MINIREVIEW
Roles of matrix metalloproteinases in cancer progression
and their pharmacological targeting
Chrisostomi Gialeli1, Achilleas D. Theocharis1 and Nikos K. Karamanos1,2
1 Department of Chemistry, Laboratory of Biochemistry, University of Patras, Greece
2 Institute of Chemical Engineering and High-Temperature Chemical Processes (FORTH ⁄ ICE-HT), Patras, Greece
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: [email protected]
(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
cell–cell and cell–ECM 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 profile. 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 field 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 efficacy 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].
Studies conducted over more than 40 years have
revealed mounting evidence supporting that extracellular matrix remodeling proteinases, such as matrix
metalloproteinases (MMPs), are the principal mediators of the alterations observed in the microenvironment during cancer progression [2,3]. MMPs belong to
a zinc-dependent family of endopeptidases implicated
in a variety of physiological processes, including
wound healing, uterine involution and organogenesis,
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 inflammatory, vascular and auto-immune disorders, and carcinogenesis [3–6]. 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].
Roles of MMPs in cancer progression
During development of carcinogenesis, tumor cells
participate in several interactions with the tumor
microenvironment involving extracellular matrix
(ECM), growth factors and cytokines associated with
ECM, as well as surrounding cells (endothelial cells,
fibroblasts, macrophages, mast cells, neutrophils,
pericytes and adipocytes) [2,10,12]. Four hallmarks of
cancer that include migration, invasion, metastasis and
angiogenesis are dependent on the surrounding microenvironment. Critical molecules in these processes are
MMPs because they degrade various cell adhesion
molecules, thereby modulating cell–cell and cell–ECM
interactions (Fig. 1). Key MMPs in relation to the
stages of cancer progression, their activity and their
effects are summarized in Table 1, as they are depicted
in the text.
The emerging view, reflected by several studies,
reveals that the expression and role of MMPs and
their natural inhibitors [i.e. tissue inhibitor of metalloproteinases (TIMP)] is quite diverse during cancer
development. The over-expression of MMPs in the
MMPs as potential targets in malignancy
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 fibroblasts 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 profile. 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 specific situations. This
dual role is based on the findings in animal models,
where it observed that MMP-9 knockdown mouse
models exhibited decreased incidence of carcinogenesis,
whereas tumors formed in MMP-9 deficient mice were
significantly 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 field.
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 cell–cell and cell–ECM interactions by processing
E-cadherin and integrins, respectively, affecting both cell phenotype (EMT) and increasing cell migration.
and invasion at a distant location (Fig. 1). During
invasion, the localization of MMPs to specialized cell
surface structures, called invadopodia, is requisite for
their ability to promote invasion. These structures represent the site where active ECM degradation takes
place. Invadopodia utilize transmembrane invadopodia-related proteinases, including MMP-14 [membranetype (MT)1-MMP], several members of the ADAM
family, as well as secreted and activated MMPs at the
site, such as MMP-2 and -9, to degrade a variety of
ECM macromolecules and facilitate cell invasion [17].
The contribution of MMP activities to several critical
steps of cancer progression is described below.
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MMPs and cancer cell proliferation
There are several mechanisms by which MMPs contribute to tumor cell proliferation. In particular, they
can modulate the bioavailability of growth factors and
the function of cell-surface receptors. The above process also involves the ADAM family. Members of the
MMP and ADAM families can release the cell-membrane-precursors of several growth factors, such as
insulin-like growth factors (IGFs) and the epidermal
growth factor receptor (EGFR) ligands that promote
proliferation. Several MMPs (MMP-1, -2, -3, -7, -9,
-11 and -19) and ADAM12 cleave IGF-binding
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MMPs as potential targets in malignancy
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
Degrade physical barriers
Cleavage of IGF-binding proteins
Shedding of membrane-anchored ligands of EGFR
(HB-EGF, TGF-a and amphiregulin)
Shedding of E-cadherin
Activation of TGF-b
Shedding of HB-EGF
Proliferation
Cleavage of Fas ligand
Shedding of tumor associated major
histocompatibility proteins complex class-I
Indirect activation of Akt through activation of
EGFR and IGFR
Anti-apoptotic
Tumor angiogenesis and vasculogenesis
Several MMPs (including MMP-2,
-9 MMP-3, -10, -11 MMP-1, -8, -13)
Degradation of COL-IV, perlecan; release of VEGF
and bFGF, respectively
Degradation of COL-IV, COL-XVIII, perlecan;
generation of tumstatin, endostatin, angiostatin
and endorepellin, respectively
