MINI REVIEW ARTICLE published: 17 July 2012 doi: 10.3389/fphar.2012.00140 New and paradoxical roles of matrix in the tumor microenvironment

Agnès Noël 1*, Ana Gutiérrez-Fernández 2, Nor Eddine Sounni 1, Niels Behrendt 3,4, Erik Maquoi 1, Ida K. Lund 3,4, Santiago Cal 2, Gunilla Hoyer-Hansen3,4 and Carlos López-Otín2

1 Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium 2 Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Asturias, Spain 3 The Finsen Laboratory, Copenhagen University Hospital, Copenhagen Biocenter, Copenhagen N, Denmark 4 Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen Biocenter, Copenhagen N, Denmark

Edited by: Processes such as cell proliferation, angiogenesis, apoptosis, or invasion are strongly influ- Pierre Sonveaux, University of enced by the surrounding microenvironment of the tumor. Therefore, the ability to change Louvain Medical School, Belgium these surroundings represents an important property through which tumor cells are able to Reviewed by: Juan Iovanna, INSERM, France acquire specific functions necessary for tumor growth and dissemination. Matrix metallo- Hervé Emonard, CNRS, France proteinases (MMPs) constitute key players in this process, allowing tumor cells to modify Cyril Rauch, Nottingham University, the (ECM) and release cytokines, growth factors, and other cell-surface UK molecules, ultimately facilitating -dependent tumor progression. Remodeling of *Correspondence: the ECM by collagenolytic such as MMP1, MMP8, MMP13, or the membrane- Agnès Noël, University of Liège, Laboratory of Tumour & Development bound MT1-MMP as well as by other membrane-anchored is required for invasion Biology, Tour de Pathologie, B23, Sart and recruitment of novel blood vessels. However, the multiple roles of the MMPs do Tilman, B-4000 Liège, Belgium. not all fit into a simple pattern. Despite the pro-tumorigenic function of certain metallo- e-mail: [email protected] proteinases, recent studies have shown that other members of these families, such as MMP8 or MMP11, have a protective role against tumor growth and metastasis in ani- mal models. These studies have been further expanded by large-scale genomic analysis, revealing that the encoding metalloproteinases, such as MMP8, MMP27, ADAM7, and ADAM29, are recurrently mutated in specific tumors, while several are epi- genetically silenced in different cancers. The importance of these proteases in modifying the tumor microenvironment highlights the need for a deeper understanding of how stroma cells and the ECM can modulate tumor progression.

Keywords: matrix metalloproteinases, ADAM, cancer, tumor, microenvironment

INTRODUCTION Weaver,2009). Remarkably,increased expression of interstitial col- Genetic alterations in tumor cells are essential for tumor devel- lagen and many of its remodeling enzymes is frequently detected in opment but not sufficient to generate malignant tumors. The signatures associated with poor prognosis in cancer patients tumor stroma resulting from an evolving crosstalk between tumor (Ramaswamy et al., 2003; Finak et al., 2008; Tavazoie et al., 2008). cells and different host cell types is required to create a permis- In addition to quantitative changes in deposition, the sive environment for the invasion of genetically altered tumor architecture of the collagen scaffold is also drastically affected dur- cells (Hanahan and Weinberg, 2011; Lu et al., 2012). Key mod- ing cancer evolution. In this context, collagen crosslinking by lysyl ifications of the stromal environment include enhanced vascu- oxidase (LOX) whose expression is increased upon hypoxic condi- larization following an “angiogenic switch” (Bergers et al., 2000), tions has emerged as a key determinant of late stage tumors (Erler quantitative and qualitative changes in the extracellular matrix et al., 2009). (ECM), and the recruitment of resident fibroblastic cells (Kalluri It is now recognized that proteinases contribute actively to the and Zeisberg, 2006), bone marrow-derived mesenchymal stem elaboration of the stromal microenvironment during early and cells (Spaeth et al., 2009) and inflammatory cells (Coussens and late stages of primary and secondary tumor development (Holm- Werb, 2001). The importance of the tumor microenvironment beck et al., 2003; Noel et al., 2008). The degradation of collagen is now recognized as fundamental for cancer progression (Joyce by cathepsins and matrix metalloproteinases (MMPs), and the and Pollard, 2009), but the critical molecular changes occurring receptor-mediated endocytosis of degraded collagen are impor- in the tumor stroma accompanying and affecting cancer evolu- tant events that regulate cancer cell survival, growth, migration, tion remain largely unknown. Desmoplasia, the fibrotic stromal and invasion. Proteinases act not only by disrupting physiological reaction associated with most carcinomas, is characterized by the barriers to ease cell migration, but importantly by releasing growth local deposition of fibrillar collagen types I, III, and V. This host and chemotactic factors from the ECM and unmasking cryptic reaction correlating with adverse prognosis in mammary carcino- domains of matrix components (Lopez-Otin and Overall, 2002; mas (Hasebe et al., 2002) is also seen in metastatic sites (Erler and Kalluri, 2003). In addition, these enzymes are key regulators of

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shedding, activation, and/or degradation of cell-surface molecules Cauwe et al., 2007; Lopez-Otin and Hunter, 2010). Most MMPs are including adhesion molecules,mediators of apoptosis,receptors of secreted as soluble enzymes but six of them are membrane-type chemokines/cytokines, and intercellular junction (Over- MMPs (MT-MMPs) that are associated with the cell membrane all and Kleifeld, 2006; Cauwe et al., 2007; Lopez-Otin and Hunter, by either a COOH-terminal transmembrane domain (MT1-, 2010). MT2-, MT3-, MT5-MMP) or a glycosylphosphatidyl-inositol In this review, we focus on secreted metalloproteinases (GPI) anchor (MT4- and MT6-MMP). For a description of the (MMPs and -metalloproteinases with structure, function, and regulation of MMPs and MT-MMPs, the domains, referred to as ADAMTSs) and the associated cell-surface reader is referred to previous reviews (Zucker et al., 2003; Sounni receptor (uPARAP/endo180) specifically involved in interstitial and Noel, 2005; Page-McCaw et al., 2007; Sohail et al., 2008; collagen remodeling. We also describe novel findings generated Fanjul-Fernandez et al., 2010; Kessenbrock et al., 2010; Stron- by the collaborative EU-FP7 funded network, MicroEnviMet (No. gin, 2010). The ADAMs are membrane-anchored proteinases that HEALTH-F2-2008-201279). This project has shed light on novel share the catalytic domain with the MMPs but which include two functions of membrane-associated MMPs in the control of cell main differences: (1) the absence of a hemopexin-like domain apoptosis and angiogenesis, as well as on the complex tumor-host and (2) the insertion of three additional domains [cysteine-rich interplay in which proteinases can either boost cancer progression domain, epidermal growth factor (EGF)-like domain and the dis- or protect the host against malignancy. integrin domain; Figure 1; Klein and Bischoff, 2011]. The related ADAMTS family contains 19 human metalloproteinases with a MMPs AND RELATED ENZYMES variable number of type-1 thrombospondin (TSP-1) domains in It is now recognized that proteinases contribute to all stages of their C-terminal region. ADAMTSs are now viewed as key regula- tumor progression (growth, angiogenesis, invasion, and evasion tors of collagen maturation (ADAMTS-2, -3, and -14; Colige et al., to immune system) and are produced not only by the tumor 2005; Dubail et al., 2010), cartilage degradation (ADAMTS-1, -4, - cells themselves, but mainly by the different non-malignant host 5, -8, and -9), microfibril biogenesis (Hubmacher and Apte, 2011), cells composing the tumor. Among the different classes of pro- von Willebrand factor maturation (ADAMTS-13), reproduction teinases implicated during different stages of cancer progression, (ADAMTS-9, -20; Llamazares et al., 2007), and cancer progression the MMPs constitute a family of 24 human zinc-binding endopep- (Handsley and Edwards, 2005; Rocks et al., 2008). tidases that can degrade virtually all ECM components and have a growing number of substrates belonging to all important fam- COLLAGEN REMODELING ilies of cell regulators: integrins, cell-surface receptors, kinases, The fibrillar (e.g., types I, II, III) are composed of three chemokines, and cytokines (Egeblad and Werb, 2002; Lopez-Otin polypeptides α-chains (homotrimers or heterotrimers) assembled and Overall,2002; Folgueras et al.,2004; Overall and Kleifeld,2006; into a triple-helical structure forming the collagenous domain.

