Table Of ContentProteases and Their Inhibitors in Cancer Metastasis
Cancer Metastasis – Biology and Treatment
VOLUME 4
Series Editors
Richard J. Ablin,Ph.D.,Innapharma, Inc., Park Ridge, NJ, U.S.A.
Wen G. Jiang, M.D., University of Wales College of Medicine, Cardiff, U.K.
Advisory Editorial Board
Harold F. Dvorak,M.D.
Phil Gold, M.D.,Ph.D.
Ian R. Hart, Ph.D.
Hiroshi Kobayashi,M.D.
Robert E. Mansel, M.S.,FRCS.
Marc Mareel, M.D.,Ph.D.
Titles published in this Series are:
Volume 1: Cancer Metastasis, Molecular and Cellular Mechanisms and
Clinical Intervention.
Editors: Wen G. Jiang and Robert E. Mansel.
ISBN 0-7923-6395-7
Volume 2: Growth Factors and Receptors in Cancer Metastasis.
Editors: Wen G. Jiang, Kunio Matsumoto and Toshikazu Nakamura.
ISBN 0-7923-7141-0
Volume 3: Cancer Metastasis-Related Genes
Editor: Danny R. Welch
ISBN 0-4020-0522-9
Proteases and
Their Inhibitors in
Cancer Metastasis
Edited by
Jean-Michel Foidart
Laboratoire de Biologie des Tumeurs et du Développement,
Faculté de Médecine Université de Liège, Belgium
and
Ruth J. Muschel
Department of Pathology & Laboratory Medicine,
University of Pennsylvania, U.S.A.
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TABLE OF CONTENTS
CHAPTER 1.....................................................................................................1
Molecular Biology of the Plasminogen System: The delicate
balance between tissue healing and tissue destruction
A. Luttun and P. Carmeliet
CHAPTER 2...................................................................................................23
Role of Serine Proteases and Their Inhibitors in Tumor
Growth and Angiogenesis
A. Noël and J.-M. Foidart
CHAPTER 3...................................................................................................39
The Gelatinases, MMP-2 and MMP-9-Implications for
Invasion and Metastasis
Ruth J. Muschel and Jiang Yong
CHAPTER 4...................................................................................................53
The Collagenases: Novel roles for matrix metalloproteinases
(MMPs) in invasion and metastasis
Constance E. Brinckerhoff, Ulrike Benbow and Grant B. Tower
CHAPTER 5...................................................................................................81
Stromelysin-3, a Particular Member of the Matrix Metallo-
proteinase Family
M.-C. Rio
CHAPTER 6.................................................................................................109
Membrane-type Matrix Metalloproteinases
Yoshifumi Itoh and Motoharu Seiki
CHAPTER 7.................................................................................................127
3D Structure and Drug Design
J. Schröder, H. Wenzel and H. Tschesche
v
CHAPTER 8.................................................................................................151
Transcriptional Control of Proteases
H. Allgayer, E. Lengyel and D. D. Boyd
CHAPTER 9.................................................................................................169
Tissue Inhibitors of Metalloproteinases in Cancer
Yves A. DeClerck
CHAPTER 10...............................................................................................195
Clinical Aspects of Matrix Metalloproteinases
Béatrice Nawrocki-Raby, Christine Clavel, Myriam Polette and
Philippe Birembaut
CHAPTER 11...............................................................................................205
Tissue Models to Study Tumor-Stroma Interactions
N. E. Fusenig, M. Skobe, S. Vosseler, M. Hansen, W. Lederle,
K. Airola, P. Tomakidi, H.-J. Stark, H. Steinbauer, N. Mirancea,
P. Boukamp and D. Breitkreutz
CHAPTER 12...............................................................................................225
Mammalian Heparanase: Molecular properties inhibition
and involvement in tumor metastasis and angiogenesis
I. Vlodavsky, Y. Friedmann, M. Elkin, O. Pappo, I. Pecker,
M. D. Hulett, C. R. Parish and C. Freeman
Index ............................................................................................................253
vi
Chapter 1
MOLECULAR BIOLOGY OF THE
PLASMINOGEN SYSTEM: THE DELICATE
BALANCE BETWEEN TISSUE HEALING
AND TISSUE DESTRUCTION
A. Luttun and P. Carmeliet
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for
Biotechnology, Campus Gasthuisberg, Herestraat 49, University of Leuven, Leuven, B-3000,
Belgium
Abstract
Proteinases play a central role in the complex response of tissues to injury by influencing cellular
behavior and matrix remodeling. Considerable information on the biology of proteinases has been
derived from gene targeting and gene transfer studies. One of the best characterised proteinase
systems is the plasminogen system, belonging to the large serine proteinase family. Using mice
with a targeted deficiency of plasminogen system components, it has become obvious that the
plasminogen system can – directly or indirectly by activation of matrix metalloproteinases – have
divergent – even opposite – roles in disease favoring healing in some cases and promoting tissue
destruction in others. This Chapter discusses the mechanisms by which the plasminogen system
can influence the response to injury in the vessel wall, the heart, the nervous system, the lungs
and the skin.