Cell adhesion, migration, and epithelial to mesenchymal transition
MMP-2
Degradation of COL-IV; generation of cryptic
peptides
MT1-MMP
Degradation of laminin-5; generation of cryptic
peptides
MMPs
Integrins as substrates
MMP-2, -3, -9, -13, -14
Over-expression; related to EMT
ADAM10
Shedding of E-cadherin
MMP-1, -7
MMP-28
Proteolytic activation of TGF-b
Immune surveillance
MMP-9
MMP-9, -2, -14
Shedding of interleukin-2 receptor-a by
T-lymphocytes surface
Release of active TGF-b
MMP-7, -11, -1, -8, -3
Release of a1-proteinase inhibitor
MMP-7, -8
Cleavage of a- and b-chemokines or regulation
of their mobilization
proteins that regulate the bioavailability of the growth
factor [18,19]. EGFR, mediator of cell proliferation, is
implicated in cancer progression because it is overexpressed in more than one-third of all solid tumors
[20]. During cancer progression, increased shedding of
the membrane-anchored ligands of EGFR, including
heparin-binding EGF (HB-EGF), transforming growth
factor (TGF)-a and amphiregulin, was observed with
the action of MMP-3, -7, ADAM17 or ADAM10
[21,22]. MMPs and ADAM also control proliferation
Up-regulation of angiogenesis
Down-regulation of angiogenesis
Promote migration
Induction of EMT; cell migration
Powerful inducer of EMT;
cell migration
Suppress T-lymphocyte proliferation
Suppress T-lymphocyte reaction
against cancer cells
Decrease cancer cell sensitivity
to NK cells
Affect leukocyte infiltration
and migration
signals through integrins because the shedding of
E-cadherin results in b-catenin translocation to the
nucleus, leading to cell proliferation [23]. It is worth
noting that the inactive proform of TGF-b, an important biomolecule in cancer, is proteolytically activated
by MMP-9, -2, -14 in a similar way [24,25].
One of the key observations that has emerged from
several studies is the pivotal role of the interactions
between glycosaminoglycans (GAGs)-MMPs-GFs,
leading to the activation of the proMMPs and their
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C. Gialeli et al.
subsequent proliferative effects. Notably, GAGs chains
can recruit MMPs to release growth factors from the
cell surface and, as a result, induce cancer cell proliferation. For example, MMP-7 exerts high affinity for
heparan sulfate chains. On the basis of this notion,
heparan sulfate chains on cell surface receptors, such
as some variant isoforms of CD44, anchor the proteolytically active MMP-7, resulting in the cleavage of
HB-EGF [26]. The above findings may explain the
diverse proliferative outcomes of the various GAG
types in human malignant mesothelioma cell lines,
as well as indicating a structure–function relationship [27].
MMPs and cancer cell apoptosis
Matrix-degrading enzymes confer both apoptotic and
anti-apoptotic actions. MMPs and ADAMs, especially
MMP-7 and ADAM10, confer anti-apoptotic signals
to cancer cells by cleaving Fas ligand, a transmembrane stimulator of the death receptor Fas, from the
cell surface. This proteolytic activity inactivates Fas
receptor and induces resistance to apoptosis and
chemoresistance to the cancer cells or promotes apoptosis to the neighboring cells depending on the system
[28–30]. Moreover, proteolytic shedding of tumorassociated major histocompatibility proteins complex
class-I related proteins by ADAM17 may suppress
natural killer (NK) cell-mediated cytotoxicity toward
cancer cells [31]. Notably, MMPs may contribute to
the anti-apoptotic effect by activating indirectly the
serine ⁄ threonine kinase Akt ⁄ protein kinase B through
the signaling cascades of EGFR and IGFR [20,32].
MMPs also promote apoptosis, most likely indirectly
by changing the ECM composition; for example, by cleaving laminin, which influences integrin
signaling [33].
MMPs and tumor angiogenesis and
vasculogenesis
MMPs display a dual role in tumor vasculature
because they can act both as positive and negative regulators of angiogenesis depending on the time point of
expression during tumor angiogenesis and vasculogenesis as well as the availability of the substrates. The key
players of the MMP family that participate in tumor
angiogenesis are mainly MMP-2, -9 and MMP-14,
and, to a lesser extent, MMP-1 and -7 [34].
For cancer cells to continue to grow and start
migrating, it is necessary to form new blood vessels.
The first step in this process is to eliminate the physical
barriers by ECM degradation and, subsequently, to
20
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 fibroblast growth factor
(bFGF), by degradation of extracellular components,
such as collagen type IV, XVIII and perlecan, respectively [35–38].
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 [38–41].
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 ECM–cell and cell–cell 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 cell–cell 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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MMPs as potential targets in malignancy
increased matrix metalloproteinase secretion, specifically 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-specific
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 significant
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 efficiently cleave several
members of the CC (b-chemokine) and CXC
(a-chemokine) chemokine subfamilies or to regulate
their mobilization, affecting leukocyte infiltration and
migration [52,53].
