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Keywords
angiogenesis; invasion and metastasis;
matrix metalloproteinase; matrix
metalloproteinase inhibitor; pharmacological
target
Correspondence
N. Karamanos, Laboratory of Biochemistry,
Department of Chemistry, University of
Patras, 26110 Patras, Greece
Fax: +30 2610 997153
Tel: +30 2610 997915
E-mail: n.k.karamanos@upatras.gr
(Received 20 June 2010, revised 20 August
2010, accepted 18 October 2010)
doi:10.1111/j.1742-4658.2010.07919.x
Matrix metalloproteinases (MMPs) consist of a multigene family of zincdependent extracellular matrix (ECM) remodeling endopeptidases implicated
in pathological processes, such as carcinogenesis. In this regard, their activity
plays a pivotal role in tumor growth and the multistep processes of invasion
and metastasis, including proteolytic degradation of ECM, alteration of the
cellcell and cellECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote
tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending
among other factors on the tumor stage, tumor site, enzyme localization and
substrate prole. MMPs are therefore amenable to therapeutic intervention
by synthetic and natural inhibitors, providing perspectives for future studies.
Multiple therapeutic agents, called matrix metalloproteinase inhibitors
(MMPIs) have been developed to target MMPs, attempting to control their
enzymatic activity. Even though clinical trials with these compounds do not
show the expected results in most cases, the eld of MMPIs is ongoing. This
minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the
design, development and efcacy of MMPIs.
Introduction
Cancer is one of the leading causes of disease and
mortality worldwide [1]. As a result, the past two decades of biomedical research have yielded an enormous
amount of information on the molecular events that
take place during carcinogenesis and the signaling
pathways participating in cancer progression. The
molecular mechanisms of the complex interplay
between the tumor cells and the tumor microenvironment play a pivotal role in this process [2].
Abbreviations
ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; bFGF, basic
fibroblast growth factor; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial to mesenchymal transition;
GAG, glycosaminoglycan; HB-EGF, heparin-binding epidermal growth factor; IGF, insulin-like growth factor; MMP, matrix metalloproteinase;
MMPI, metalloproteinase inhibitor; MT-MMP, membrane-type matrix metalloproteinase; NK, natural killer; siRNA, small interfering RNA;
TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinase; VEGF, vascular endothelial growth factor.
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C. Gialeli et al.
as well as in pathological conditions, such as inammatory, vascular and auto-immune disorders, and carcinogenesis [36]. MMPs have been considered as potential
diagnostic and prognostic biomarkers in many types
and stages of cancer [7]. The notion of MMPs as therapeutic targets of cancer was introduced 25 years ago
because the metastatic potential of various cancers was
correlated with the ability of cancer cells to degrade the
basement membrane [8]. Subsequently, a growing number of MMP inhibitors (MMPIs) have been developed
and evaluated in several clinical trials.
A zinc-dependent family of proteinases related to
the MMPs is represented by a disintegrin and metalloproteinase (ADAM), which includes two subgroups:
the membrane-bound ADAM and a disintegrin and
metalloproteinase with thrombospondin motifs (ADAMTS). Recent studies show that ADAM and ADAMTS present altered expression in diverse tumor
types, suggesting that these proteins are involved in
different steps of cancer progression including carcinogenesis [9,10]. ADAM molecules are implicated in
tumor cell prolireration apoptosis, cell adhesion migration and cell signaling. In particular, they
exhibit proteolytic activity like MMPs, although their
main roles focus on ectodomain shedding and nonproteolytic functions, such as binding to adhesion molecules, integrins and interacting with phosphorylation
sites for serine threonine and tyrosine kinases, thus
contributing to cancer development [11].
tumor microenvironment depends not only on the cancer cells, but also on the neighboring stromal cells,
which are induced by the cancer cells in a paracrine
manner. Cancer cells stimulate host cells such as broblasts to constitute an important source of MMPs
through the secretion of interleukins and growth factors and direct signaling through extracellular MMP
inducer [10]. The cellular source of MMPs can therefore have critical consequences on their function and
activity. For example, in this regard, neutrophils
express MMP-9 free of TIMP-1, which results in activation of the proteinase more readily [13].
Recent studies show that members of the MMP
family exert different roles at different stages during
cancer progression. In particular, they may promote or
inhibit cancer development depending among other
factors on the tumor stage, tumor site (primary, metastasis), enzyme localization (tumor cells, stroma) and
substrate prole. For example, MMP-8 provides a protective effect in the metastatic process, decreasing the
metastatic potential of breast cancer cells when it is
over-expressed [14]. Similarly, MMP-8 expression in
squamous cell carcinoma of the tongue is correlated
with improved survival of patients and it is proposed
that this protective action is probably correlated with
the role of estrogen in the growth of tongue squamous
cell carcinomas [12,15]. On the other hand, MMP-9
might function as tumor promoter in the process of
carcinogenesis as well as an anticancer enzyme at later
stages of the disease in some specic situations. This
dual role is based on the ndings in animal models,
where it observed that MMP-9 knockdown mouse
models exhibited decreased incidence of carcinogenesis,
whereas tumors formed in MMP-9 decient mice were
signicantly more aggressive [12].
