European Journal of Cell Biology 93 (2014) 23–29

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Mini Review

Metalloproteinases in melanoma Nives Moro, Cornelia Mauch, Paola Zigrino ∗ Department of Dermatology and Venerology, University of Cologne, Germany

a r t i c l e

i n f o

Article history: Received 13 September 2013 Received in revised form 8 November 2013 Accepted 8 January 2014 Keywords: ADAM MMP Proteases Melanoma Metastasis

a b s t r a c t Tumour cell adhesion, motility, proteolytic activities and cell receptors have important roles in cancer invasion. These processes are involved from early development of melanoma within the epidermis, to tumour cell invasion of the underlying tissue until intravasation of lymphatic or blood vessels, and thereafter, dissemination into distant organs occur. The activity of several proteolytic enzymes was shown to be pivotal in promoting melanoma cell invasion. These enzymes not only remodel the extracellular matrix, but also release active factors and shed cell surface receptors thereby mediating melanoma crosscommunication with their microenvironment. This leads to the generation of a favourable environment for melanoma growth. Several proteases are involved in melanoma invasion and include serine, cysteine proteases, matrix metalloproteases (MMPs) and the disintegrin and metalloproteases (ADAMs). This study summarises the current knowledge on the role of metalloproteinases, MMPs and ADAMs, in melanoma. © 2014 Elsevier GmbH. All rights reserved.

Introduction Over the last years it has become obvious that the reciprocal interaction of tumour cells with their environment is a key step in cancer progression. Despite the progresses made to treat melanoma patients, the most reliable approach to prolong tumour-free life and reduce metastasis to distant organs remains early diagnosis and resection of the primary tumour. Once melanocytes transform to melanoma cells, the primary tumour initially grows horizontally within the epidermis and then starts to enlarge and invade the deeper levels of the dermis (vertical growth phase). In these processes a continuous cross-talk with the neighbouring epithelial, stromal and inflammatory cells occurs (Gaggioli and Sahai, 2007). Proteolysis in the pericellular and stromal compartments has been shown to largely contribute to altering the tumour microenvironment being pivotal in promoting melanoma invasion. Several protease families are involved in these processes including serine proteases, cysteine proteases, matrix metalloproteases (MMPs) and disintegrin and metalloproteases (ADAMs) (Egeblad and Werb, 2002; Mochizuki and Okada, 2007). Among these, enzymes containing a metalloproteinase domain (MMPs and ADAMs) have been shown to play an important role in tumour progression. Even though previously believed to be exclusively active as matrix degrading enzymes, their activity towards cell and growth factors

∗ Corresponding author at: Department of Dermatology and Venerology, University Hospital of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel.: +49 221 478 97443; fax: +49 221 478 5949. E-mail address: [email protected] (P. Zigrino). http://dx.doi.org/10.1016/j.ejcb.2014.01.002 0171-9335/© 2014 Elsevier GmbH. All rights reserved.

receptors and many other important molecules has been described and shown to be of particular importance in the progression of several life-threatening disease including cancer. This review will focus on the roles and major functions of metalloproteinases, MMPs and ADAMs, in melanoma. General characteristics Metalloproteinases include the matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTS) enzymes which all present a conserved methionine residue in the active site and depend on the zinc ion for enzymatic reactions. MMPs, 24 in man and 23 in mouse, were originally classified on the bases of their specificity for ECM components. They are now grouped in a way that also considers their structural features (Egeblad and Werb, 2002; Lopez-Otin et al., 2009). Activity of metalloproteases in tissues is tightly controlled ensuring that in steady-state conditions metalloproteases are mostly held inactive. Enzymatic activities or chemicals are required to remove the pro-domain, which by binding the Zn2+ ion of the active centre by a cysteine residue ensures enzyme latency. Activity is also regulated by endogenous inhibitors, the tissue inhibitors of metalloproteinase (TIMP) that in small amounts contribute to enzyme activation but, when their concentration is increased, contribute to inhibit enzymatic activity (Page-McCaw et al., 2007). MMPs are generally secreted proteases and function in the extracellular environment, though several MMPs are present as membrane bound (membrane-type matrix metalloproteinases; MMP-14, -15, -16) or anchored by GPI (MMP-17, -25) (Page-McCaw et al., 2007). MMP

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Fig. 1. Topographical distribution of metalloproteinases expression in nevi and melanoma. Known pro- (P) and anti-tumour (A) function of metalloproteinases during tumour progression has been indicated.

expression is regulated mostly at the transcriptional level by a variety of growth factors, cytokines, and chemokines (Clark et al., 2008). Based on their structural diversity, MMPs play multiple functions and influence cell behaviour, cell death and survival. Accordingly in cancer MMPs play diverse roles in all stages of tumour development targeting growth factors and their receptors, cytokines, chemokines and adhesion components (Lopez-Otin et al., 2009). Structurally, ADAMs are type I transmembrane proteins which consist of a pro-domain, a zinc metalloprotease domain, a disintegrin domain, a cysteine-rich region, an EGF-like sequence, a transmembrane region and a cytoplasmic tail. The cytoplasmic tail interacts with Src homology 3 domain-containing proteins, but a clear role for ADAMs in signal transduction is not yet been characterised (Klein and Bischoff, 2011). ADAMs, 21 in man and 37 in mouse, have similar regulation of proteolytic activity as described above for MMPs. However, about half of human ADAMs are proteolytically active and can interact with integrin receptors (Bridges and Bowditch, 2005). This function was shown to be mediated by the cysteine-rich and disintegrin domains. ADAMs lack the classical RGD motif (ADAM-15 excluded) but have an ECD motif that influences adhesive capability (Edwards et al., 2008). After activation ADAMs cleave other membrane associated proteins as shown for the activation of different growth factors (TNF-alpha, IL-6), shedding of growth factor receptors (EGFR) and cell adhesion molecules (Edwards et al., 2008). Another proteolytic process in which ADAMs are involved is regulated intramembrane proteolysis (RIP). This process has been well described for example in the shedding of the Notch receptor and amyloid precursor protein (APP). After an initial shedding by ADAMs at a site outside the membrane, a second proteolytic cleavage within the cell membrane performed by the ␥-secretases leads to release of an intracellular domain which translocate to the nucleus and modulates gene expression (Edwards et al., 2008; Lichtenthaler et al., 2011). ADAMTS are related to the ADAMs, they all preserve both the metalloprotease and a disintegrin-like domain. In contrast to