FIGURE 1 | Schematic representation of MMPs, MT-MMPs,ADAMs, and ADAMTSs.

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The N-terminal non-collagenous domain of these fibrillar col- lymphangiogenesis,the formation of new lymphatic vessels (Detry lagens is proteolytically removed by ADAMTS-2 (Dubail et al., et al., 2011). The other , MMP9, plays a critical role in 2010). Interstitial are the only known mammalian tumor-induced angiogenesis through release of vascular endothe- enzymes able to degrade triple-helical fibrillar collagens through lial growth factor (VEGF) sequestered from the ECM (Bergers specific cleavage of all three α-chains at a single three- et al., 2000). quarters from the N-terminus. Collagenolytic MMPs include In addition to this MMP-driven collagen degradation process, soluble MMPs (MMP1, MMP8, MMP13) and the membrane- separate pathways, mediated by cysteine protease cathepsins, are associated MMP14/MT1-MMP, MMP15, and MMP16. More operative in acidic extracellular or intracellular microenviron- recently, MMP2 has been identified as an interstitial ments. The intracellular pathway involves the binding of collagen that can cleave native type I collagen in a distinctive way from other fibrils to specific cell-surface receptors followed by the cellular collagenases without generating the classical 3/4 and 1/4 fragments uptake and proteolytic degradation of internalized collagen in the (Egeblad et al., 2007). The very similar gelatinase, MMP9, does lysosomal compartment. One such receptor is uPARAP/Endo180, not cleave collagen but shares gelatinolytic activity with MMP2 a member of the macrophage mannose receptor family of endo- (Vihinen et al., 2005). cytic transmembrane glycoproteins. This receptor plays a key Interestingly, microarray analyses have identified collagenolytic role in the cellular uptake and lysosomal degradation of collagen MMP1 in a gene expression signature able to predict distant metas- fragments generated through the initial MMP-mediated collagen tasis in breast cancer patients (van’t Veer et al., 2002; Gupta et al., cleavage (Kjoller et al., 2004; Curino et al., 2005; Engelholm et al., 2007). Moreover, MMP1 appears to be a key determinant that 2009). In cell lines, the amount of internalized collagen correlates selectively mediates lung metastasis in a murine breast cancer with the levels of uPARAP expression (Madsen et al., 2007, 2011). model (Minn et al., 2005, 2007; Nguyen and Massague, 2007). The genetic ablation of uPARAP/Endo180 in mice demonstrated MMP13 (collagenase-3) originally identified in human breast can- that the uPARAP-driven endocytic route of collagen breakdown is cer tissue (Freije et al., 1994) is viewed as a potential tumor marker a rate-limiting factor in collagenolysis by fibroblastic cells, chon- for breast cancer diagnosis (Chang et al., 2009) and its expression drocytes, and osteoclasts (Engelholm et al., 2003; Kjoller et al., is correlated with metastasis formation (Ellsworth et al., 2009; Lee 2004; Sulek et al., 2007), as well as in collagen turnover in fibro- et al., 2009). In experimental models, MMP13 appears as a key sis (Bundesmann et al., 2012; Lopez-Guisa et al., 2012; Madsen stromal mediator of cancer progression that regulates the release et al., 2012) and in the invasive growth of breast tumors in mice of angiogenic factors (Lederle et al., 2009) and metastatic dissemi- (Curino et al., 2005). Notably, uPARAP regulates the autolysis and nation (Zigrino et al.,2009). Interestingly,the presence of microin- cell-surface level of MT1-MMP reinforcing the functional inter- vasion in ductal carcinoma in situ (DCIS) is associated with focal play between two collagen degradation pathways (Kogianni et al., expression of MMP13 mRNA in stromal fibroblasts (Nielsen et al., 2009; Messaritou et al., 2009). 2001, 2007). However, in the aggressive mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) model of breast PRO-TUMORIGENIC FUNCTIONS OF MT-MMPs cancer, the absence of MMP13 did not influence tumor growth, Beside its role in tumor cells, MT1-MMP is recognized as a vascularization, or metastasis to the lungs, suggesting that the role crucial regulator of angiogenesis in collagen- or fibrin-rich envi- of MMP13 in breast cancer may depend on the nature of the ronments (Chun et al., 2004; Stratman et al., 2009). MT1-MMP’s genetic lesions driving malignancy (Nielsen et al., 2008). pro-angiogenic capacities in both physiological and pathological MT1-MMP (MMP14) has emerged as an important collage- conditions are related to several mechanisms including: (1) ECM nase that cancer cells use to degrade and invade in a collagen- remodeling (Hotary et al., 2003), (2) interaction with cell-surface rich environment (Poincloux et al., 2009; Sabeh et al., 2009). molecules, such as CD44 (Kajita et al., 2001) and sphingosine Mmp14−/− mice exhibit skeletal defects with craniofacial abnor- 1-phosphate (S1P; Langlois et al., 2004), (3) degradation of anti- malities, osteopenia, and impaired angiogenesis (Holmbeck et al., angiogenic factors such as decorin in cornea (Mimura et al., 2009), 1999; Zhou et al., 2000). These mutant mice are the unique Mmp- or (4) interaction with TIMP-2 and signaling through ERK1/2 deficient mice generated up to now that are associated with a severe during cell migration (Sounni et al., 2010b). In addition, MT1- phenotype leading to death after birth. Type I collagen cleavage MMP plays a role in transcriptional and posttranslational control by MT1-MMP at the endothelial cell-surface stimulates migra- of VEGF expression and bio-availability (Deryugina et al., 2002; tion, guidance, and organization of endothelial cells into tubular Sounni et al., 2002, 2004; Eisenach et al., 2010), as well as in structures (Collen et al., 2003). In the tumor microenvironment, hematopoietic progenitor cell mobilization (Vagima et al., 2009), type I collagen remodeling by MT1-MMP enables cancer cells to due to so far unknown molecular mechanisms. Furthermore, a escape the mechanical barriers confined by the collagen matrix, number of recent reports have shed light on an important interplay and stimulates tumor growth in vivo (Hotary et al., 2003). We between MT1-MMP and TGFβ during angiogenesis and vessel have recently demonstrated that while poorly invasive breast ade- maturation (Tatti et al., 2008; Hawinkels et al., 2010; Sounni et al., nocarcinoma cells undergo apoptosis when confronted with a 2010a, 2011). collagen-rich environment, the production of MT1-MMP endows In contrast to MT1-MMP, MT4-MMP is unable to acti- these cells with the capacity to escape from collagen-induced vate proMMP2. Furthermore, MT4-MMP is rather inefficient apoptosis (Maquoi et al., 2012). Beyond its well known gelati- in hydrolyzing most ECM components compared to the other nolytic functions, MMP2 also displays interstitial collagenolytic MT-MMPs (Zucker et al., 2003). Its catalytic domain is able to activity (Egeblad et al., 2007) that unexpectedly contributes to cleave very few substrates in vitro, including gelatin, fibrin(ogen),

