Báo cáo khoa học: Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting pdf

MINIREVIEW Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting Chrisostomi Gialeli 1 , Achilleas D. Theocharis 1 and Nikos K. Karamanos 1,2 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 Introduction Cancer is one of the leading causes of disease and mortality worldwide [1]. As a result, the past two dec- ades 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 microenviron- ment play a pivotal role in this process [2]. Studies conducted over more than 40 years have revealed mounting evidence supporting that extracellu- lar matrix remodeling proteinases, such as matrix metalloproteinases (MMPs), are the principal media- tors of the alterations observed in the microenviron- ment 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, 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 zinc- dependent 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 under- lying premise of the current minireview is that MMPs are able to proteolyti- cally process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert con- tradicting 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 pro- gression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs. 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. 16 FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS as well as in pathological conditions, such as inflamma- tory, vascular and auto-immune disorders, and carcino- genesis [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 thera- peutic 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 num- ber 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 metallo- proteinase (ADAM), which includes two subgroups: the membrane-bound ADAM and a disintegrin and metalloproteinase with thrombospondin motifs (AD- AMTS). Recent studies show that ADAM and AD- AMTS present altered expression in diverse tumor types, suggesting that these proteins are involved in different steps of cancer progression including carcino- genesis [9,10]. ADAM molecules are implicated in tumor cell prolireration ⁄ apoptosis, cell adhe- sion ⁄ migration and cell signaling. In particular, they exhibit proteolytic activity like MMPs, although their main roles focus on ectodomain shedding and nonpro- teolytic functions, such as binding to adhesion mole- cules, 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 micro- environment. 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 metallo- proteinases (TIMP)] is quite diverse during cancer development. The over-expression of MMPs in the tumor microenvironment depends not only on the can- cer 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 fibro- blasts to constitute an important source of MMPs through the secretion of interleukins and growth fac- tors and direct signaling through extracellular MMP inducer [10]. The cellular source of MMPs can there- fore have critical consequences on their function and activity. For example, in this regard, neutrophils express MMP-9 free of TIMP-1, which results in acti- vation 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, metas- tasis), enzyme localization (tumor cells, stroma) and substrate profile. For example, MMP-8 provides a pro- tective 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 dis- play anti-angiogenic and antimetastatic properties. One possible explanation to consider, especially for ADAMTS-1, is that this molecule undergoes auto-pro- teolytic 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 C. Gialeli et al. MMPs as potential targets in malignancy FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS 17 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 rep- resent the site where active ECM degradation takes place. Invadopodia utilize transmembrane invadopodi- a-related proteinases, including MMP-14 [membrane- type (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. MMPs and cancer cell proliferation There are several mechanisms by which MMPs con- tribute to tumor cell proliferation. In particular, they can modulate the bioavailability of growth factors and the function of cell-surface receptors. The above pro- cess also involves the ADAM family. Members of the MMP and ADAM families can release the cell-mem- brane-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 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 micro- environment 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. MMPs as potential targets in malignancy C. Gialeli et al. 18 FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS proteins that regulate the bioavailability of the growth factor [18,19]. EGFR, mediator of cell proliferation, is implicated in cancer progression because it is over- expressed 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 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 impor- tant 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 Table 1. Key matrix metalloproteinases in relation with the stages of cancer progression, their activity and effect. MMP Activity Effect Cancer cell invasion Several MMPs such as MT1-MMP, MMP-2 and MMP-9 Proteolytic Degrade physical barriers Several members of the ADAM family Cancer cell proliferation MMP-1, -2, -3, -7, -9, -11, -19, ADAM12 Cleavage of IGF-binding proteins Proliferation MMP-3, -7, ADAM17, ADAM10 Shedding of membrane-anchored ligands of EGFR (HB-EGF, TGF-a and amphiregulin) ADAM10 Shedding of E-cadherin MMP-9, -2, -14 Activation of TGF-b MMP-7 (anchored to CD44) Shedding of HB-EGF Cancer cell apoptosis MMP-7, ADAM10 Cleavage of Fas ligand Anti-apoptotic ADAM10 Shedding of tumor associated major histocompatibility proteins complex class-I Several MMPs and ADAMs Indirect activation of Akt through activation of EGFR and IGFR 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 Up-regulation of angiogenesis Degradation of COL-IV, COL-XVIII, perlecan; generation of tumstatin, endostatin, angiostatin and endorepellin, respectively Down-regulation of angiogenesis Cell adhesion, migration, and epithelial to mesenchymal transition MMP-2 Degradation of COL-IV; generation of cryptic peptides Promote migration 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 Induction of EMT; cell migration ADAM10 MMP-1, -7 Shedding of E-cadherin MMP-28 Proteolytic activation of TGF-b Powerful inducer of EMT; cell migration Immune surveillance MMP-9 Shedding of interleukin-2 receptor-a by T-lymphocytes surface Suppress T-lymphocyte proliferation MMP-9, -2, -14 Release of active TGF-b Suppress T-lymphocyte reaction against cancer cells MMP-7, -11, -1, -8, -3 Release of a1-proteinase inhibitor Decrease cancer cell sensitivity to NK cells MMP-7, -8 Cleavage of a- and b-chemokines or regulation of their mobilization Affect leukocyte infiltration and migration C. Gialeli et al. MMPs as potential targets in malignancy FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS 19 subsequent proliferative effects. Notably, GAGs chains can recruit MMPs to release growth factors from the cell surface and, as a result, induce cancer cell prolifer- ation. 