1. INTRODUCTION
Genetic studies have provided important insights in proteinase biology. Although
most of these proteinases seem dispensible during development, they have been
implicated in numerous diseases often having divergent – even opposite –
effects. One of the main reasons for this diversity is that proteinases can affect
disease progression by different mechanisms, i.e. by influencing cellular migra-
tion, cytokine activation, extracellular matrix turnover, growth factor availability
and blood vessel formation. These functions need to be carefully balanced.
Consequently, the biological activity of proteinases is tightly regulated at the
level of gene transcription as well as the protein level by latency of the proen-
zyme and by the existence of proteinase inhibitors and cellular receptors.
The group of proteinases comprises four different families based on the nature
of the chemical group responsible for catalytic activity: the serine, cysteine,
1
J.-M. Foidart and R.J. Muschel (eds.), Proteases and Their Inhibitors in Cancer Metastasis,1–22.
©2002Kluwer Academic Publishers. Printed in the Netherlands.
aspartic and metalloproteinases (Barrett, 1992). This Chapter focuses on a serine
proteinase family, e.g. the plasminogen system, which plays a major role in
physiologic and pathologic processes including blood coagulation, tumor growth
and metastasis, cardiovascular disease and wound healing.
The plasminogen system (reviewed in Collen, 1999; Wiman, 2000) is
composed of an inactive proenzyme plasminogen (Plg) that can be converted
to plasmin by either of two plasminogen activators (PAs), tissue-type PA
(t-PA) or urokinase-type PA (u-PA) (Collen and Lijnen, 1991; Vassalli et al,
1991). This system is controlled at the level of plasminogen activators by
plasminogen activator inhibitors (PAIs), of which PAI-1 is believed to be
physiologically the most important (Schneiderman et al, 1991; Wiman, 1995),
and at the level of plasmin by α -antiplasmin (directly inhibiting plasmin)
2
(Collen and Lijnen, 1991). Due to its fibrin-specificity, t-PA is primarily
involved in clot dissolution (Collen and Lijnen, 1991; Vassalli et al, 1991).
u-PA binds a cellular receptor (u-PAR) and has been implicated in cell migra-
tion and tissue remodeling (Blasi et al, 1994; Vassalli, 1994). The lipoprotein-
like receptor protein (LRP) mediates rapid clearance of t-PA from plasma
(Noorman and Rijken, 1997). Plasmin is able to degrade fibrin and extracel-
lular matrix proteins directly or, indirectly, via activation of other proteinases
(such as the matrix metalloproteinases or MMPs) (Carmeliet et al, 1997a;
Saksela and Rifkin, 1988). Plasmin can also activate or liberate growth factors
from the extracellular matrix (Saksela and Rifkin, 1988; Martin et al, 1993).
Over the last decade, mice deficient of one of the plasminogen system com-
ponents have been generated (Carmeliet et al, 1993a, b, 1994; Dewerchin et al,
1996; Lijnen et al, 1999a; Ploplis et al, 1995) allowing to directly study their
role in disease. Not only have these studies emphasized the complex and
pleiotropic nature of this system, they also revealed that the same system can
promote opposite processes like tissue healing and tissue destruction. This
Chapter documents the involvement of plasminogen system components in
healing and/or destruction processes in several tissues, including the vessel wall,
the heart, the nervous system, the lung and the skin, as unveiled by gene
targeting and gene transfer studies (Figure 1). Given the possibility that plasmin
mediates some of its effects through activation of MMPs, genetic studies with
MMPs will also be discussed where appropriate. The role of the plasminogen
system in tumor growth and metastasis is reviewed in Chapter 2.
2
Figure 1. Role of the plasminogen system in tissue healing and destruction.
2. THE VESSEL WALL
2.1. Systemic arteries
2.1.1. Arterial stenosis
Vascular interventions for the treatment of atherothrombosis (balloon angio-
plasty, stenting) induce restenosis of the vessel within three to six months in
30 to 50% of treated patients. Arterial stenosis may result from remodeling of
the vessel wall and/or from accumulation of cells and extracellular matrix in
the intimal layer. Proteinases participate in the proliferation and migration of
smooth muscle cells (SMCs), and in the matrix remodeling during arterial
wound healing. In a mouse model of arterial wound healing we demonstrated
that u-PA but not t-PA mediates vascular wound healing and arterial neointima
formation, as indicated by the significantly reduced degree and rate of arterial
3