Pharmacological targeting of matrix
metalloproteinases
On the basis of the pivotal roles that MMPs and
ADAMs play in several steps of cancer progression,
the pharmaceutical industry has invested considerable
effort over the past 20 years aiming to develop safe
and effective agents targeting MMPs. In this regard,
multiple MMPIs have been developed, in an attempt
to control the synthesis, secretion, activation and enzymatic activity of MMPs.
Several generations of synthetic MMPIs were tested
in phase III clinical trials in humans, including peptidomimetics, nonpeptidomimetics inhibitors and tetracycline derivatives, which target MMPs in the
extracellular space [54]. In addition, various natural
compounds have been identified as inhibiting MMPs
[55]. Other strategies of MMP inhibition in development involve antisense and small interfering RNA
(siRNA) technology. Antisense strategies are directed
selectively against the mRNA of a specific MMP,
resulting in decrease of RNA translation and downregulation of MMP synthesis [55–57]. Despite the
noted low toxicity of these strategies, they are still
immature with respect to the effectiveness of the targeted delivery of oligonucleotides or siRNA to tumor
cancer cells. Categories of the potential matrix metalloproteinase inhibitors and their specificities are summarized in Table 2.
Peptidomimetic MMPIs
The first geneneration of MMPIs introduced comprised the peptidomimetic. These pseudopeptide derivatives mimic the structure of collagen at the MMP
cleavage site, functioning as competitive inhibitors,
and chelating the zinc ion present at the activation site
[58]. On the basis of the group that binds and chelates
the zinc ion, peptidomimetis are subdivided into
Table 2. Potential matrix metalloproteinase inhibitors.
MMPI
Synthetic inhibitors
Batimastat
Marimastat
Tanomastat (BAY12-9666)
Prinomastat (AG3340)
BMS-275291
CGS27023A
Minocycline
Metastat (COL-3)
SB-3CT
INCB7839
Off-target inhibitors
Bisphosphonates
Letrozole
Natural inhibitors
Neovastat (AE-941)
Genistein
Type of drug ⁄ source
Enzymes inhibited
Peptidomimetic
Peptidomimetic
Nonpeptidomimetic
Nonpeptidomimetic
Nonpeptidomimetic
Nonpeptidomimetic
Chemically modified tetracycline
Chemically modified tetracycline
Reform proenzyme structure
Small molecule sheddase inhibitor
MMP-1, -2, -3, -7, -9
Broad spectrum
MMP-2, -3, -9
MMP-2, -3, -7, -9, -13
MMP-2, -9
MMP-1, -2, -3
MMP-1, -2, -3
MMP-1, -2, -8, -9, -13
MMP-2, -9
ADAM-10, 17
Analogues of PPi
Nonsteroidal inhibitor of aromatase
MMP-1, -2, -7, 9, MT1-, MT2MMP
MMP-2, -9
Extract from shark cartilage
Soy isoflavone
MMP-1, -2, -7, -9, -13
MMP-2, -9, MT1-, MT2-, MT3-MMP
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hydroxamates, carboxylates, hydrocarboxylates, sulfhydryls and phosphoric acid derivatives. The earliest
representative of this generation and the first 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 specificity 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 efficacy 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
modified 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 modified 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 Kaposi’s
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.
Specifically, 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
cies. It was reported to inhibit liver metastasis and
increase survival in mouse models [68].
On the basis of the importance of the ADAM family
in cancer progression, small molecule inhibitors have
been developed, such as INCB7839, and are currently
being tested in clinical trials [69]. Such agents may be
administered as single agents or in combination with
agents that block the EGFR family at EGFR-dependent tumors [70].
Off-target inhibitors of MMPs
There are several other drugs that have been shown to
influence MMPs and other ECM molecules in a beneficial way beyond their primary target. This is the case
for bisphosphonates, analogs of PPi, which inhibit the
function of the mevalonate pathway. Besides the inhibition of osteoclast activity and bone resorption, bisphosphonates inhibit the enzymatic activity of various
MMPs [71]. According to data obtained in our laboratory (P.G. Dedes and N.K. Karamanos, unpublished
data), certain bisphosphonates show beneficial effects
as a result of altering the expression pattern of
MMPs ⁄ TIMPs by inhibiting and increasing the gene
and protein expression of several MMPs and TIMPs,
respectively, in breast cancer cells.
Another agent that has exhibited inhibitory effects
on MMPs is letrozole, a reversible nonsteroidal inhibitor of P450 aromatase. In particular, letrozole prevents
the aromatase from converting androgens to estrogens,
the most crucial step in the estrogen synthesis pathway
in post-menopausal women, by binding to the heme of
its cytochrome P450 unit. In addition, the gelatinases
(MMP-2 and -9) released by breast cancer cells, as well
as functional invasion in vitro, are considerably suppressed by letrozole in a dose-dependent fashion, limiting the metastatic potential of these cells [72]. The
above observation is in accordance with the results
obtained in the British International Group 1-98 study
showing that letrozole lowers the occurrence of distant
metastases [73].