ADAMs, ADAMTS contain thrombospondin repeats and lack transmembrane domain and are primarily found as secreted enzymes (Kuno et al., 1997). Like ADAMs, ADAMTSs are activated intracellularly and secreted as active forms. The precise function of the disintegrin domain remains unclear (Porter et al., 2005). Matrix metalloproteinases (MMPs) In physiological conditions, skin matrix remodelling occurs by a continuous process of synthesis and degradation of matrix components and among others, MMPs are strongly involved in perpetuating skin integrity. During skin ageing, changes in ECM deposition and degradation are frequently leading to malignancies (Reed et al., 2000). In melanoma, both tumour cells and tumour-associated stromal cells show increased expression of several MMPs as well as of tissue inhibitors, TIMPs (Hofmann et al., 2000). The major findings about the roles and expression of some metalloproteinases in melanoma progression and metastasis (Fig. 1) are summarised according to their subgroup. Collagenases MMP-1 is an interstitial collagenase cleaving collagen types I, II, and III. Initially MMP-1 was detected in a highly invasive vertical growth phase of malignant melanoma together with MMP13 (Airola et al., 1999). Following studies provided evidence that these two collagenases are released predominantly by peritumoural fibroblasts (Uria et al., 1997; Wandel et al., 2000). MMP-1 expression by stromal fibroblasts has also been implicated in the processing of PAR1, a thrombin receptor, thereby promoting the metastatic potential of cancer cells (Boire et al., 2005). Furthermore, MMP-1-mediated activation of PAR1 in endothelial cells induces acute endothelial cell activation (ECA) generating a proinflammatory environment associated with increased tumour

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progression (Goerge et al., 2006). In advanced melanoma MMP-1 is also detected in melanoma cells (Blackburn et al., 2007). Interestingly these authors also showed that expression of MMP-1 in RGP melanoma cells leads to enhanced tumour growth and conferred metastatic capability in vivo (Blackburn et al., 2009). MMP-1 displays several promoter polymorphisms which correlate with ulceration patient status, but did not significantly associate with overall survival and other clinical factors (Liu et al., 2012; Wang et al., 2011). Despite a broad acceptance that most MMPs play a central role in invasion and metastasis, some MMPs may have anti-tumour properties. The neutrophil collagenase MMP-8 was found in serum of melanoma patients with vascularised primary tumours suggesting a pro-tumourigenic function of this enzyme (Vihinen et al., 2008). On the contrary, in experimental squamous cell carcinoma mouse models MMP-8 was found to have anti-tumoural properties and functions as a metastasis suppressor through the modulation of tumour cell adhesion and invasion (Balbin et al., 2003; Lopez-Otin et al., 2009). In human melanoma, 23% somatic mutations of MMPs have been identified and 5 of these were found in the MMP-8 gene that lost thereby enzymatic activity (Palavalli et al., 2009). Moreover, Debniak et al. (2011) suggested that MMP-8 gene variation might associate with an increased risk of malignant melanoma. Like MMP-1, MMP-13 was shown to be expressed during invasive vertical growth phase of melanoma, but its expression is higher when the tumour starts to invade surrounding tissues (Airola et al., 1999). In addition, there is increasing evidence that expression of MMP-13 in the surrounding stroma plays an important role in melanoma growth. For example, using mice lacking MMP-13 we could show that lack of this protease in the host restrains melanoma growth by reducing tumour vascularisation (Zigrino et al., 2009). Additional studies confirmed (corroborated) the important role of MMP-13 in epidermal tumours and identified the proteolytic release of VEGF from the matrix as the mechanism underlying MMP-13 promotion of vascularisation (Lederle et al., 2010).

Gelatinases MMP-2 and MMP-9, also known as gelatinases A and B, were detected by immunohistochemical stainings in stroma and melanoma cells. Using in situ enzymatic assays, proteolytic activity of MMP-2 and MMP-9 was predominantly localised in peritumoural areas while no activity was observed within the tumour cell nests (Kurschat et al., 2002). The activity of MMP-2 in these peripheral areas of the tumours was suggested to be necessary to process collagen type I, cleave fibronectin and promote adhesion and migration of melanoma cells (Jiao et al., 2012). MMP-2 itself can be regulated among others by BRG1 (Brachma Related Gene 1; a component in a multisubunit SWI/SNF – SWItch/Sucrose NonFermentable nucleosome remodelling complex), whose expression increases during melanoma progression. Mechanistically, BRG1 was shown to be recruited to the MMP-2 promoter to directly activate expression of this gene (Saladi et al., 2010). Recently MMP-2 expression in tumour was proposed to be a prognostic marker for melanoma patients (Rotte et al., 2012). It was shown that VEGF secretion by the primary tumour in the blood resulted in enhanced MMP-9 expression selectively in lung endothelial cells in vivo. The authors suggested that this spatially limited induction is due to the high expression of VEGFR-1 in endothelial cells of the lungs as compared to other organs (Hiratsuka et al., 2002). MMP-9 may also act as tumour-suppressor by processing matrix macromolecules. Enzymatic activity of MMP9 towards the basement membrane collagen type IV was shown to generate a proteolytic active fragment, tumstatin, that suppresses