Similarly, ADAMTS exhibits some contradictive
outcomes because ADAMTS-12 and ADAMTS-1 display anti-angiogenic and antimetastatic properties. One
possible explanation to consider, especially for
ADAMTS-1, is that this molecule undergoes auto-proteolytic cleavage or even proteolytically impairment of
its catalytic site that can account for these outcomes
[11,16]. In both cases, the story will mature over the
next few years because much research is in progress
within this eld.
MMPs and cancer cell invasion
The ECM is a dynamic structure that orchestrates the
behavior of the cells by interacting with them. The
proteolytic activity of MMPs is required for a cancer
cell to degrade physical barriers during local expansion
and intravasation at nearby blood vessels, extravasation
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Fig. 1. Pivotal roles of MMPs in cancer progression. Cancer progression involves different stages, including tumor growth and the multistep
processes of invasion, metastasis and angiogenesis, all of which can be modulated by MMPs. The expression of MMPs in the tumor microenvironment depends not only on the cancer cells, but also on the neighboring stromal cells. MMPs exert their proteolytic activity and
degrade the physical barriers, facilitating angiogenesis, tumor cells invasion and metastasis. Tumor growth and angiogenesis also depend on
the increased availability of signaling molecules, such as growth factors and cytokines, by MMPs making these factors more accessible to
the cancer cells and the tumor microenvironment. This occurs by liberating them from the ECM (IGF, bFGF and VEGF) or by shedding them
by from the cell surface (EGF, TGF-a, HB-EGF). Angiogenesis is also tightly modulated by the release of negative regulators of angiogenesis,
such as angiostatin, tumstatin, endostatin and endorepellin. MMPs also modulate the cellcell and cellECM interactions by processing
E-cadherin and integrins, respectively, affecting both cell phenotype (EMT) and increasing cell migration.
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Table 1. Key matrix metalloproteinases in relation with the stages of cancer progression, their activity and effect.
MMP
Cancer cell invasion
Several MMPs such as MT1-MMP,
MMP-2 and MMP-9
Several members of the ADAM family
Cancer cell proliferation
MMP-1, -2, -3, -7, -9, -11, -19, ADAM12
MMP-3, -7, ADAM17, ADAM10
ADAM10
MMP-9, -2, -14
MMP-7 (anchored to CD44)
Cancer cell apoptosis
MMP-7, ADAM10
ADAM10
Several MMPs and ADAMs
Activity
Effect
Proteolytic
Proliferation
Anti-apoptotic
MMP-7, -8
Up-regulation of angiogenesis
Down-regulation of angiogenesis
Promote migration
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generate pro-angiogenic factors. Indeed, MMP-9 participates in the angiogenic switch because it increases
the biovailability of important factors in this process,
such as the vascular endothelial growth factor
(VEGF), which is the most potent mediator of tumor
vasculature, and basic broblast growth factor
(bFGF), by degradation of extracellular components,
such as collagen type IV, XVIII and perlecan, respectively [3538].
The angiogenic balance is tightly regulated by
MMPs because they can also down-regulate blood vessel formation through the generation of degradation
fragments that inhibit angiogenesis. Such molecules
include tumstatin, endostatin, angiostatin and endorepellin, which are generated via cleavage of type IV,
XVII collagen, plasminogen, an inactive precursor of a
serine proteinase plasmin, and perlecan [3841].
MMPs and cell adhesion, migration, and
epithelial to mesenchymal transition
Cell movement is highly related to the proteolytic
activity of MMPs and ADAMs, regulating the
dynamic ECMcell and cellcell interactions during
migration. Initially, the generation of cryptic peptides
via degradation of ECM molecules, such as collagen
type IV and laminin-5, promotes the migration of cancer cells [35,42]. Several integrins play an active role in
regulation of cell migration because they can serve as
substrates for MMPs [43].
Over-expression of several MMPs (MMP-2, -3, -9,
-13, -14) has been associated with epithelial to mesenchymal transition (EMT), a highly conserved and
fundamental process of morphological transition [5].