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lipoprotein receptor-related , proTNF-alpha, and the carcinogens showed a markedly increased susceptibility to tumori- ADAMTS-4 (Sohail et al., 2008). The largely over- genesis in comparison with corresponding wild-type mice (Balbin looked functions of the GPI-anchored MT4-MMP have been et al., 2003). Further histopathological studies demonstrated that explored by the MicroEnviMet partners. In human breast can- sustained inflammation resulting from MMP8-deficiency creates a cer samples, a higher intensity of MT4-MMP immunostaining is permissive environment for cancer progression. Importantly,bone observed in cancer cells compared to normal breast epithelial cells marrow transplantation assays in those mutant mice revealed that (Chabottaux et al., 2006). The overexpression of MT4-MMP in MMP8-producing neutrophils are sufficient to rescue the anti- the breast cancer cell line MDA-MB-231 enhances subcutaneous tumor protection conferred by this (Balbin et al., 2003). tumor growth and most importantly leads to lung metastasis when This study provided the first evidence for a protective role of a cells are inoculated in RAG-1 immunodeficient mice (Chabot- MMP family member in tumor progression, which has been fur- taux et al., 2006, 2009). The pro-metastatic effect of MT4-MMP is ther extended to other proteases (Lopez-Otin and Matrisian,2007) dependent on its proteolytic activity (Chabottaux et al., 2006) and as out-lined below. These findings underline the dual functions relies on the induction of an early angiogenic switch (Host et al., of host cells that can either boost the tumor or protect the host 2012) and the perturbation of blood vessel structure characterized toward cancer expansion (Figure 2). In addition,MMP8 downreg- by pericyte detachment (Chabottaux et al., 2009). These obser- ulation in non-metastatic cells increases their metastatic potential vations identify MT4-MMP as a cancer cell-derived MMP with (Montel et al., 2004; Gutierrez-Fernandez et al., 2008), and high pro-angiogenic and pro-metastatic effect that deserves further MMP8 levels in human carcinomas correlate with lower metas- in-depth investigations. tasis incidence and a better prognosis to patients with breast or oral cancer (Decock et al., 2007; Korpi et al., 2008). Such anti- THE PROTECTIVE EFFECTS OF MMPs AND RELATED tumor effects or dual functions with protective roles in specific ENZYMES circumstances have been extended to other proteinases including After years of considering MMPs as pro-tumorigenic enzymes, an MMP11, MMP12, MMP19, MMP26 (Lopez-Otin and Matrisian, intriguing observation has prompted re-evaluation of the roles 2007; Lopez-Otin et al., 2009). Furthermore, we reported that of MMPs in cancer. In fact, MMP8 deficient mice challenged with ADAMTS-12 exhibits anti-tumorigenic properties by modulating

FIGURE 2 | Schematic representation of the brake and booster their implication in ECM remodeling and growth factor signaling that favor functions of metalloproteinases. Recent advances in genomic and angiogenesis and boost tumor development, some metalloproteinases proteomic technologies have increased our knowledge on MMP exert protective effects that brake the tumor development. Several cancer contributions to different processes associated with tumor development protective enzymes are silenced through epigenetic and genetic such as tumor growth, angiogenesis, invasion and inflammation. Despite modifications in malignant cancer.

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Table 1 | Lessons from the past, present advances, and future challenges for MMP inhibition in cancer.

Strategies applied Lessons learnt

PAST Design of broad spectrum MMP inhibitors (MMPIs) in the decade of 1990’s: First clinical trials era: (non-exhaustive list) No significant evidence of efficacy, and even adverse effects Zinc-binding MMPIs Disconnection between promising preclinical studies and clinical trials, most Mechanism-based MMPIs of them being conducted in patients with late stage tumors Chemically modified tetracycline Coussens et al.(2002), Overall and Lopez-Otin(2002), Fingleton(2003), Synthesized peptides Kruger et al.(2010) Shark cartilage extracts Kleifeld et al.(2001), Hu et al.(2007), Devel et al.(2010) PRESENT Novel strategies to generate selective MMPIs: Era of MMP complexity elucidation: (non-exhaustive list) MMPs belong to a protease network (protease degradome) Specific zinc-binding MMPIs MMPs as cell regulators beyond matrix degradating enzymes MMPIs without zinc-binding groups MMPs with intracellular activities Neutralizing antibodies toward recombinant enzymes MMPs as builders of the tumor microenvironment in primary and secondary Neutralizing antibodies toward catalytic zinc complex sites (i.e., inflammation, angiogenesis, lymphangiogenesis) Non-catalytic hemopexin domain (PEX) inhibitors MMPs with opposite functions depending on cancer type/stage Humanizing neutralizing monoclonal antibodies raised in MMPs with tumor suppressive functions MMP knock-out mice Lopez-Otin et al.(2009), Cauwe and Opdenakker(2010), Fingleton and Lynch Devel et al.(2006, 2010), Devy et al.(2009), Remacle et al. (2010), Kruger et al.(2010), Rodriguez et al.(2010), Hua et al.(2011), Schelter (2012), Sela-Passwell et al.(2012) et al.(2011a,b), Sounni et al.(2011), Detry et al.(2012)

FUTURE Toward new therapeutic approaches: Challenging issues: Personalized therapy using selective MMPIs combined with Design of efficient selective inhibitors other therapies, including kinase inhibitors Design of appropriate clinical trials and endpoints given the fact that MMP Lopez-Otin and Hunter(2010) inhibitors are expected to be efficient at early stages Identification of biomarkers with added values for clinical practice to predict or monitor drug response Define which patients will benefit from a specific anti-MMP drug and at which disease stage Fingleton(2007, 2008), Hu et al.(2007), Zucker and Cao(2009), Cauwe and Opdenakker(2010), Decock et al.(2011), Hua et al.(2011) the Ras-dependent ERK pathway (Llamazares et al., 2007). A Similarly,somatic mutations are found in Adamts-15 (Viloria et al., knock-out mouse strain in which the Adamts-12 gene is deleted 2009) and Adamts-18 (Wei et al., 2010) in human colorectal can- (Adamts-12−/−) has been established to elucidate the in vivo func- cer and melanoma samples, respectively. Likewise, Adam7 and tions of ADAMTS-12 (El Hour et al., 2010). A protective effect Adam29 genes are frequently mutated in melanoma (Wei et al., of host cell-derived ADAMTS-12 is seen when different in vivo 2010). These findings of tumor-specific mutations, likely to affect models of angiogenesis (malignant keratinocyte transplantation, tumor cell behavior, implicate these genes as drivers in human Matrigel plug, and aortic ring assays) are applied to these knock- cancers and underscore the necessity to revisit the initial con- out mice. In the absence of ADAMTS-12, both the angiogenic cept that alteration of proteinase expression was secondary to response and tumor invasion into host tissue are increased. This transcriptional changes rather than genetic mutations. Beyond finding is in line with the anti-angiogenic functions reported for somatic mutations, several of the ADAMTS genes are epigenet- other ADAMTS family members such as ADAMTS-1,ADAMTS-2, ically silenced in various cancers (Moncada-Pazos et al., 2009). and ADAMTS-8 (Lee et al., 2006; Rodriguez-Manzaneque et al., The Adamts-12 promoter is hypermethylated in cancer cell lines 2009; Dubail et al., 2010). and tumor tissues leading to reduced production of ADAMTS- Interestingly, recent large-scale genomic studies have explored 12 (Moncada-Pazos et al., 2009) that exerts anti-tumorigenic the possibility that metalloproteinases could be genetically or epi- effect (Cal et al., 2002). Remarkably, this epigenetic silencing in genetically altered in various human malignant tumors. It appears the tumor cells is associated with a concurrent overexpression that human melanomas are frequently associated with muta- of ADAMTS-12 in the stromal compartment (Moncada-Pazos tions in Mmp8 and Mmp27 genes leading to loss-of-function et al., 2009) where it exerts an anti-angiogenic effect (El Hour and enhanced progression of the cancer (Palavalli et al., 2009). et al., 2010). These findings suggest that fibroblasts or more likely

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specific subsets of fibroblasts might react to the presence of tumor properties at the molecular level are largely unknown and repre- cells by overexpressing tumor-inhibiting enzymes. These data pro- sent a challenging issue for the near future. In fact, several MMPs, vide a strong support for the concept that several proteinases such as MMP9 or MMP12, might have dual roles either promot- have the ability to apply a brake on cancer cells and protect the ing or suppressing tumorigenesis depending on the type of cell host toward cancer progression (Figure 2). Furthermore, they in which they are expressed. Given that MMP family members underline the complexity of the tumor-host interface that deserves can exert promoting or protective effects and that some individual further in-depth investigation. MMPs can display opposite roles in different cancer types or phases of progression, a required step toward personalized cancer therapy CONCLUSION AND PERSPECTIVES is now the identification of the most appropriate MMP(s) to be tar- The emerging picture arising from these studies reveals a complex geted in each case. Discerning which MMP(s) to target and when interplay between tumor-derived proteases produced in cancer to inhibit are major issues that are facing researchers in the field. In cells and tumor associated stromal cells, the surrounding cells addition, the design of highly selective MMP inhibitors is manda- and the ECM. Tumor cells acquire some of the required prop- tory to overcome the failure of broad spectrum MMP inhibitors erties for growth and invasion by the specific modification of the in clinical trials (Table 1). In this context, novel strategies are tumor microenvironment. However, due to the complex nature emerging to generate new specific synthetic inhibitors or neu- of these interactions, it is only by altering specific components of tralizing antibodies (Table 1). Hopefully, the clarification of these this network that it has been possible to identify proteases with questions will finally result in clinical introduction of inhibitors pro-tumorigenic or pro-metastatic functions, as well as proteases of selected matrix-remodeling enzymes as new components of with tumor-defying properties. The recent identification of recur- anticancer therapies. rently mutated proteases in melanoma and colorectal cancer high- lights the growing list of metalloproteinases with protective func- ACKNOWLEDGMENTS tions against tumor development. Nevertheless, the mechanisms This work was supported by grants from the FP7-HEALTH-F2- by which these proteases exert their pro- or anti-tumorigenic 2008-201279 “MICROENVIMET.”