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activity of endothelial cells and inhibits pathological angiogenesis (Hamano and Kalluri, 2005). Stromelysins and matrilysins Expression of MMP-3 was not found in melanoma specimens (Thewes et al., 1999), but it was high in melanoma metastasis and correlated with shorter disease-free survival of metastatic patients. This suggested a role for MMP-3 in melanoma metastasis formation (Nikkola et al., 2002). In vitro MMP-3 has been shown to be expressed in more aggressive metastatic cell lines and its proinvasive function in melanoma cells was attributed to its capability to activate latent MMP-1 (Benbow et al., 1999). If this finding has significant relevance in vivo remains to be investigated. In vivo, functional polymorphisms in the promoter regions of MMP-3 were not associated with melanoma progression (Cotignola et al., 2007). MMP-12 might have protective effects also on survival of TNF/IFN␥induced inflammation in mouse grafts of B16 melanoma cells (Van Roy et al., 2007). Of note is that, MMP-12 together with MMP-9 may have anti-angiogenic activity by hydrolysing plasminogen to form the angiogenesis inhibitor angiostatin (Ribatti, 2009). MMP7, known as matrilysin, is expressed in primary cutaneous and metastatic melanoma but not in nevi or Spitz nevi (Kawasaki et al., 2007). However a direct role for MMP-7 in melanoma development has not been shown. Membrane type MMPs MT1-MMP (MMP-14) was the first discovered membrane-type MMP (Sato et al., 1994). It is expressed in tumour cells mainly at the leading edge of the invasive front of melanomas (Kurschat et al., 2002). In these areas localisation of both MMP-2 in the stroma and MMP-14 primarily in tumour cells is likely required for enzyme activation, highlighting how the different cells cooperatively act to promote tumour progression (Sato and Takino, 2010). In vivo the cleaved form of laminin 332 was found in tumours and in tissues undergoing remodelling but not in quiescent tissues (Lohi, 2001). Cleavage fragments of the ␥2 chain of laminin 332 generated by MMP-14 were detected in high invasive melanoma cells and played a crucial role in cell adhesion, migration and vasculogenic mimicry (Chung et al., 2011; Seftor et al., 2001). MMP-14 is also believed to be a mediator of endothelial cell migration and tube formation processes in vitro and in vivo (Stratman et al., 2009; Yana et al., 2007). Inhibition of MMP-14, using a selective human MMP-14 antibody, inhibited cellular proliferation and angiogenesis in mouse melanomas in preclinical studies pointing to an increasing importance of MMP-14 in invasive and angiogenic processes (Devy et al., 2009). Importantly, MMP-14 can serve as prognostic factor as its expression strongly associates with cancer progression and metastasis and poor prognosis of patients (Kondratiev et al., 2008). Interestingly, B-RAF and N-RAS mutations up-regulate MMP-14 gene expression and promote selective invasion and increased growth of malignant melanoma in vivo (Iida et al., 2004). The expression of MT2-MMP (MMP-15) and MT3-MMP (MMP16) as well as MMP-14 is generally increased in primary and metastatic melanoma cells. MMP-16 is also overexpressed in human melanoma metastases and metastatic melanoma call lines (Ohnishi et al., 2001). Interestingly, expression of MMP-16 is associated with rapid fibrin and poor collagen invasion suggesting that MMP-16 might be important for infiltration of melanoma cells in perivascular space which is frequently abundant with fibrin (Tatti et al., 2011). MT4-MMP (MMP-17) was shown to be highly expressed in two melanoma cell lines A375 and G-361 as well as in normal skin, the precise role of MMP-17 expression is up to date not investigated in contest of melanoma (Grant et al., 1999).

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Other MMPs MMP-19 expression in melanoma cell lines was correlated to their migratory abilities being reduced in cells with low expression of MMP-19. The authors suggested that increased MMP-19 expression hallmarks the progression of cutaneous melanoma and might boost melanoma growth by promoting the invasion of tumour cells (Muller et al., 2010). MMP-21 was suggested to be up regulated at early stages of melanoma progression but disappears with more aggressive phenotype, suggestive that MMP-21 may serve as a marker for malignant transformation in melanocytes (Kuivanen et al., 2005).

A disintegrin and metalloproteinases (ADAMs) ADAMs exhibit a conserved domain structure containing a proand a metalloprotease domain, a disintegrin-like and a cysteinerich domain. Additionally most ADAMs contain an EGF-like domain and a short cytoplasmic tail (Edwards et al., 2008). By proteolysis, alternative splicing or simple gene duplication soluble ADAM variants can be generated. These soluble forms were found to be proteolytically active or to have adhesive functions on distant cells (Tousseyn et al., 2006). The disintegrin and the cysteine-rich domains of ADAMs are both involved in mediating cell adhesion and fusion processes. This occurs via binding to integrins or heparansulfate proteoglycans, e.g. syndecans (Edwards et al., 2008). Among ADAM substrates are surface molecules as TGF-␣, HBEGF, EGFR and HER2 which have been shown implicated in the progression of pancreas, colon, breast and lung cancers, as well as melanoma (Blobel, 2005; Tousseyn et al., 2006). Shedding of these surface molecules was shown to induce para- and autocrine signalling thereby affecting not only the tumour cells but also those of the peritumoural microenvironment (Blobel, 2005). The versatile functions of ADAMs and the documented evidence of their over-expression in a variety of tumours suggest that these proteins are potential targets for tumour therapy (Arribas et al., 2006). Recent studies have identified driver mutations in ADAMs, namely ADAM-29 and 7, which often occur in melanoma and enhance cell migration or alter cell adhesive capacity (Wei et al., 2011). Nevertheless limited information is available on the role of the different ADAM family members in the pathogenesis of melanoma. In the following we will describe the recent knowledge about expression and functions of specific ADAMs in this context. By grafting B16F0 melanoma cells in mice lacking expression of ADAM-8, Guaiquil et al. (2010) could show that this protease is a negative regulator of retinal neovascularization and tumour growth. However, in humans expression of this protease in melanoma has not been investigated. ADAM-9 expression was demonstrated in various human cancers including melanoma where it is detected in increased amounts at the invasive border of tumour in both, tumour and adjacent stroma cells (Zigrino et al., 2005). Further, a high-throughput analysis of human melanomas correlated ADAM-9 expression and tumour progression (Alonso et al., 2007). In in vitro studies we have shown that ADAM-9 plays an important role in mediating cell–cell interaction of fibroblasts and melanoma cells. Moreover, by interacting via ADAM-9 synthesis of proteolytic enzymes was induced in stromal cells (Zigrino et al., 2011). The importance of ADAM-9 in melanoma growth was further substantiated in animals depleted of ADAM-9 expression. Using these animals the group of Guaiquil et al. (2009) found that growth of subcutaneously injected B16-F0 melanoma cells was reduced. In contrast, using the same mice, we detected a rather increased growth of intradermally grafted B16-F1 cells (Abety et al., 2012). Although the two systems differ in the strain of melanoma cells used as well as in the injection technique, this finding also raises

