
Multiple pathways of cell invasion are regulated by multiple families of serine proteases.
Clin Exp Metastasis.
2002;
19
193-207
- 5
Martin D MA, Boys C WG, Ruf W.
Tissue factor: molecular recognition and cofactor function.
FASEB J.
1995;
9
852-859
- 6
Hillen H F.
Thrombosis in cancer patients.
Ann Oncol.
2000;
11
273-276
- 7
Tsopanoglou N E, Pipili-Synetos E, Maragoudakis M E.
Thrombin promotes angiogenesis by a mechanism independent of fibrin formation.
Am J Physiol.
1993;
264
C1302-C1307
- 8
Folkman J.
Tumour angiogenesis.
Adv Cancer Res.
1985;
43
175-203
- 9
Wojtukiewicz M Z, Tang D G, Benjosef E et al..
Solid tumor cells express functional tethered ligand thrombin receptor.
Cancer Res.
1995;
55
698-704
- 10
Even-Ram S, Uziely B, Cohen P et al..
Thrombin receptor overexpression in malignant and physiological invasion processes.
Nat Med.
1998;
4
909-914
- 11
Zacharski L R, Memoli V A, Morain W D et al..
Cellular localization of enzymatically active thrombin in intact human tissues by
hirudin binding.
Thromb Haemost.
1995;
73
793-797
- 12
Mohle R, Green D, Moore M A et al..
Constitutive production and thrombin-induced release of vascular endothelial growth
factor by human megakaryocytes and platelets.
Proc Natl Acad Sci USA.
1997;
94
663-669
- 13
Tsopanoglou N E, Maragoudakis M E.
On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial
growth factor activity on endothelial cells by upregulation of its receptors.
J Biol Chem.
1999;
274
23969-23976
- 14
Klepfish B, Greco M A, Karpatkin S.
Thrombin stimulates melanoma tumor cell binding to endothelial cells and subendothelial
matrix.
Int J Cancer.
1993;
53
978-982
- 15
Wojtukiewicz M Z, Tang D G, Ciarelli J J et al..
Thrombin increases the metastatic potential of tumor cells.
Int J Cancer.
1993;
54
793-806
- 16
Nierodzik M L, Klepfish B, Karpatkin S.
Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willenbrand factor
on tumor adhesion in vitro and metastasis in vivo.
Thromb Haemost.
1995;
74
282-290
- 17
Dardik R, Savion N, Kaufman Y et al..
Thrombin promotes platelets-mediated melanoma cell adhesion to endothelial cells under
flow conditions: role of platelet glycoprotein P-selectin and GPIIb-IIIa.
Br J Cancer.
1998;
77
2069-2075
- 18
Haralambopoulos G C, Grant D S, Klienman H K, Maragoudakis M E.
Thrombin promotes endothelial cell alignment in matrigel in vitro and angiogenesis
in vivo.
Am J Physiol.
1997;
273
C239-C242
- 19
Dimitropoulou C, Malkush W, Fait E, Maragoudakis M E, Konerding M A.
The vascular architecture of the chick chorioallantoic membrane: sequential quantitative
evaluation using corrosion casting.
Angiogenesis.
1998;
2
255-263
- 20
Maragoudakis M E, Tsopanoglou N E, Sakkoula E, Pipili-Synetos E.
On the mechanism of promotion of angiogenesis by thrombin [abstract].
FASEB J.
1995;
9
A587
- 21
Herbert J M, Dupuy E, Laplace M C et al..
Thrombin induces endothelial cell growth via both proteolytic and non-proteolytic
pathways.
Biochem J.
1994;
303
227-231
- 22
McNamara C A, Sarembock I J, Gimple L W et al..
Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a
proteolytically activated receptor.
J Clin Invest.
1993;
91
94-98
- 23
Macfarlane S R, Seatter M J, Kanke T et al..
Proteinase-activated receptors.
Pharmacol Rev.
2001;
53
245-282
- 24
Tsopanoglou N E, Maragoudakis M E.
On the mechanism of thrombin-induced angiogenesis: inhibition of attachment of endothelial
cells on basement membrane components.
Angiogenesis.
1998;
1
192-200
- 25
Maragoudakis M E, Kraniti N, Giannopoulou E et al..