It is worth noting that estrogen receptor-a suppression with siRNA in breast cancer cells lines abolishes
the ability of estradiol to up-regulate the expression of
MMP-9, highlighting the importance of signaling by
estrogen receptors in the expression pattern of MMPs
and therefore their potential pharmacological targeting
[74].
Natural inhibitors of MMPs
TIMPs, the natural inhibitors of MMPs, were also
used to block MMPs activity. Although they have
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demonstrated efficacy in experimental models, TIMPs
may exert MMP-independent promoting effects [75].
To avoid the negative results and toxicity issues
raised by the use of synthetic MMPIs, one answer
was provided by the field of natural compounds. One
compound taken into consideration was extracted
from shark cartilage. Oral administration of a standardized extract, neovastat, exerts anti-angiogenic and
anti-metastatic activities and these effects depend not
only on the inhibition of MMPs enzymatic activity,
but also on the inhibition of VEGF [76]. Another
natural agent that has anticancer effects is genistein,
a soy isoflavonoid structurally similar to estradiol.
Apart from its estrogening and anti-estrogenic properties, genistein confers tumor inhibition growth
and invasion effects, interfering with the expression
ratio and activity of several MMPs and TIMPs
[77,78].
Challenges and future prospects
MMPs have well-established complex and key roles in
cancer progression. However, in most cases, the agents
targeting MMPs exhibited poor performance in clinical
trials, in contrast to their promising activity in many
preclinical models [79]. There are several possible
explanations for these contradictive outcomes. First,
the failure observed in phase III clinical trials with
respect to MMPIs reaching the endpoints of progression-free survival and overall survival may be attributed to no proper subgroup selection, with mostly
endstage disease patients [80]. As is the case for many
anticancer agents, the administration of MMPIs
should be made after thorough consideration of the
specific cancer-types and stages of disease. In particular, for certain cancer types, especially those where the
stroma is an essential player in carcinogenesis, the inhibition of MMPs is proven to be more effective [81]. In
addition, the timeframe of targeting MMPs differs,
depending on the stage of cancer, because the expression profile, as well as the activity of MMPs, is not the
same in the early stage compared to advanced cancer
disease. Recent studies show that members of the
MMP family exert different roles at different steps of
cancer progression. As a consequence, the use of
broad-spectrum MMPI raises concerns when certain
MMPs that exert anticancer effects are inhibited. In
this regard, the use of such MMPIs may lead to unsatisfying clinical outcomes as a result of the wide range
of MMPs that are inhibited [82]. In addition, toxicity
effects, such as muscolosceletal syndrome, have limited
the maximum-tolerated dose of certain MMPIs, thus
limiting drug efficacy. The challenge is to distinguish
MMPs as potential targets in malignancy
the specific role of individual enzymes in each case
using both widespread gene and tissue microarrays
[83].
Considering all of the above, one of the major
challenges for the future is the development of inhibitors or monoclonal antibodies that bind to the
active site of the enzyme and are specific for certain
MMPs, showing little or no cross-reaction with other
MMPs [81]. In this respect, a potent and highly
selective antibody, DX-2400, against the catalytic
domain of MMP-14 was designed with high binding
affinity [84,85]. To further increase the specificity of
MMPIs, the future of drug development comprises
the use of drugs targeting specific exosites [86]. Exosites are binding sites outside the active domain of
the MMPs and are related to substrate selection of
MMPs [87]. Therefore, future drugs targeting less
conserved exosites rather than the catalytic domain
will result in drugs that are both MMP- and substrate-specific. In this respect, a new class of selectives MMPIs, triple-helical transition state analogs, is
introduced, modulating the collagenolytic activity of
MMPIs [88].
In addition, the molecular complexity of cancer
progression suggests that the appropriate combination
of MMPIs with other chemotherapeutic or molecular
targeted agents may play an important role with
respect to increasing drug efficacy. Last, but not
least, imaging activity of specific MMPs in vivo with
probes will make it possible to evaluate the therapeutic efficacy of MMPIs, as well as their activity, at different stages of cancer progression in certain tumors
[89].
Taking into consideration the data presented in the
present minireview, the minireview by Murphy and
Nagase in this same series [90], and knowledge that
enhanced MMP activity may be required to counterbalance excessive ECM deposition by myofibroblasts
in the tumor microenvironment, as well as the findings
of a recent study [91] reporting amoeboid-like nonproteolytic cell invasion may affect the action of MMPI,
it is concluded that that the pharmacological targeting
of cancer by the development of a new generation of
effective and selective MMPIs is an emerging and
promising area of research.
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.
FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS
23
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C. Gialeli et al.
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