the possibility that the contribution of ADAM-9 to the tumour environment is dependent on the location. Moreover, down-regulation of ADAM-9 synthesis (by miR-126&126*) in the tumour cell but not in the stroma of the host, resulted in reduced melanoma growth and metastasis in nude mice (Felli et al., 2013). Thus the precise role of ADAM-9 in melanoma is still unclear. Interestingly, ADAM-9 has been described as being produced as membrane-anchored or as a soluble splice variant (Hotoda et al., 2002; Mazzocca et al., 2005). In a study performed on breast cancer cells, it was shown that the balance between membrane bound and soluble ADAM-9 expression is crucial to determine the functional activity having the membranebound form a suppressive and the soluble form a promoting activity on cell migration (Fry and Toker, 2010). Recently a new important function for ADAM-9 in cancer has been described by Kohga et al. (2010). In hepatocellular carcinoma these authors demonstrated that ADAM-9 mediates shedding of the NKG2D ligand MICA. Another group, however, found that MICA shedding not only involves ADAM-9 but also MMP-14 (Liu et al., 2010). Nevertheless, these data implicate ADAM-9, together with MMP-14, in the immune evasion which is of particular relevance for immunotherapies. Whether these proteases exert this function in melanoma has not been described yet. ADAM-10 is expressed in primary melanoma and in metastases (Anderegg et al., 2009; Lee et al., 2010). In melanoma cells this protease is involved in constitutive shedding of CD44. Silencing ADAM-10 expression results in decreased shedding and increased cell proliferation (Anderegg et al., 2009). Several cell surface receptors have been demonstrated to be substrates for ADAM-10, these include E-, N- and VE-cadherin whose shedding profoundly alters cellular interactions, migration and cell proliferation (Reiss and Saftig, 2009). This is also the case for the L1-CAM receptor that can be also shed by ADAM-10 thereby altering motility and invasion of lymphoma, lung carcinoma and melanoma cells (Gutwein et al., 2000; Lee et al., 2010). ADAM-10 is regulated by PAX2, a member of PAX transcription factor family involved in cell survival that has a binding site in ADAM-10 promoter (Epstein et al., 1994). PAX2-mediated down-regulation of ADAM-10 inhibited anchorage-independent cell growth and decreased the migratory and invasive capacity of melanoma cells. In line with this reduced expression of ADAM-10 resulted in inhibition of the L1-CAM release and lead to reduced melanoma progression (Lee et al., 2011). Interestingly, ADAM-10 can also be released upon shedding mediated by ADAM-9 and ADAM-15, and a second proteolytic event mediated by presenilin/␣-secretase releases the intracellular domain that can translocate to the nucleus where potentially may be involved in gene regulation (Tousseyn et al., 2009). ADAM-15 is the only ADAM family member with a RGD sequence, and its role in cancer is unclear. Despite of the fact that the recombinant disintegrin-like domain of human ADAM-15 supports adhesion of A375 melanoma cells (Zhang et al., 1998), overexpression of the recombinant disintegrin domain in melanoma cells led to reduced tumour growth in vivo (Trochon-Joseph et al., 2004). Furthermore, Wu et al. (2008) provide evidence that ADAM-15 disintegrin domain inhibits melanoma cell proliferation partly through p38 kinase activation. In human tissues ADAM-15 is expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue; however it is significantly down-regulated in melanoma metastases compared to primary tumours (Ungerer et al., 2010). ADAM-15 overexpression in melanoma cells reduced invasion and growth in vitro, suggesting a tumour suppressor role for ADAM-15 in melanoma (Ungerer et al., 2010). On the other hand, selective inactivation of ADAM-15 in the host, resulted in reduced growth and metastasis of injected melanoma cells to lungs and lymph nodes thus suggesting a pro-metastatic role of ADAM-15 in melanoma when expressed by the host (Horiuchi et al., 2003; Schonefuss et al., 2012).

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In human melanoma, ADAM-17 gene is strongly overexpressed with advanced tumour stage where its expression also correlates with the increased TNF expression in the blood of patients (Cireap and Narita, 2013). Using mouse models with conditional depletion of ADAM-17 in endothelial cells, Weskamp et al. (2010) could show that in vivo growth of B16 melanoma cells growth is significantly reduced owing to an impaired neovascularisation.

2013). Promising results have been shown in vitro using inhibitory antibodies. Of importance, the non-catalytic activity in MMPs could also provide in the future a new window for targeting. In addition, addressing the tissue/cell specific expression function of metalloproteinase will fill up the gaps in the current knowledge and give better understanding of metalloproteinase complexity giving a foundation for new treatment options.

ADAMTS

Acknowledgements

Another class of ADAM-related enzymes are the ADAMTS, which contain in their structure thrombospondin domains. These domains are believed to function as a sulphated glycosaminoglycan-binding domain and maintain appropriate location in the extracellular matrix (Tang, 2001). High levels of ADAMTS transcripts have also been detected in tumour biopsies and in cell lines from osteosarcoma and melanoma tumours (Cal et al., 2002). ADAMTS-4 and its catalytically active N-terminal autocatalytic fragment was shown to promote B16 melanoma growth and angiogenesis in mice, whereas its catalytically inactive mutant increased tumour cell apoptosis (Rao et al., 2013). This group also showed that single thrombospondin-type 1 repeat domain is essential and sufficient for the anti-tumourigenic activity displayed by the catalytically inactive ADAMTS-4 isoforms. As all three forms coexist in human cancer tissues, the net outcome likely depends on functional balance between proand anti-tumourigenic ADAMTS-4 isoforms (Rao et al., 2013). In contrast, overexpression of full-length ADAMTS-5 suppressed B16 melanoma growth in mice that correlated with diminished angiogenesis reduced proliferation and increased apoptosis of tumour cells (Kumar et al., 2012). This study provides evidence for an anti-tumourigenic and anti-angiogenic role for ADAMTS-5. Finally, recent data identified ADAMTS-18 as a player in melanoma progression. Wei et al. (2010) showed that expression of the mutated protein reduced growth dependency of tumour cells on growth factors, increased migration in vitro and led to increased metastasis in vivo.

We apologise to the authors whose work was not cited to comply with the length of a mini review. This work was supported by the Melanoma Research Network of the Deutsche Krebshilfe.