REFERENCES biochemical, biological, and patho- extracellular matrix. J. Cell Biol. 167, Decock, J., Hendrickx, W., Drijkonin- Balbin, M., Fueyo, A., Tester, A. M., Pen- logical kaleidoscope of cell surface 757–767. gen, M., Wildiers, H., Neven, P., das, A. M., Pitiot, A. S., Astudillo, substrates processed by matrix met- Colige, A., Ruggiero, F., Vandenberghe, Smeets, A., and Paridaens, R. (2007). A., Overall, C. M., Shapiro, S. D., alloproteinases. Crit. Rev. Biochem. I., Dubail, J., Kesteloot, F., Van Matrix expres- and Lopez-Otin, C. (2003). Loss of Mol. Biol. 42, 113–185. Beeumen, J., Beschin, A., Brys, L., sion patterns in luminal A type collagenase-2 confers increased skin Chabottaux, V., Ricaud, S., Host, L., Lapiere, C. M., and Nusgens, B. breast carcinomas. Dis. Markers 23, tumor susceptibility to male mice. Blacher, S., Paye, A., Thiry, M., Garo- (2005). Domains and maturation 189–196. Nat. Genet. 35, 252–257. falakis, A., Pestourie, C., Gombert, processes that regulate the activ- Decock, J., Thirkettle, S., Wagstaff, Bergers, G., Brekken, R., McMahon, K., Bruyere, F., Lewandowsky, ity of ADAMTS-2, a metallopro- L., and Edwards, D. R. (2011). G., Vu, T. H., Itoh, T., Tamaki, D., Tavitian, B., Foidart, J. M., teinase cleaving the aminopropep- Matrix metalloproteinases: pro- K., Tanzawa, K., Thorpe, P., Ito- Duconge, F., and Noel, A. (2009). tide of fibrillar procollagens types tective roles in cancer. J. Cell hara, S., Werb, Z., and Hanahan, D. Membrane-type 4 matrix metal- I-III and V. J. Biol. Chem. 280, Mol. Med. 15, 1254–1265. (2000). -9 loproteinase (MT4-MMP) induces 34397–34408. Deryugina, E. I., Soroceanu, L., triggers the angiogenic switch dur- lung metastasis by alteration of Collen, A., Hanemaaijer, R., Lupu, and Strongin, A. Y. (2002). Up- ing carcinogenesis. Nat. Cell Biol. 2, primary breast tumour vascular F., Quax, P. H., van Lent, N., regulation of vascular endothelial 737–744. architecture. J. Cell. Mol. Med. 13, Grimbergen, J., Peters, E., Kool- growth factor by membrane-type 1 Bundesmann, M. M., Wagner, T. E., 4002–4013. wijk, P., and van Hinsbergh, V. matrix metalloproteinase stimulates Chow, Y. H., Altemeier, W. A., Stein- Chabottaux, V., Sounni, N. E., Pen- W. (2003). Membrane-type matrix human glioma xenograft growth bach, T., and Schnapp, L. M. (2012). nington, C. J., English, W. R., van metalloproteinase-mediated angio- and angiogenesis. Cancer Res. 62, Role of urokinase plasminogen acti- den Brule, F., Blacher, S., Gilles, C., genesis in a fibrin-collagen matrix. 580–588. vator receptor-associated protein in Munaut, C., Maquoi, E., Lopez-Otin, Blood 101, 1810–1817. Detry, B., Bruyere, F., Erpicum, C., Pau- mouse lung. Am. J. Respir. Cell Mol. C., Murphy, G., Edwards, D. R., Coussens, L. M., Fingleton, B. B., and pert, J., Lamaye, F., Maillard, C., Biol. 46, 233–239. Foidart, J. M., and Noel, A. (2006). Matrisian, L. M. (2002). Matrix met- Lenoir, B., Foidart, J. M., Thiry, Cal, S., Obaya, A. J., Llamazares, M., Membrane-type 4 matrix metallo- alloproteinase inhibitors and cancer: M., and Noel, A. (2011). Digging Garabaya, C., Quesada, V., and proteinase promotes breast cancer trials and tribulations. Science 295, deeper into lymphatic vessel forma- Lopez-Otin, C. (2002). Cloning, growth and metastases. Cancer Res. 2387–2392. tion in vitro and in vivo. BMC Cell expression analysis, and structural 66, 5165–5172. Coussens, L. M., and Werb, Z. (2001). Biol. 12, 29. doi:10.1186/1471-2121- characterization of seven novel Chang, H. J., Yang, M. J., Yang, Y. Inflammatory cells and cancer: 12-29 human ADAMTSs, a family of met- H., Hou, M. F., Hsueh, E. J., and think different! J. Exp. Med. 193, Detry, B., Erpicum, C., Paupert, J., alloproteinases with disintegrin and Lin, S. R. (2009). MMP13 is poten- F23–F26. Blacher, S., Maillard, C., Bruyere, F., thrombospondin-1 domains. Gene tially a new tumor marker for breast Curino, A. C., Engelholm, L. H., Pendeville, H., Remacle, T., Lam- 283, 49–62. cancer diagnosis. Oncol. Rep. 22, Yamada, S. S., Holmbeck, K., Lund, bert, V., Balsat, C., Ormenese, S., Cauwe, B., and Opdenakker, G. (2010). 1119–1127. L. R., Molinolo, A. A., Behrendt, Lamaye, F., Janssens, E., Moons, L., Intracellular substrate cleavage: a Chun, T. H., Sabeh, F., Ota, I., N., Nielsen, B. S., and Bugge, Cataldo, D., Kridelka, F., Carmeliet, novel dimension in the biochem- Murphy, H., McDonagh, K. T., T. H. (2005). Intracellular col- P., Thiry, M., Foidart, J. M., Stru- istry, biology and pathology of Holmbeck, K., Birkedal-Hansen, lagen degradation mediated by man, I., and Noel, A. (2012). matrix metalloproteinases. Crit. Rev. H., Allen, E. D., and Weiss, S. uPARAP/Endo180 is a major path- Matrix metalloproteinase-2 governs Biochem. Mol. Biol. 45, 351–423. J. (2004). MT1-MMP-dependent way of extracellular matrix turnover lymphatic vessel formation as an Cauwe, B., Van den Steen, P. E., neovessel formation within the during malignancy. J. Cell Biol. 169, . Blood 119, and Opdenakker, G. (2007). The confines of the three-dimensional 977–985. 5048–5056.