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 proteo- lytically 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 relation- ship [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 transmem- brane 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 apop- tosis to the neighboring cells depending on the system [28–30]. Moreover, proteolytic shedding of tumor- associated 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 exam- ple, 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 reg- ulators of angiogenesis depending on the time point of expression during tumor angiogenesis and vasculogene- sis 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 generate pro-angiogenic factors. Indeed, MMP-9 par- ticipates 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, respec- tively [35–38]. The angiogenic balance is tightly regulated by MMPs because they can also down-regulate blood ves- sel formation through the generation of degradation fragments that inhibit angiogenesis. Such molecules include tumstatin, endostatin, angiostatin and endore- pellin, 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 can- cer 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 mesen- chymal 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 migra- tory 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 migra- tion [23]. MMP-1 and -7 also appear to contribute to this morphological transition by cleaving E-cadherin [45]. Recent studies indicate the implication of MMP- 28 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 hyal- uronan 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 MMPs as potential targets in malignancy C. Gialeli et al. 20 FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS increased matrix metalloproteinase secretion, specifi- cally 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 macrophag- es. By contrast, cancer cells evolve escaping mecha- nisms using MMPs to acquire immunity. MMPs shed interleukin-2 receptor-a by the cell sur- face of T-lymphocytes, thereby suppressing their prolif- eration [49]. In addition, TGF-b, a significant suppressor of T-lymphocyte reaction against cancer cells, is released as a result of MMP activity [50]. Simi- larly, MMPs decrease cancer-cell sensitivity to NK cells by generating a bioactive fragment from a1-pro- teinase 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 enzy- matic activity of MMPs. Several generations of synthetic MMPIs were tested in phase III clinical trials in humans, including pepti- domimetics, nonpeptidomimetics inhibitors and tetra- cycline 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 develop- ment 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 down- regulation of MMP synthesis [55–57]. Despite the noted low toxicity of these strategies, they are still immature with respect to the effectiveness of the tar- geted delivery of oligonucleotides or siRNA to tumor cancer cells. Categories of the potential matrix metallo- proteinase inhibitors and their specificities are summa- rized in Table 2. Peptidomimetic MMPIs The first geneneration of MMPIs introduced com- prised the peptidomimetic. These pseudopeptide deriv- atives 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 Type of drug ⁄ source Enzymes inhibited Synthetic inhibitors Batimastat Peptidomimetic MMP-1, -2, -3, -7, -9 Marimastat Peptidomimetic Broad spectrum Tanomastat (BAY12-9666) Nonpeptidomimetic MMP-2, -3, -9 Prinomastat (AG3340) Nonpeptidomimetic MMP-2, -3, -7, -9, -13 BMS-275291 Nonpeptidomimetic MMP-2, -9 CGS27023A Nonpeptidomimetic MMP-1, -2, -3 Minocycline Chemically modified tetracycline MMP-1, -2, -3 Metastat (COL-3) Chemically modified tetracycline MMP-1, -2, -8, -9, -13 SB-3CT Reform proenzyme structure MMP-2, -9 INCB7839 Small molecule sheddase inhibitor ADAM-10, 17 Off-target inhibitors Bisphosphonates Analogues of PPi MMP-1, -2, -7, 9, MT1-, MT2MMP Letrozole Nonsteroidal inhibitor of aromatase MMP-2, -9 Natural inhibitors Neovastat (AE-941) Extract from shark cartilage MMP-1, -2, -7, -9, -13 Genistein Soy isoflavone MMP-2, -9, MT1-, MT2-, MT3-MMP C. Gialeli et al. MMPs as potential targets in malignancy FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS 21 hydroxamates, carboxylates, hydrocarboxylates, sul- fhydryls and phosphoric acid derivatives. The earliest representative of this generation and the first MMPI that entered clinical trials is batimastat (BB-94), a hy- droxymate derivative with low water solubility and a broad spectrum of inhibition [59]. To overcome the solubility factor, marimastat, another hydroxymate- based 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 cur- rently 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 spe- 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-depen- dent 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 benefi- cial way beyond their primary target. This is the case for bisphosphonates, analogs of PPi, which inhibit the function of the mevalonate pathway. Besides the inhi- bition of osteoclast activity and bone resorption, bis- phosphonates inhibit the enzymatic activity of various MMPs [71]. According to data obtained in our labora- tory (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 inhibi- tor 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 sup- pressed by letrozole in a dose-dependent fashion, limit- ing 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 suppres- sion 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 MMPs as potential targets in malignancy C. Gialeli et al. 22 FEBS Journal 278 (2011) 16–27 ª 2010 The Authors Journal compilation ª 2010 FEBS 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 stan- dardized 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 prop- erties, 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 progres- sion-free survival and overall survival may be attrib- uted 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 particu- lar, for certain cancer types, especially those where the stroma is an essential player in carcinogenesis, the inhi- bition 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 expres- sion 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 unsat- isfying 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 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 inhib- itors 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]. Exo- sites 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 sub- strate-specific. In this respect, a new class of selec- tives 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 therapeu- tic efficacy of MMPIs, as well as their activity, at dif- ferent 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 counter- balance excessive ECM deposition by myofibroblasts in the tumor microenvironment, as well as the findings of a recent study [91] reporting amoeboid-like nonpro- teolytic 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 ‘Demokri- tos’, 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. C. Gialeli et al. 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