Inhibition of metalloproteinases – perspective MMPs are inhibited by the endogenous tissue inhibitors of metalloproteinases (TIMPs), a family that comprises four members (TIMP-1 to -4). In contrast to the MMPs, ADAMs are only selectively inhibited by TIMPs, thus for example ADAM-17 is exclusively inhibited by TIMP-3 and ADAM-10 can be inhibited by TIMP-1 and -3, but not by TIMP-2 and -4 (Edwards et al., 2008). Other ADAMs, like ADAM-8 and -9, are not sensitive to inhibition by TIMPs at all (Amour et al., 2000). Unfortunately, TIMPs are not specific enough to be considered for therapeutic approaches. Moreover, they often have additional functions such as mediating the activation (MMP2) or simple stabilisation of metalloproteinases against proteolytic degradation (ADAM-17) (Murphy, 2011). More than fifty MMP inhibitors have been pursued in clinical trials so far, mainly developed to target proteolytical activity. Another approach to inhibit protease activity has been employed by Tape et al. (2011) who have produced a more specific antibody to ADAM-17 by two-step phage display. In vivo, the specific ADAM-17 inhibitory antibody was also shown to reduce significantly the development of ovarian cancer cell tumours (Richards et al., 2012). Even though its activity was not tested with other tumour entities, its effect may potentially be higher in other EGF ligand-dependent tumours. Recent studies consider targeting signalling molecules that regulate MMP synthesis, such as Aurora kinase that is a naturally occurring compound targeting adhesive molecules as for instance lumican and inhibiting MMP-2 expression (Brezillon et al., 2013; Xie and Meyskens,

References Abety, A.N., Fox, J.W., Schonefuss, A., Zamek, J., Landsberg, J., Krieg, T., Blobel, C., Mauch, C., Zigrino, P., 2012. Stromal fibroblast-specific expression of ADAM-9 modulates proliferation and apoptosis in melanoma cells in vitro and in vivo. J. Invest. Dermatol. 132, 2451–2458. Airola, K., Karonen, T., Vaalamo, M., Lehti, K., Lohi, J., Kariniemi, A.L., Keski-Oja, J., Saarialho-Kere, U.K., 1999. Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas. Br. J. Cancer 80, 733–743. Alonso, S.R., Tracey, L., Ortiz, P., Perez-Gomez, B., Palacios, J., Pollan, M., Linares, J., Serrano, S., Saez-Castillo, A.I., Sanchez, L., Pajares, R., Sanchez-Aguilera, A., Artiga, M.J., Piris, M.A., Rodriguez-Peralto, J.L., 2007. A high-throughput study in melanoma identifies epithelial–mesenchymal transition as a major determinant of metastasis. Cancer Res. 67, 3450–3460. Amour, A., Knight, C.G., Webster, A., Slocombe, P.M., Stephens, P.E., Knauper, V., Docherty, A.J., Murphy, G., 2000. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett. 473, 275–279. Anderegg, U., Eichenberg, T., Parthaune, T., Haiduk, C., Saalbach, A., Milkova, L., Ludwig, A., Grosche, J., Averbeck, M., Gebhardt, C., Voelcker, V., Sleeman, J.P., Simon, J.C., 2009. ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells. J. Invest. Dermatol. 129, 1471–1482. Arribas, J., Bech-Serra, J.J., Santiago-Josefat, B., 2006. ADAMs, cell migration and cancer. Cancer Metastasis Rev. 25, 57–68. Balbin, M., Fueyo, A., Tester, A.M., Pendas, A.M., Pitiot, A.S., Astudillo, A., Overall, C.M., Shapiro, S.D., Lopez-Otin, C., 2003. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat. Genet. 35, 252–257. Benbow, U., Schoenermark, M.P., Mitchell, T.I., Rutter, J.L., Shimokawa, K., Nagase, H., Brinckerhoff, C.E., 1999. A novel host/tumor cell interaction activates matrix metalloproteinase 1 and mediates invasion through type I collagen. J. Biol. Chem. 274, 25371–25378. Blackburn, J.S., Liu, I., Coon, C.I., Brinckerhoff, C.E., 2009. A matrix metalloproteinase1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis. Oncogene 28, 4237–4248. Blackburn, J.S., Rhodes, C.H., Coon, C.I., Brinckerhoff, C.E., 2007. RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. Cancer Res. 67, 10849–10858. Blobel, C.P., 2005. ADAMs: key components in EGFR signalling and development. Nat. Rev. Mol. Cell Biol. 6, 32–43. Boire, A., Covic, L., Agarwal, A., Jacques, S., Sherifi, S., Kuliopulos, A., 2005. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313. Brezillon, S., Pietraszek, K., Maquart, F.X., Wegrowski, Y., 2013. Lumican effects in the control of tumour progression and their links with metalloproteinases and integrins. FEBS J. 280, 2369–2381. Bridges, L.C., Bowditch, R.D., 2005. ADAM–integrin interactions: potential integrin regulated ectodomain shedding activity. Curr. Pharm. Des. 11, 837–847. Cal, S., Obaya, A.J., Llamazares, M., Garabaya, C., Quesada, V., Lopez-Otin, C., 2002. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Gene 283, 49–62. Chung, H., Suh, E.K., Han, I.O., Oh, E.S., 2011. Keratinocyte-derived laminin-332 promotes adhesion and migration in melanocytes and melanoma. J. Biol. Chem. 286, 13438–13447. Cireap, N., Narita, D., 2013. Molecular profiling of ADAM12 and ADAM17 genes in human malignant melanoma. Pathol. Oncol. Res. 19, 755–762. Clark, I.M., Swingler, T.E., Sampieri, C.L., Edwards, D.R., 2008. The regulation of matrix metalloproteinases and their inhibitors. Int. J. Biochem. Cell Biol. 40, 1362–1378. Cotignola, J., Roy, P., Patel, A., Ishill, N., Shah, S., Houghton, A., Coit, D., Halpern, A., Busam, K., Berwick, M., Orlow, I., 2007. Functional polymorphisms in the promoter regions of MMP2 and MMP3 are not associated with melanoma progression. J. Negat. Results Biomed. 6, 9. Debniak, T., Jakubowska, A., Serrano-Fernandez, P., Kurzawski, G., Cybulski, C., Chauhan, S.R., Laxton, R.C., Maleszka, R., Lubinski, J., Ye, S., 2011. Association of MMP8 gene variation with an increased risk of malignant melanoma. Melanoma Res. 21, 464–468.