Frontiers in Pharmacology | Pharmacology of Anti-Cancer Drugs July 2012 | Volume 3 | Article 140| 6 Noël et al. Matrix metalloproteinases in the tumor microenvironment

Devel, L., Czarny, B., Beau, F., Geor- Engelholm, L. H., Ingvarsen, S., Jur- matrix metalloproteinase produced I matrix metalloproteinase usurps giadis, D., Stura, E., and Dive, V. gensen, H. J., Hillig, T., Madsen, D. by breast carcinomas. J. Biol. Chem. tumor growth control imposed by (2010). Third generation of matrix H., Nielsen, B. S., and Behrendt, 269, 16766–16773. the three-dimensional extracellular metalloprotease inhibitors: gain in N. (2009). The collagen receptor Gupta, G. P., Perk, J., Acharyya, S., matrix. Cell 114, 33–45. selectivity by targeting the depth uPARAP/Endo180. Front. Biosci. 14, de Candia, P., Mittal, V., Todorova- Hu, J., Van den Steen, P. E., Sang, Q. X., of the S1’ cavity. Biochimie 92, 2103–2114. Manova, K., Gerald, W. L., Brogi, E., and Opdenakker, G. (2007). Matrix 1501–1508. Engelholm, L. H., List, K., Netzel- Benezra, R., and Massague, J. (2007). metalloproteinase inhibitors as ther- Devel, L., Rogakos, V., David, A., Arnett, S., Cukierman, E., Mitola, ID genes mediate tumor reinitiation apy for inflammatory and vascular Makaritis, A., Beau, F., Cuniasse, D. J., Aaronson, H., Kjoller, L., during breast cancer lung metasta- diseases. Nat. Rev. Drug Discov. 6, P., Yiotakis, A., and Dive, V. Larsen, J. K., Yamada, K. M., Strick- sis. Proc. Natl. Acad. Sci. U.S.A. 104, 480–498. (2006). Development of selective land, D. K., Holmbeck, K., Dano, 19506–19511. Hua, H., Li, M., Luo, T., Yin, Y., and inhibitors and substrate of matrix K., Birkedal-Hansen, H., Behrendt, Gutierrez-Fernandez, A., Fueyo, A., Jiang, Y. (2011). Matrix metallopro- metalloproteinase-12. J. Biol. Chem. N., and Bugge, T. H. (2003). Folgueras, A. R., Garabaya, C., Pen- teinases in tumorigenesis: an evolv- 281, 11152–11160. uPARAP/Endo180 is essential for nington, C. J., Pilgrim, S., Edwards, ing paradigm. Cell. Mol. Life Sci. 68, Devy, L., Huang, L., Naa, L., Yanaman- cellular uptake of collagen and pro- D. R., Holliday, D. L., Jones, J. L., 3853–3868. dra, N., Pieters, H., Frans, N., Chang, motes fibroblast collagen adhesion. Span, P. N., Sweep, F. C., Puente, Hubmacher, D., and Apte, S. S. E., Tao, Q., Vanhove, M., Lejeune, J. Cell Biol. 160, 1009–1015. X. S., and Lopez-Otin, C. (2008). (2011). Genetic and functional link- A., van Gool, R., Sexton, D. J., Erler, J. T., Bennewith, K. L., Cox, Matrix metalloproteinase-8 func- age between ADAMTS superfam- Kuang, G., Rank, D., Hogan, S., Paz- T. R., Lang, G., Bird, D., Koong, tions as a metastasis suppressor ily proteins and fibrillin-1: a novel many, C., Ma, Y. L., Schoonbroodt, A., Le, Q. T., and Giaccia, A. J. through modulation of tumor cell mechanism influencing microfibril S., Nixon, A. E., Ladner, R. C., (2009). Hypoxia-induced lysyl oxi- adhesion and invasion. Cancer Res. assembly and function. Cell. Mol. Hoet, R., Henderikx, P., Tenhoor, dase is a critical mediator of bone 68, 2755–2763. Life Sci. 68, 3137–3148. C., Rabbani, S. A., Valentino, M. marrow cell recruitment to form the Hanahan, D., and Weinberg, R. A. Joyce, J. A., and Pollard, J. W. (2009). L., Wood, C. R., and Dransfield, premetastatic niche. Cancer Cell 15, (2011). Hallmarks of cancer: the Microenvironmental regulation of D. T. (2009). Selective inhibition of 35–44. next generation. Cell 144, 646–674. metastasis. Nat. Rev. Cancer 9, matrix metalloproteinase-14 blocks Erler, J. T., and Weaver, V. M. (2009). Handsley, M. M., and Edwards, D. R. 239–252. tumor growth, invasion, and angio- Three-dimensional context regula- (2005). Metalloproteinases and their Kajita, M., Itoh, Y., Chiba, T., Mori, genesis. Cancer Res. 69, 1517–1526. tion of metastasis. Clin. Exp. Metas- inhibitors in tumor angiogenesis. H., Okada, A., Kinoh, H., and Seiki, Dubail, J., Kesteloot, F., Deroanne, C., tasis 26, 35–49. Int. J. Cancer 115, 849–860. M. (2001). Membrane-type 1 matrix Motte, P., Lambert, V., Rakic, J. M., Fanjul-Fernandez, M., Folgueras, A. R., Hasebe, T., Sasaki, S., Imoto, S., Mukai, metalloproteinase cleaves CD44 and Lapiere, C., Nusgens, B., and Col- Cabrera, S., and Lopez-Otin, C. K., Yokose, T., and Ochiai, A. (2002). promotes cell migration. J. Cell Biol. ige,A. (2010). ADAMTS-2 functions (2010). Matrix metalloproteinases: Prognostic significance of fibrotic 153, 893–904. as anti-angiogenic and anti-tumoral evolution, gene regulation and func- focus in invasive ductal carcinoma Kalluri, R. (2003). Basement mem- molecule independently of its cat- tional analysis in mouse models. of the breast: a prospective obser- branes: structure, assembly and role alytic activity. Cell. Mol. Life Sci. 67, Biochim. Biophys. Acta 1803, 3–19. vational study. Mod. Pathol. 15, in tumour angiogenesis. Nat. Rev. 4213–4232. Finak,G.,Bertos,N.,Pepin,F.,Sadekova, 502–516. Cancer 3, 422–433. Egeblad, M., Shen, H. C., Behonick, D. S., Souleimanova, M., Zhao, H., Hawinkels, L. J., Kuiper, P., Wiercinska, Kalluri, R., and Zeisberg, M. (2006). J., Wilmes, L., Eichten, A., Korets, L. Chen, H., Omeroglu, G., Meteriss- E., Verspaget, H. W., Liu, Z., Pardali, Fibroblasts in cancer. Nat. Rev. Can- V., Kheradmand, F., Werb, Z., and ian, S., Omeroglu, A., Hallett, M., E.,Sier,C. F.,and ten Dijke,P.(2010). cer 6, 392–401. Coussens, L. M. (2007). Type I col- and Park, M. (2008). Stromal gene Matrix metalloproteinase-14 (MT1- Kessenbrock, K., Plaks, V., and Werb, Z. lagen is a genetic modifier of matrix expression predicts clinical outcome MMP)-mediated endoglin shedding (2010). Matrix metalloproteinases: metalloproteinase 2 in murine skele- in breast cancer. Nat. Med. 14, inhibits tumor angiogenesis. Cancer regulators of the tumor microenvi- tal development. Dev. Dyn. 236, 518–527. Res. 70, 4141–4150. ronment. Cell 141, 52–67. 1683–1693. Fingleton, B. (2003). Matrix metallo- Holmbeck, K., Bianco, P., and Birkedal- Kjoller, L., Engelholm, L. H., Hoyer- Egeblad, M., and Werb, Z. (2002). New proteinase inhibitors for cancer ther- Hansen, B. (2003). MT1-MMP: a Hansen, M., Dano, K., Bugge, functions for the matrix metallopro- apy: the current situation and future collagenase essential for tumor cell T. H., and Behrendt, N. (2004). teinases in cancer progression. Nat. prospects. Expert Opin. Ther. Targets invasive growth. Cancer Cell. 81–84. uPARAP/endo180 directs lysosomal Rev. Cancer 2, 161–174. 7, 385–397. Holmbeck, K., Bianco, P., Caterina, J., delivery and degradation of collagen Eisenach, P. A., Roghi, C., Fogarasi, Fingleton, B. (2007). Matrix metallo- Yamada, S., Kromer, M., Kuznetsov, IV. Exp. Cell Res. 293, 106–116. M., Murphy, G., and English, W. R. proteinases as valid clinical targets. S. A., Mankani, M., Robey, P. G., Kleifeld, O., Kotra, L. P., Gervasi, D. C., (2010). MT1-MMP regulates VEGF- Curr. Pharm. Des. 13, 333–346. Poole, A. R., Pidoux, I., Ward, J. Brown, S., Bernardo, M. M., Frid- A expression through a complex Fingleton, B. (2008). MMPs as thera- M., and Birkedal-Hansen, H. (1999). man, R., Mobashery, S., and Sagi, I. with VEGFR-2 and Src. J. Cell. Sci. peutic targets–still a viable option? MT1-MMP-deficient mice develop (2001). X-Ray absorption studies of 123, 4182–4193. Semin. Cell Dev. Biol. 19, 61–68. dwarfism, osteopenia, arthritis, and human matrix metalloproteinase-2 El Hour, M., Moncada-Pazos, A., Fingleton, B., and Lynch, C. C. (2010). A connective tissue disease due to (MMP-2) bound to a highly selective Blacher, S., Masset, A., Cal, S., new dress code for MMPs: cleavage inadequate collagen turnover. Cell mechanism-based inhibitor. Com- Berndt, S., Detilleux, J., Host, L., optional. Dev. Cell 18, 3–4. 99, 81–92. parison with the latent and active Obaya, A. J., Maillard, C., Foidart, J. Folgueras,A. R., Pendas,A. M., Sanchez, Host, L., Paye, A., Detry, B., Blacher, forms of the enzyme. J. Biol. Chem. M., Ectors, F., Noel, A., and Lopez- L. M., and Lopez-Otin, C. (2004). S., Munaut, C., Foidart, J. M., Seiki, 276, 17125–17131. Otin, C. (2010). Higher sensitivity of Matrix metalloproteinases in can- M., Sounni, N. E., and Noel, A. Klein, T., and Bischoff, R. (2011). Active Adamts12-deficient mice to tumor cer: from new functions to improved (2012). The proteolytic activity of metalloproteases of the A disintegrin growth and angiogenesis. Oncogene inhibition strategies. Int. J. Dev. Biol. MT4-MMP is required for its proan- and metalloprotease (ADAM) fam- 29, 3025–3032. 48, 411–424. giogenic and pro-metastatic pro- ily: biological function and struc- Ellsworth, R. E., Hooke, J. A., Shriver, Freije, J. M., Diez-Itza, I., Balbin, M., moting effects. Int. J. Cancer. doi: ture. J. Proteome Res. 10, 17–33. C. D., and Ellsworth, D. L. (2009). Sanchez, L. M., Blasco, R., Tolivia, 10.1002/ijc.27436 Kogianni, G., Walker, M. M., Waxman, Genomic heterogeneity of breast J., and Lopez-Otin, C. (1994). Hotary, K. B., Allen, E. D., Brooks, P. J., and Sturge, J. (2009). Endo180 tumor pathogenesis. Clin. Med. Molecular cloning and expression C., Datta, N. S., Long, M. W., and expression with cofunctional part- Oncol. 3, 77–85. of collagenase-3, a novel human Weiss, S. J. (2003). Membrane type ners MT1-MMP and uPAR-uPA is