Modulation of angiogenesis and progelatinase A by thrombin receptor mimetic and antagonists.
Endothelium.
2001;
8
195-205
- 26
Folkman J.
Angiogenesis in cancer, vascular, rheumatoid and other disease.
Nat Med.
1995;
1
27-31
- 27
Ferrara N, Davis-Smyth T.
The biology of vascular endothelial growth factor.
Endocr Rev.
1997;
18
4-25
- 28
Eliceiri B P, Cheresh D A.
Adhesion events in angiogenesis.
Curr Opin Cell Biol.
2001;
13
563-568
- 29
Felding-Habermann B, Mueller B M, Romerdahl C A, Cheresh D A.
Involvement of integrin αv gene expression in human melanoma tumorigenicity.
J Clin Invest.
1992;
89
2018-2022
- 30
Enenstein J, Kramer R H.
Confocal microscopic analysis of integrin expression on the microvasculature and its
sprouts in the neonatal foreskin.
J Invest Dermatol.
1994;
103
381-386
- 31
Brooks P C, Clark R A, Cheresh D A.
Requirement of vascular integrin αvβ3 for angiogenesis.
Science.
1994;
264
569-571
- 32
Bader B L, Rayburn H, Crowley D, Hynes R O.
Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice
lacking all alpha v integrins.
Cell.
1998;
95
507-519
- 33
Kumar C C, Malkowski M, Yin Z et al..
Inhibition of angiogenesis and tumor growth by SCH221153, and dual αvβ3 and αvβ5 integrin receptor antagonist.
Cancer Res.
2001;
61
2232-2238
- 34
Storgard C M, Stupack D G, Jonczyk A.
Decreased angiogenesis and arthritis disease in rabbit treated with an αvβ3 antagonist.
J Clin Invest.
1999;
103
47-54
- 35
Tsopanoglou N E, Andriopoulou P, Maragoudakis M E.
On the mechanism of thrombin-induced angiogenesis: involvement of αvβ3 integrin.
Am J Physiol.
2002;
283
C1501-C1510
- 36
Conforti G C, Dominguez-Jimenez B, Zanetti M A et al..
Human endothelial cells express integrin receptors on the luminal aspect of their
membrane.
Blood.
1992;
80
437-446
- 37
Ruoslahti E.
RGD and other recognition sequences for integrins.
Annu Rev Cell Dev Biol.
1996;
12
697-715
- 38
Giancotti F G, Ruoslahti E.
Integrin signaling.
Science.
1999;
285
1028-1032
- 39
Brooks P C, Silletti S, von Schalscha T L, Friedlander M, Cheresh D A.
Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with
integrin binding activity.
Cell.
1998;
92
391-400
- 40
Zucker S, Conner C, Massimo B et al..
Thrombin induces the activation of progelatinase A in vascular endothelial cells.
J Biol Chem.
1995;
270
23730-23738
- 41
Johnsen M, Lund L R, Romer J, Amholt K, Dano K.
Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation.
Curr Opin Cell Biol.
1998;
10
667-671
- 42
Zucker S, Mirza H, Conner C E et al..
Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase
production in endothelial cells: conversion of prothrombin to thrombin results in
progelatinase A activation and cell proliferation.
Int J Cancer.
1998;
75
780-786
- 43
Nierodzik M L, Kajumo F, Karpatkin S.
Effects of thrombin treatment of tumor cells on adhesion of tumor cells to platelets
in vitro and tumor metastasis in vivo.
Cancer Res.
1992;
52
3267-3272
- 44
Even-Ram S C, Maoz M, Pokroy E et al..
Tumor invasion is promoted by activation of protease activated receptor-1 in cooperation
with the αvβ5 integrin.
J Biol Chem.
2001;
276
10952-10962
- 45
Bar-Shavit R, Gridley G, Vlodavsky I.
Binding of thrombin to subendothelial extracellular matrix: protection and expression
of functional properties.
J Clin Invest.
1989;
84
1096-1104
Prof.
Michael E Maragoudakis
Department of Pharmacology, Medical School, University of Patras
25110 Patras, Greece
Email: maragoud@med.upatras.gr