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Devy, L., Huang, L., Naa, L., Yanamandra, N., Pieters, H., Frans, N., Chang, E., Tao, Q., Vanhove, M., Lejeune, A., van Gool, R., Sexton, D.J., Kuang, G., Rank, D., Hogan, S., Pazmany, C., Ma, Y.L., Schoonbroodt, S., Nixon, A.E., Ladner, R.C., Hoet, R., Henderikx, P., Tenhoor, C., Rabbani, S.A., Valentino, M.L., Wood, C.R., Dransfield, D.T., 2009. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 69, 1517–1526. Edwards, D.R., Handsley, M.M., Pennington, C.J., 2008. The ADAM metalloproteinases. Mol. Aspects Med. 29, 258–289. Egeblad, M., Werb, Z., 2002. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174. Epstein, J., Cai, J., Glaser, T., Jepeal, L., Maas, R., 1994. Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes. J. Biol. Chem. 269, 8355–8361. Felli, N., Felicetti, F., Lustri, A.M., Errico, M.C., Bottero, L., Cannistraci, A., De Feo, A., Petrini, M., Pedini, F., Biffoni, M., Alvino, E., Negrini, M., Ferracin, M., Mattia, G., Care, A., 2013. miR-126&126* restored expressions play a tumor suppressor role by directly regulating ADAM9 and MMP7 in melanoma. PLoS ONE 8, e56824. Fry, J.L., Toker, A., 2010. Secreted and membrane-bound isoforms of protease ADAM9 have opposing effects on breast cancer cell migration. Cancer Res. 70, 8187–8198. Gaggioli, C., Sahai, E., 2007. Melanoma invasion – current knowledge and future directions. Pigment Cell Research/sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society 20, 161–172. Goerge, T., Barg, A., Schnaeker, E.M., Poppelmann, B., Shpacovitch, V., Rattenholl, A., Maaser, C., Luger, T.A., Steinhoff, M., Schneider, S.W., 2006. Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation. Cancer Res. 66, 7766–7774. Grant, G.M., Giambernardi, T.A., Grant, A.M., Klebe, R.J., 1999. Overview of expression of matrix metalloproteinases (MMP-17, MMP-18, and MMP-20) in cultured human cells. Matrix Biol. 18, 145–148. Guaiquil, V., Swendeman, S., Yoshida, T., Chavala, S., Campochiaro, P.A., Blobel, C.P., 2009. ADAM9 is involved in pathological retinal neovascularization. Mol. Cell Biol. 29, 2694–2703. Guaiquil, V.H., Swendeman, S., Zhou, W., Guaiquil, P., Weskamp, G., Bartsch, J.W., Blobel, C.P., 2010. ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice. J. Mol. Med. (Berl.) 88, 497–505. Gutwein, P., Oleszewski, M., Mechtersheimer, S., Agmon-Levin, N., Krauss, K., Altevogt, P., 2000. Role of Src kinases in the ADAM-mediated release of L1 adhesion molecule from human tumor cells. J. Biol. Chem. 275, 15490–15497. Hamano, Y., Kalluri, R., 2005. Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. Biochem. Biophys. Res. Commun. 333, 292–298. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J.M., Senior, R.M., Shibuya, M., 2002. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300. Hofmann, U.B., Westphal, J.R., Van Muijen, G.N., Ruiter, D.J., 2000. Matrix metalloproteinases in human melanoma. J. Invest. Dermatol. 115, 337–344. Horiuchi, K., Weskamp, G., Lum, L., Hammes, H.P., Cai, H., Brodie, T.A., Ludwig, T., Chiusaroli, R., Baron, R., Preissner, K.T., Manova, K., Blobel, C.P., 2003. Potential role for ADAM15 in pathological neovascularization in mice. Mol. Cell Biol. 23, 5614–5624. Hotoda, N., Koike, H., Sasagawa, N., Ishiura, S., 2002. A secreted form of human ADAM9 has an alpha-secretase activity for APP. Biochem. Biophys. Res. Commun. 293, 800–805. Iida, J., Wilhelmson, K.L., Price, M.A., Wilson, C.M., Pei, D., Furcht, L.T., McCarthy, J.B., 2004. Membrane type-1 matrix metalloproteinase promotes human melanoma invasion and growth. J. Invest. Dermatol. 122, 167–176. Jiao, Y., Feng, X., Zhan, Y., Wang, R., Zheng, S., Liu, W., Zeng, X., 2012. Matrix metalloproteinase-2 promotes alphavbeta3 integrin-mediated adhesion and migration of human melanoma cells by cleaving fibronectin. PLoS ONE 7, e41591. Kawasaki, K., Kawakami, T., Watabe, H., Itoh, F., Mizoguchi, M., Soma, Y., 2007. Expression of matrilysin (matrix metalloproteinase-7) in primary cutaneous and metastatic melanoma. Br. J. Dermatol. 156, 613–619. Klein, T., Bischoff, R., 2011. Active metalloproteases of the A disintegrin and metalloprotease (ADAM) family: biological function and structure. J. Proteome Res. 10, 17–33. Kohga, K., Takehara, T., Tatsumi, T., Ishida, H., Miyagi, T., Hosui, A., Hayashi, N., 2010. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology 51, 1264–1273. Kondratiev, S., Gnepp, D.R., Yakirevich, E., Sabo, E., Annino, D.J., Rebeiz, E., Laver, N.V., 2008. Expression and prognostic role of MMP2, MMP9, MMP13, and MMP14 matrix metalloproteinases in sinonasal and oral malignant melanomas. Hum. Pathol. 39, 337–343. Kuivanen, T., Ahokas, K., Virolainen, S., Jahkola, T., Holtta, E., Saksela, O., SaarialhoKere, U., 2005. MMP-21 is upregulated at early stages of melanoma progression but disappears with more aggressive phenotype. Virchows Arch. 447, 954–960. Kumar, S., Sharghi-Namini, S., Rao, N., Ge, R., 2012. ADAMTS5 functions as an antiangiogenic and anti-tumorigenic protein independent of its proteoglycanase activity. Am. J. Pathol. 181, 1056–1068. Kuno, K., Kanada, N., Nakashima, E., Fujiki, F., Ichimura, F., Matsushima, K., 1997. Molecular cloning of a gene encoding a new type of metalloproteinase–disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J. Biol. Chem. 272, 556–562.