www.frontiersin.org July 2012 | Volume 3 | Article 140| 7 Noël et al. Matrix metalloproteinases in the tumor microenvironment

correlated with prostate cancer pro- Lopez-Otin, C., and Overall, C. M. genes couple breast tumor size and Overall, C. M., and Lopez-Otin, C. gression. Eur. J. Cancer 45, 685–693. (2002). Protease degradomics: a new metastatic spread. Proc. Natl. Acad. (2002). Strategies for MMP inhibi- Korpi, J. T., Kervinen, V., Maklin, H., challenge for proteomics. Nat. Rev. Sci. U.S.A. 104, 6740–6745. tion in cancer: innovations for the Vaananen, A., Lahtinen, M., Laara, Mol. Cell Biol. 3, 509–519. Minn, A. J., Gupta, G. P., Siegel, P. M., post-trial era. Nat. Rev. Cancer 2, E., Ristimaki, A., Thomas, G., Yli- Lopez-Otin, C., Palavalli, L. H., and Bos, P. D., Shu, W., Giri, D. D., Viale, 657–672. palosaari, M., Astrom, P., Lopez- Samuels, Y. (2009). Protective roles A., Olshen, A. B., Gerald, W. L., Page-McCaw, A., Ewald, A. J., and Otin, C., Sorsa, T., Kantola, S., Pirila, of matrix metalloproteinases: from and Massague, J. (2005). Genes that Werb, Z. (2007). Matrix metallopro- E.,and Salo,T.(2008). Collagenase-2 mouse models to human cancer. Cell mediate breast cancer metastasis to teinases and the regulation of tissue (matrix metalloproteinase-8) plays a Cycle 8, 3657–3662. lung. Nature 436, 518–524. remodelling. Nat. Rev. Mol. Cell Biol. protective role in tongue cancer. Br. Lu, P., Weaver, V. M., and Werb, Z. Moncada-Pazos, A., Obaya, A. J., Fraga, 8, 221–233. J. Cancer 98, 766–775. (2012). The extracellular matrix: a M. F., Viloria, C. G., Capella, G., Palavalli, L. H., Prickett, T. D., Wun- Kruger, A., Kates, R. E., and Edwards, dynamic niche in cancer progres- Gausachs, M., Esteller, M., Lopez- derlich, J. R., Wei, X., Burrell, A. S., D. R. (2010). Avoiding spam in the sion. J. Cell Biol. 196, 395–406. Otin, C., and Cal, S. (2009). The Porter-Gill, P., Davis, S., Wang, C., proteolytic internet: future strategies Madsen, D. H., Engelholm, L. H., ADAMTS12 metalloprotease gene Cronin, J. C., Agrawal, N. S., Lin, for anti-metastatic MMP inhibition. Ingvarsen, S., Hillig, T., Wagenaar- is epigenetically silenced in tumor J. C., Westbroek, W., Hoogstraten- Biochim. Biophys. Acta 1803,95–102. Miller, R. A., Kjoller, L., Gardsvoll, cells and transcriptionally activated Miller, S., Molinolo, A. A., Fetsch, Langlois, S., Gingras, D., and Beliv- H., Hoyer-Hansen, G., Holmbeck, in the stroma during progression P., Filie, A. C., O’Connell, M. P., eau, R. (2004). Membrane type K., Bugge, T. H., and Behrendt, of colon cancer. J. Cell. Sci. 122, Banister, C. E., Howard, J. D., 1-matrix metalloproteinase (MT1- N. (2007). Extracellular col- 2906–2913. Buckhaults, P., Weeraratna, A. T., MMP) cooperates with sphingosine lagenases and the endocytic Montel, V., Kleeman, J., Agarwal, Brody, L. C., Rosenberg, S. A., 1-phosphate to induce endothelial receptor, urokinase plasmino- D., Spinella, D., Kawai, K., and and Samuels, Y. (2009). Analysis of cell migration and morphogenic dif- gen activator receptor-associated Tarin, D. (2004). Altered metasta- the matrix metalloproteinase fam- ferentiation. Blood 103, 3020–3028. protein/Endo180, cooperate in tic behavior of human breast can- ily reveals that MMP8 is often Lederle, W., Hartenstein, B., Meides, A., fibroblast-mediated collagen cer cells after experimental manip- mutated in melanoma. Nat. Genet. Kunzelmann, H., Werb, Z., Angel, degradation. J. Biol. Chem. 282, ulation of matrix metalloproteinase 41, 518–520. P., and Mueller, M. M. (2009). 27037–27045. 8 gene expression. Cancer Res. 64, Poincloux, R., Lizarraga, F., and MMP13 as a stromal mediator in Madsen, D. H., Ingvarsen, S., Jurgensen, 1687–1694. Chavrier, P. (2009). Matrix invasion controlling persistent angiogenesis H. J., Melander, M. C., Kjoller, L., Nguyen, D. X., and Massague, J. by tumour cells: a focus on MT1- in skin carcinoma. Carcinogenesis Moyer, A., Honore, C., Madsen, C. (2007). Genetic determinants of MMP trafficking to invadopodia. J. 31, 1175–1184. A., Garred, P., Burgdorf, S., Bugge, cancer metastasis. Nat. Rev. Genet. 8, Cell. Sci. 122, 3015–3024. Lee, C. F., Ling, Z. Q., Zhao, T., Fang, S. T. H., Behrendt, N., and Engelholm, 341–352. Ramaswamy, S., Ross, K. N., Lander, E. H., Chang, W.C., Lee, S. C., and Lee, L. H. (2011). The non-phagocytic Nielsen, B. S., Egeblad, M., Rank, F., S., and Golub, T. R. (2003). A mole- K. R. (2009). Genomic-wide analysis route of collagen uptake: a distinct Askautrud, H. A., Pennington, C. cular signature of metastasis in pri- of lymphatic metastasis-associated degradation pathway. J. Biol. Chem. J., Pedersen, T. X., Christensen, I. mary solid tumors. Nat. Genet. 