In particular, during this event, epithelial cells actively
down-regulate cellcell adhesion systems, lose their
polarity, and acquire a mesenchymal phenotype with
reduced intercellular interactions and increased migratory capacity [44]. The communication between the
cells is disrupted by the shedding of E-cadherin by
ADAM10, leading to disrupted cell adhesion and
induction of EMT, followed by increased cell migration [23]. MMP-1 and -7 also appear to contribute to
this morphological transition by cleaving E-cadherin
[45]. Recent studies indicate the implication of MMP28 in the proteolytic activation of TGF-b, a powerful
inducer of EMT, leading to EMT [46,47].
It is worth noting that the interaction between hyaluronan and its major cell surface receptor, CD44,
results in the activation of signaling molecules such as
Ras, Rho, PI-3 kinases and AKT, consequently
promoting cancer progression. A recent study reported
that hyaluronan promotes cancer cell migration and
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increased matrix metalloproteinase secretion, specically the increased active form of MMP-2, through
Rho kinase-mediated signaling [48].
MMPs and immune surveillance
The host immune system is capable of recognizing and
attacking cancer cells by recruiting tumor-specic
T-lymphocytes, NK cells, neutrophils and macrophages. By contrast, cancer cells evolve escaping mechanisms using MMPs to acquire immunity.
MMPs shed interleukin-2 receptor-a by the cell surface of T-lymphocytes, thereby suppressing their proliferation [49]. In addition, TGF-b, a signicant
suppressor of T-lymphocyte reaction against cancer
cells, is released as a result of MMP activity [50]. Similarly, MMPs decrease cancer-cell sensitivity to NK
cells by generating a bioactive fragment from a1-proteinase inhibitor [51]. A number of studies have also
shown the ability of MMPs to efciently cleave several
members of the CC (b-chemokine) and CXC
(a-chemokine) chemokine subfamilies or to regulate
their mobilization, affecting leukocyte inltration and
migration [52,53].
Enzymes inhibited
Peptidomimetic
Peptidomimetic
Nonpeptidomimetic
Nonpeptidomimetic
Nonpeptidomimetic
Nonpeptidomimetic
Chemically modified tetracycline
Chemically modified tetracycline
Reform proenzyme structure
Small molecule sheddase inhibitor
Analogues of PPi
Nonsteroidal inhibitor of aromatase
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hydroxamates, carboxylates, hydrocarboxylates, sulfhydryls and phosphoric acid derivatives. The earliest
representative of this generation and the rst MMPI
that entered clinical trials is batimastat (BB-94), a hydroxymate derivative with low water solubility and a
broad spectrum of inhibition [59]. To overcome the
solubility factor, marimastat, another hydroxymatebased inhibitor, was introduced for oral administered.
However, it was also associated with musculoskeletal
syndrome, probably as a result of the broad spectrum
of inhibition [60,61]. In addition, in vitro studies with
batimastat and marimastat showed that they can act
synergistically with TIMP-2 in the promotion of
proMMP-2 activation by MT1-MMP, increasing overall
pericellular proteolysis [62].
Nonpeptidomimetic MMPIs
To improve specicity and oral bioavailability, the
nonpeptidomimetic MMPIs were synthesized on the
basis of the current knowledge of the 3D conformation
of the MMP active site. This generation comprises of
BAY12-9566, prinomastat (AG3340), BMS-275291
and CGS27023A [63]. The latter agent was aborted as
a result of limited efcacy and musculoskeletal side
effects in phase I clinical trials [64]. Musculoskeletal
toxicity has also been reported in clinical trials with
prinomastat and BMS-275291 [65,66].
Chemically modified tetracyclines
Another generation of MMPIs, tetracycline derivatives,
inhibit both the enzymatic activity and the synthesis of
MMPs via blocking gene transcription. Chemically
modied tetracyclines, lacking antibiotic activities, may
inhibit MMPs by binding to metal ions such as zinc and
calcium. This family of inhibitors, including metastat
(COL-3), minocycline and doxycycline, cause limited
systemic toxicity compared to regular tetracyclines. The
chemically modied tetracycline, doxycycline, is currently the only Food and Drug Administration
approved MMPI for the prevention of periodontitis,
whereas metastat has entered phase II trials for Kaposis
sarcoma and brain tumors [67].
Novel mechanism-based inhibitors
A novel inhibitor, SB-3CT, was designed aiming to
selectively bind to the active site of gelatinases (MMP-2
and MMP-9) and reform the proenzyme structure.
Specically, the fundamental step in the inhibition of
gelatinases by SB-3CT is an enzyme-catalyzed ring
opening of the thirane, giving a stable zinc-thiolate spe22
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Acknowledgements
We thank Professor G. N. Tzanakakis (University of
Crete, Greece) and Dr D. Kletsas (NCSR Demokritos, Greece) for their critical reading and valuable
advice. We apologize to the authors whose work could
not be cited as a result of space limitations.
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