Kurschat, P., Wickenhauser, C., Groth, W., Krieg, T., Mauch, C., 2002. Identification of activated matrix metalloproteinase-2 (MMP-2) as the main gelatinolytic enzyme in malignant melanoma by in situ zymography. J. Pathol. 197, 179–187. Lederle, W., Hartenstein, B., Meides, A., Kunzelmann, H., Werb, Z., Angel, P., Mueller, M.M., 2010. MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma. Carcinogenesis 31, 1175–1184. Lee, S.B., Doberstein, K., Baumgarten, P., Wieland, A., Ungerer, C., Burger, C., Hardt, K., Boehncke, W.H., Pfeilschifter, J., Mihic-Probst, D., Mittelbronn, M., Gutwein, P., 2011. PAX2 regulates ADAM10 expression and mediates anchorageindependent cell growth of melanoma cells. PLoS ONE 6, e22312. Lee, S.B., Schramme, A., Doberstein, K., Dummer, R., Abdel-Bakky, M.S., Keller, S., Altevogt, P., Oh, S.T., Reichrath, J., Oxmann, D., Pfeilschifter, J., Mihic-Probst, D., Gutwein, P., 2010. ADAM10 is upregulated in melanoma metastasis compared with primary melanoma. J. Invest. Dermatol. 130, 763–773. Lichtenthaler, S.F., Haass, C., Steiner, H., 2011. Regulated intramembrane proteolysis – lessons from amyloid precursor protein processing. J. Neurochem. 117, 779–796. Liu, G., Atteridge, C.L., Wang, X., Lundgren, A.D., Wu, J.D., 2010. The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases. J. Immunol. 184, 3346–3350. Liu, H., Wei, Q., Gershenwald, J.E., Prieto, V.G., Lee, J.E., Duvic, M., Grimm, E.A., Wang, L.E., 2012. Influence of single nucleotide polymorphisms in the MMP1 promoter region on cutaneous melanoma progression. Melanoma Res. 22, 169–175. Lohi, J., 2001. Laminin-5 in the progression of carcinomas. Int. J. Cancer 94, 763–767. Lopez-Otin, C., Palavalli, L.H., Samuels, Y., 2009. Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle 8, 3657–3662. Mazzocca, A., Coppari, R., De Franco, R., Cho, J.Y., Libermann, T.A., Pinzani, M., Toker, A., 2005. A secreted form of ADAM9 promotes carcinoma invasion through tumor–stromal interactions. Cancer Res. 65, 4728–4738. Mochizuki, S., Okada, Y., 2007. ADAMs in cancer cell proliferation and progression. Cancer Sci. 98, 621–628. Muller, M., Beck, I.M., Gadesmann, J., Karschuk, N., Paschen, A., Proksch, E., Djonov, V., Reiss, K., Sedlacek, R., 2010. MMP19 is upregulated during melanoma progression and increases invasion of melanoma cells. Mod. Pathol. 23, 511–521. Murphy, G., 2011. Tissue inhibitors of metalloproteinases. Genome Biol. 12, 233. Nikkola, J., Vihinen, P., Vlaykova, T., Hahka-Kemppinen, M., Kahari, V.M., Pyrhonen, S., 2002. High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma. Int. J. Cancer 97, 432–438. Ohnishi, Y., Tajima, S., Ishibashi, A., 2001. Coordinate expression of membrane type-matrix metalloproteinases-2 and 3 (MT2-MMP and MT3-MMP) and matrix metalloproteinase-2 (MMP-2) in primary and metastatic melanoma cells. Eur. J. Dermatol. 11, 420–423. Page-McCaw, A., Ewald, A.J., Werb, Z., 2007. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8, 221–233. Palavalli, L.H., Prickett, T.D., Wunderlich, J.R., Wei, X., Burrell, A.S., Porter-Gill, P., Davis, S., Wang, C., Cronin, J.C., Agrawal, N.S., Lin, J.C., Westbroek, W., Hoogstraten-Miller, S., Molinolo, A.A., Fetsch, P., Filie, A.C., O‘Connell, M.P., Banister, C.E., Howard, J.D., Buckhaults, P., Weeraratna, A.T., Brody, L.C., Rosenberg, S.A., Samuels, Y., 2009. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat. Genet. 41, 518–520. Porter, S., Clark, I.M., Kevorkian, L., Edwards, D.R., 2005. The ADAMTS metalloproteinases. Biochem. J. 386, 15–27. Rao, N., Ke, Z., Liu, H., Ho, C.J., Kumar, S., Xiang, W., Zhu, Y., Ge, R., 2013. ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice. Int. J. Cancer 133, 294–306. Reed, M.J., Corsa, A.C., Kudravi, S.A., McCormick, R.S., Arthur, W.T., 2000. A deficit in collagenase activity contributes to impaired migration of aged microvascular endothelial cells. J. Cell. Biochem. 77, 116–126. Reiss, K., Saftig, P., 2009. The A disintegrin and metalloprotease (ADAM) family of sheddases: physiological and cellular functions. Semin. Cell Dev. Biol. 20, 126–137. Ribatti, D., 2009. Endogenous inhibitors of angiogenesis: a historical review. Leukemia Res. 33, 638–644. Richards, F.M., Tape, C.J., Jodrell, D.I., Murphy, G., 2012. Anti-tumour effects of a specific anti-ADAM17 antibody in an ovarian cancer model in vivo. PLoS ONE 7, e40597. Rotte, A., Martinka, M., Li, G., 2012. MMP2 expression is a prognostic marker for primary melanoma patients. Cell. Oncol. (Dordr.) 35, 207–216. Saladi, S.V., Keenen, B., Marathe, H.G., Qi, H., Chin, K.V., de la Serna, I.L., 2010. Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness. Mol. Cancer 9, 280. Sato, H., Takino, T., 2010. Coordinate action of membrane-type matrix metalloproteinase-1 (MT1-MMP) and MMP-2 enhances pericellular proteolysis and invasion. Cancer Sci. 101, 843–847. Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., Seiki, M., 1994. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370, 61–65. Schonefuss, A., Abety, A.N., Zamek, J., Mauch, C., Zigrino, P., 2012. Role of ADAM-15 in wound healing and melanoma development. Exp. Dermatol. 21, 437–442. Seftor, R.E., Seftor, E.A., Koshikawa, N., Meltzer, P.S., Gardner, L.M., Bilban, M., StetlerStevenson, W.G., Quaranta, V., Hendrix, M.J., 2001. Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res. 61, 6322–6327.