33, genes in human hepatocellular car- 286, 26996–27010. J., Edwards, D. R., Werb, Z., and 49–54. cinoma. World J. Gastroenterol. 15, Madsen, D. H., Jurgensen, H. J., Ing- Lund, L. R. (2008). Matrix met- Remacle, A. G., Golubkov, V. S., 356–365. varsen, S., Melander, M. C., Vainer, alloproteinase 13 is induced in Shiryaev, S. A., Dahl, R., Steb- Lee, N. V., Sato, M., Annis, D. S., Loo, J. B., Egerod, K. L., Hald, A., Rono, fibroblasts in polyomavirus middle bins, J. L., Chernov, A. V., Cheltsov, A., Wu, L., Mosher, D. F., and Iruela- B., Madsen, C. A., Bugge, T. H., T antigen-driven mammary carci- A. V., Pellecchia, M., and Stron- Arispe, M. L. (2006). ADAMTS1 Engelholm, L. H., and Behrendt, N. noma without influencing tumor gin, A. Y. (2012). Novel MT1-MMP mediates the release of antiangio- (2012). Endocytic collagen degrada- progression. PLoS ONE 3, e2959. small-molecule inhibitors based on genic polypeptides from TSP1 and tion: a novel mechanism involved doi:10.1371/journal.pone.0002959 insights into hemopexin domain 2. EMBO J. 25, 5270–5283. in protection against liver fibrosis. J. Nielsen, B. S., Rank, F., Illemann, M., function in tumor growth. Cancer Llamazares, M., Obaya, A. J., Moncada- Pathol. 227, 94–105. Lund, L. R., and Dano, K. (2007). Res. 72, 2339–2349. Pazos, A., Heljasvaara, R., Espada, J., Maquoi, E., Assent, D., Detilleux, J., Stromal cells associated with early Rocks, N., Paulissen, G., El Hour, M., Lopez-Otin, C., and Cal, S. (2007). Pequeux, C., Foidart, J. M., and invasive foci in human mammary Quesada, F., Crahay, C., Gueders, The ADAMTS12 metalloproteinase Noel, A. (2012). MT1-MMP pro- ductal carcinoma in situ coexpress M., Foidart, J. M., Noel, A., and exhibits anti-tumorigenic properties tects breast carcinoma cells against urokinase and urokinase receptor. Cataldo, D. (2008). Emerging roles through modulation of the Ras- type I collagen-induced apoptosis. Int. J. Cancer 120, 2086–2095. of ADAM and ADAMTS metallo- dependent ERK signalling pathway. Oncogene 31, 480–493. Nielsen, B. S., Rank, F., Lopez, J. M., proteinases in cancer. Biochimie 90, J. Cell. Sci. 120, 3544–3552. Messaritou, G., East, L., Roghi, C., Balbin, M., Vizoso, F., Lund, L. 369–379. Lopez-Guisa, J. M., Cai, X., Collins, Isacke, C. M., and Yarwood, H. R., Dano, K., and Lopez-Otin, C. Rodriguez, D., Morrison, C. J., and S. J., Yamaguchi, I., Okamura, D. (2009). Membrane type-1 matrix (2001). Collagenase-3 expression in Overall, C. M. (2010). Matrix met- M., Bugge, T. H., Isacke, C. M., metalloproteinase activity is reg- breast myofibroblasts as a molecu- alloproteinases: what do they not Emson, C. L., Turner, S. M., Shank- ulated by the endocytic collagen lar marker of transition of ductal do? New substrates and biological land, S. J., and Eddy, A. A. (2012). receptor Endo180. J. Cell. Sci. 122, carcinoma in situ lesions to invasive roles identified by murine models Mannose receptor 2 attenuates renal 4042–4048. ductal carcinomas. Cancer Res. 61, and proteomics. Biochim. Biophys. fibrosis. J. Am. Soc. Nephrol. 23, Mimura, T., Han, K. Y., Onguchi, T., 7091–7100. Acta 1803, 39–54. 236–251. Chang, J. H., Kim, T. I., Kojima, T., Noel, A., Jost, M., and Maquoi, E. Rodriguez-Manzaneque, J. C., Carpizo, Lopez-Otin, C., and Hunter, T. (2010). Zhou, Z., and Azar, D. T. (2009). (2008). Matrix metalloproteinases at D., Plaza-Calonge Mdel, C., Torres- The regulatory crosstalk between MT1-MMP-mediated cleavage of cancer tumor-host interface. Semin. Collado, A. X., Thai, S. N., Simons, kinases and proteases in cancer. Nat. decorin in corneal angiogenesis. J. Cell Dev. Biol. 19, 52–60. M., Horowitz, A., and Iruela-Arispe, Rev. Cancer 10, 278–292. Vasc. Res. 46, 541–550. Overall, C. M., and Kleifeld, O. (2006). M. L. (2009). Cleavage of syndecan- Lopez-Otin, C., and Matrisian, L. Minn, A. J., Gupta, G. P.,Padua, D., Bos, Tumour microenvironment– 4 by ADAMTS1 provokes defects in M. (2007). Tumour microenviron- P.,Nguyen, D. X., Nuyten, D., Kreike, opinion: validating matrix adhesion. Int. J. Biochem. Cell Biol. ment: emerging roles of proteases B., Zhang, Y.,Wang, Y.,Ishwaran, H., metalloproteinases as drug targets 41, 800–810. in tumour suppression. Nat. Rev. Foekens, J. A., van de Vijver, M., and and anti-targets for cancer therapy. Sabeh, F., Li, X. Y., Saunders, T. L., Cancer 7, 800–808. Massague, J. (2007). Lung metastasis Nat. Rev. Cancer 6, 227–239. Rowe, R. G., and Weiss, S. J.

Frontiers in Pharmacology | Pharmacology of Anti-Cancer Drugs July 2012 | Volume 3 | Article 140| 8 Noël et al. Matrix metalloproteinases in the tumor microenvironment

(2009). Secreted versus membrane- C., Deroanne, C., Thompson, E. cancer. J. Histochem. Cytochem. 55, Zhou, Z., Apte, S. S., Soininen, R., anchored collagenases: relative roles W., Foidart, J. M., and Noel, A. 347–353. Cao, R., Baaklini, G. Y., Rauser, R. in fibroblast-dependent collagenoly- (2002). MT1-MMP expression pro- Tatti, O., Vehvilainen, P., Lehti, K., W., Wang, J., Cao, Y., and Tryg- sis and invasion. J. Biol. Chem. 284, motes tumor growth and angiogen- and Keski-Oja, J. (2008). MT1- gvason, K. (2000). Impaired endo- 23001–23011. esis through an up-regulation of MMP releases latent TGF-beta1 chondral ossification and angiogen- Schelter, F., Grandl, M., Seubert, B., vascular endothelial growth factor from endothelial cell extracellu- esis in mice deficient in membrane- Schaten, S., Hauser, S., Gerg, M., expression. FASEB J. 16, 555–564. lar matrix via proteolytic process- type matrix metalloproteinase I. Boccaccio, C., Comoglio, P., and Sounni, N. E., and Noel, A. (2005). ing of LTBP-1. Exp. Cell Res. 314, Proc. Natl. Acad. Sci. U.S.A. 97, Kruger, A. (2011a). Tumor cell- Membrane type-matrix metallopro- 2501–2514. 4052–4057. derived Timp-1 is necessary for teinases and tumor progression. Tavazoie, S. F., Alarcon, C., Oskars- Zigrino, P., Kuhn, I., Bauerle, T., maintaining metastasis-promoting Biochimie 87, 329–342. son, T., Padua, D., Wang, Q., Zamek, J., Fox, J. W., Neumann, Met-signaling via inhibition of Sounni, N. E., Paye, A., Host, L., Bos, P. D., Gerald, W. L., and S., Licht, A., Schorpp-Kistner, M., Adam-10. Clin. Exp. Metastasis 28, and Noël, A. (2011). MT-MMPs Massague, J. (2008). Endogenous Angel, P., and Mauch, C. (2009). 793–802. as regulators of vessel stability human microRNAs that suppress Stromal expression of MMP-13 is Schelter, F., Halbgewachs, B., Baumler, associated with angiogene- breast cancer metastasis. Nature 451, required for melanoma invasion and P., Neu, C., Gorlach, A., Schrotzl- sis. Front. Pharmacol. 2:111. 147–152. metastasis. J. Invest. Dermatol. 129, mair, F., and Kruger, A. (2011b). Tis- doi:10.3389/fphar.2011.00111 Vagima, Y., Avigdor, A., Goichberg, P., 2686–2693. sue inhibitor of metalloproteinases- Sounni, N. E., Roghi, C., Chabot- Shivtiel, S., Tesio, M., Kalinkovich, Zucker, S., and Cao, J. (2009). Selective 1-induced scattered liver metasta- taux, V., Janssen, M., Munaut, C., A., Golan, K., Dar, A., Kollet, O., matrix metalloproteinase (MMP) sis is mediated by hypoxia-inducible Maquoi, E., Galvez, B. G., Gilles, Petit, I., Perl, O., Rosenthal, E., inhibitors in cancer therapy: ready factor-1alpha. Clin. Exp. Metastasis C., Frankenne, F., Murphy, G., Resnick, I., Hardan, I., Gellman, Y. for prime time? Cancer Biol. Ther. 8, 28, 91–99. Foidart, J. M., and Noel, A. (2004). N., Naor, D., Nagler, A., and Lapidot, 2371–2373. Sela-Passwell, N., Kikkeri, R., Dym, Up-regulation of vascular endothe- T. (2009). MT1-MMP and RECK are Zucker, S., Pei, D., Cao, J., and Lopez- O., Rozenberg, H., Margalit, R., lial growth factor-A by active involved in human CD34+ prog- Otin, C. (2003). Membrane type- Arad-Yellin, R., Eisenstein, M., membrane-type 1 matrix metallo- enitor cell retention, egress, and matrix metalloproteinases (MT- Brenner, O., Shoham, T., Danon, proteinase through activation of Src- mobilization. J. Clin. Invest. 119, MMP). Curr. Top. Dev. Biol. 54, T., Shanzer, A., and Sagi, I. (2012). tyrosine kinases. J. Biol. Chem. 279, 492–503. 1–74. Antibodies targeting the catalytic 13564–13574. van’t Veer, L. J., Dai, H., van de Vijver, zinc complex of activated matrix Spaeth, E. L., Dembinski, J. L., Sasser, M. J., He, Y. D., Hart, A. A., Mao, metalloproteinases show thera- A. K., Watson, K., Klopp, A., Hall, M., Peterse, H. L., van der Kooy, Conflict of Interest Statement: The peutic potential. Nat. Med. 18, B., Andreeff, M., and Marini, F. K., Marton, M. J., Witteveen, A. T., authors declare that the research was 143–147. (2009). Mesenchymal stem cell tran- Schreiber, G. J., Kerkhoven, R. M., conducted in the absence of any com- Sohail, A., Sun, Q., Zhao, H., Bernardo, sition to tumor-associated fibrob- Roberts, C., Linsley, P. S., Bernards, mercial or financial relationships that M. M., Cho, J. A., and Fridman, R. lasts contributes to fibrovascular R., and Friend, S. H. (2002). Gene could be construed as a potential con- (2008). MT4-(MMP17) and MT6- network expansion and tumor pro- expression profiling predicts clini- flict of interest. MMP (MMP25), a unique set of gression. PLoS ONE 4, e4992. cal outcome of breast cancer. Nature membrane-anchored matrix metal- doi:10.1371/journal.pone.0004992 415, 530–536. Received: 08 May 2012; accepted: 27 June loproteinases: properties and expres- Stratman, A. N., Saunders, W. B., Viloria, C. G., Obaya, A. J., Moncada- 2012; published online: 17 July 2012. sion in cancer. Cancer Metastasis Rev. Sacharidou, A., Koh, W., Fisher, K. Pazos, A., Llamazares, M., Astudillo, Citation: Noël A,Gutiérrez-Fernández A, 27, 289–302. E., Zawieja, D. C., Davis, M. J., A., Capella, G., Cal, S., and Lopez- Sounni NE, Behrendt N, Maquoi E, Lund Sounni, N. E., Dehne, K., van Kempen, and Davis, G. E. (2009). Endothe- Otin, C. (2009). Genetic inactivation IK, Cal S, Hoyer-Hansen G and López- L., Egeblad, M., Affara, N. I., Cuevas, lial cell lumen and vascular guid- of ADAMTS15 metalloprotease in Otín C (2012) New and paradoxical roles I., Wiesen, J., Junankar, S., Korets, ance tunnel formation requires human colorectal cancer. Cancer Res. of matrix metalloproteinases in the tumor L., Lee, J., Shen, J., Morrison, C. J., MT1-MMP-dependent proteolysis 69, 4926–4934. microenvironment. Front. Pharmacol. Overall, C. M., Krane, S. M., Werb, in 3-dimensional collagen matrices. Vihinen, P., Ala-aho, R., and Kahari, 3:140. doi: 10.3389/fphar.2012.00140 Z., Boudreau, N., and Coussens, Blood 114, 237–247. V. M. (2005). Matrix metallopro- This article was submitted to Frontiers in L. M. (2010a). Stromal regula- Strongin, A. Y. (2010). Proteolytic teinases as therapeutic targets in can- Pharmacology of Anti-Cancer Drugs, a tion of vessel stability by MMP14 and non-proteolytic roles of cer. Curr. Cancer Drug Targets 5, specialty of Frontiers in Pharmacology. and TGFbeta. Dis Model Mech. 3, membrane type-1 matrix met- 203–220. Copyright © 2012 Noël, Gutiérrez- 317–332. alloproteinase in malignancy. Wei, X., Prickett, T. D., Viloria, C. G., Fernández, Sounni, Behrendt, Maquoi, Sounni, N. E., Rozanov, D. V., Remacle, Biochim. Biophys. Acta 1803, Molinolo, A., Lin, J. C., Cardenas- Lund, Cal, Hoyer-Hansen and López- A. G., Golubkov, V. S., Noel, A., and 133–141. Navia, I., Cruz, P., Rosenberg, S. Otín. This is an open-access article dis- Strongin, A. Y. (2010b). Timp-2 Sulek, J., Wagenaar-Miller, R. A., Shire- A., Davies, M. A., Gershenwald, J. tributed under the terms of the Creative binding with cellular MT1-MMP man, J., Molinolo, A., Madsen, D. E., Lopez-Otin, C., and Samuels, Commons Attribution License, which stimulates invasion-promoting H., Engelholm, L. H., Behrendt, N., Y. (2010). Mutational and func- permits use, distribution and reproduc- MEK/ERK signaling in cancer cells. and Bugge, T. H. (2007). Increased tional analysis reveals ADAMTS18 tion in other forums,provided the original Int. J. Cancer 126, 1067–1078. expression of the collagen internal- metalloproteinase as a novel driver authors and source are credited and sub- Sounni, N. E., Devy, L., Hajitou, A., ization receptor uPARAP/Endo180 in melanoma. Mol. Cancer Res. 8, ject to any copyright notices concerning Frankenne, F., Munaut, C., Gilles, in the stroma of head and neck 1513–1525. any third-party graphics etc.

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