N. Moro et al. / European Journal of Cell Biology 93 (2014) 23–29 Stratman, A.N., Saunders, W.B., Sacharidou, A., Koh, W., Fisher, K.E., Zawieja, D.C., Davis, M.J., Davis, G.E., 2009. Endothelial cell lumen and vascular guidance tunnel formation requires MT1-MMP-dependent proteolysis in 3-dimensional collagen matrices. Blood 114, 237–247. Tang, B.L., 2001. ADAMTS: a novel family of extracellular matrix proteases. Int. J. Biochem. Cell Biol. 33, 33–44. Tape, C.J., Willems, S.H., Dombernowsky, S.L., Stanley, P.L., Fogarasi, M., Ouwehand, W., McCafferty, J., Murphy, G., 2011. Cross-domain inhibition of TACE ectodomain. Proc. Natl. Acad. Sci. U.S.A. 108, 5578–5583. Tatti, O., Arjama, M., Ranki, A., Weiss, S.J., Keski-Oja, J., Lehti, K., 2011. Membrane-type-3 matrix metalloproteinase (MT3-MMP) functions as a matrix composition-dependent effector of melanoma cell invasion. PLoS ONE 6, e28325. Thewes, M., Worret, W.I., Engst, R., Ring, J., 1999. Stromelysin-3 (ST-3): immunohistochemical characterization of the matrix metalloproteinase (MMP)-11 in benign and malignant skin tumours and other skin disorders. Clin. Exp. Dermatol. 24, 122–126. Tousseyn, T., Jorissen, E., Reiss, K., Hartmann, D., 2006. (Make) stick and cut loose – disintegrin metalloproteases in development and disease. Birth Defects Res. C: Embryo Today 78, 24–46. Tousseyn, T., Thathiah, A., Jorissen, E., Raemaekers, T., Konietzko, U., Reiss, K., Maes, E., Snellinx, A., Serneels, L., Nyabi, O., Annaert, W., Saftig, P., Hartmann, D., De Strooper, B., 2009. ADAM10, the rate-limiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase. J. Biol. Chem. 284, 11738–11747. Trochon-Joseph, V., Martel-Renoir, D., Mir, L.M., Thomaidis, A., Opolon, P., Connault, E., Li, H., Grenet, C., Fauvel-Lafeve, F., Soria, J., Legrand, C., Soria, C., Perricaudet, M., Lu, H., 2004. Evidence of antiangiogenic and antimetastatic activities of the recombinant disintegrin domain of metargidin. Cancer Res. 64, 2062–2069. Ungerer, C., Doberstein, K., Burger, C., Hardt, K., Boehncke, W.H., Bohm, B., Pfeilschifter, J., Dummer, R., Mihic-Probst, D., Gutwein, P., 2010. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma. Biochem. Biophys. Res. Commun. 401, 363–369. Uria, J.A., Stahle-Backdahl, M., Seiki, M., Fueyo, A., Lopez-Otin, C., 1997. Regulation of collagenase-3 expression in human breast carcinomas is mediated by stromal–epithelial cell interactions. Cancer Res. 57, 4882–4888. Van Roy, M., Van Lint, P., Van Laere, I., Wielockx, B., Wilson, C., Lopez-Otin, C., Shapiro, S., Libert, C., 2007. Involvement of specific matrix metalloproteinases during tumor necrosis factor/IFNgamma-based cancer therapy in mice. Mol. Cancer Ther. 6, 2563–2571. Vihinen, P., Koskivuo, I., Syrjanen, K., Tervahartiala, T., Sorsa, T., Pyrhonen, S., 2008. Serum matrix metalloproteinase-8 is associated with ulceration and vascular invasion of malignant melanoma. Melanoma Res. 18, 268–273.

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Wandel, E., Grasshoff, A., Mittag, M., Haustein, U.F., Saalbach, A., 2000. Fibroblasts surrounding melanoma express elevated levels of matrix metalloproteinase-1 (MMP-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro. Exp. Dermatol. 9, 34–41. Wang, L.E., Huang, Y.J., Yin, M., Gershenwald, J.E., Prieto, V.G., Lee, J.E., Duvic, M., Grimm, E.A., Wei, Q., 2011. Promoter polymorphisms in matrix metallopeptidase 1 and risk of cutaneous melanoma. Eur. J. Cancer 47, 107–115. Wei, X., Moncada-Pazos, A., Cal, S., Soria-Valles, C., Gartner, J., Rudloff, U., Lin, J.C., Rosenberg, S.A., Lopez-Otin, C., Samuels, Y., 2011. Analysis of the disintegrinmetalloproteinases family reveals ADAM29 and ADAM7 are often mutated in melanoma. Hum. Mutat. 32, E2148–E2175. Wei, X., Prickett, T.D., Viloria, C.G., Molinolo, A., Lin, J.C., Cardenas-Navia, I., Cruz, P., Rosenberg, S.A., Davies, M.A., Gershenwald, J.E., Lopez-Otin, C., Samuels, Y., 2010. Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol. Cancer Res. 8, 1513–1525. Weskamp, G., Mendelson, K., Swendeman, S., Le Gall, S., Ma, Y., Lyman, S., Hinoki, A., Eguchi, S., Guaiquil, V., Horiuchi, K., Blobel, C.P., 2010. Pathological neovascularization is reduced by inactivation of ADAM17 in endothelial cells but not in pericytes. Circ. Res. 106, 932–940. Wu, J., Zhang, L., Ma, X., Zhang, X., Jin, J., 2008. Screening cellular proteins involved in the anti-proliferative effect of the ADAM15 disintegrin domain in murine melanoma cells. Oncol. Rep. 20, 669–675. Xie, L., Meyskens Jr., F.L., 2013. The pan-Aurora kinase inhibitor, PHA-739358, induces apoptosis and inhibits migration in melanoma cell lines. Melanoma Res. 23, 102–113. Yana, I., Sagara, H., Takaki, S., Takatsu, K., Nakamura, K., Nakao, K., Katsuki, M., Taniguchi, S., Aoki, T., Sato, H., Weiss, S.J., Seiki, M., 2007. Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells. J. Cell Sci. 120, 1607–1614. Zhang, X.P., Kamata, T., Yokoyama, K., Puzon-McLaughlin, W., Takada, Y., 1998. Specific interaction of the recombinant disintegrin-like domain of MDC15 (metargidin, ADAM-15) with integrin alphavbeta3. J. Biol. Chem. 273, 7345–7350. Zigrino, P., Kuhn, I., Bauerle, T., Zamek, J., Fox, J.W., Neumann, S., Licht, A., SchorppKistner, M., Angel, P., Mauch, C., 2009. Stromal expression of MMP-13 is required for melanoma invasion and metastasis. J. Invest. Dermatol. 129, 2686–2693. Zigrino, P., Mauch, C., Fox, J.W., Nischt, R., 2005. Adam-9 expression and regulation in human skin melanoma and melanoma cell lines. Int. J. Cancer 116, 853–859. Zigrino, P., Nischt, R., Mauch, C., 2011. The disintegrin-like and cysteine-rich domains of ADAM-9 mediate interactions between melanoma cells and fibroblasts. J. Biol. Chem. 286, 6801–6807.