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ADAMTS Proteases and Cancer View metadata, citation and similar papers at core.ac.uk brought to you by CORE Review provided by Repositorio Institucional de la Universidad de Oviedo ADAMTS proteases and cancer Santiago Cal and Carlos López-Otín Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, IUOPA, Universidad de Oviedo, 33006 Oviedo, Asturias, Spain Correspondence to Santiago Cal: Corresponding author at: Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, C/Fernando Bongera s/n, 33006 Oviedo, Asturias, Spain. Tel.: +34 98 5106282; fax: +34 98 5103564. [email protected] http://dx.doi.org/10.1016/j.matbio.2015.01.013 Edited by W.C. Parks and S. Apte Abstract ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are complex extracellular proteases that have been related to both oncogenic and tumor-protective functions. These enzymes can be secreted by cancer and stromal cells and may contribute to modify the tumor microenvironment by multiple mechanisms. Thus, ADAMTSs can cleave or interact with a wide range of extracellular matrix components or regulatory factors, and therefore affect cell adhesion, migration, proliferation and angiogenesis. The balance of protumor versus antitumor effects of ADAMTSs may depend on the nature of their substrates or interacting-partners upon secretion from the cell. Moreover, different ADAMTS genes have been found overexpressed, mutated or epigenetically silenced in tumors from different origins, suggesting the direct impact of these metalloproteases in cancer development. However, despite the important advances on the tumor biology of ADAMTSs in recent years, more mechanistic and functional studies are necessary to fully understand how these proteases can influence tumor microenvironment to potentiate cancer growth or to induce tumor regression. This review outlines current and emerging connections between ADAMTSs and cancer. © 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction were metalloproteases largely associated with tumor- igenesis [2], therefore it was proposed that ADAMTS-1 In 1997, Kuno et al. reported the identification and could also influence tumor growth through modulation cloning of a new ADAM (ADisintegrin And Metallopro- of cell proliferation, migration, inflammation and angio- teinase domains) metalloprotease in a cell model of genesis processes. colon cancer cachexia [1]. This enzyme was named The discovery of ADAMTS-1 encouraged the search ADAMTS-1 (ADisintegrin And Metalloproteinase with for new ADAMTS genes. The availability of the first ThromboSpondin motifs) to remark the presence of draft of the human genome sequence and the efforts of three thrombospondin type-1 (TS1) motifs within its different laboratories allowed to complete the molecular structure. The first TS1 motif was located in the middle cloning of the 19 human ADAMTSs in 2003 [3,4].Each region of the amino acid sequence of this enzyme, and newly identified ADAMTS displayed a domain organi- the remaining two were situated in tandem at the zation similar to that shown by ADAMTS-1, character- carboxy-terminal region of the protein. Another impor- ized by the presence of a central TS1 motif and a tant difference with respect to the classical ADAMs was variable number of TS1 repeats at the carboxy-terminal the finding that ADAMTS-1 was a secreted enzyme region, as well as the absence of a transmembrane lacking the transmembrane domain placed at the domain. In addition, other ancillary domains described carboxy-terminal end of the membrane-anchored in ADAMTSs but not in ADAMs were the spacer region, ADAMs. Both ADAMs and the closely related MMPs locatedafteracysteine-richregioninallADAMTSs;a 0022-2836/© 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Matrix Biol. (2015) 44–46,77–85 78 ADAMTS proteases and cancer Inhibition of Gene promoter cell migration hypermethylation ADAMTS gene ADAMTS1, ADAMTS5, ADAMTS8, ADAMTS9, ADAMTS12, ADAMTS18 ADAMTS gene Erk Tumor cells Erk P Akt ADAMTS gene Akt Stromal ADAMTS cells P n ADAMTS-1 VEGF Thrombospondin-1 Nidogen-1 Thrombospondin-2 Nidogen-2 Inhibition of Inhibition of lymphangiogenesis angiogenesis Lymphatic vessel Proteolytic products Blood Pro-domain Thrombospondin vessel Type I domain Catalytic domain Cysteine-rich domain Disintegrin domain Spacer Fig. 1. Schematic representation of the antitumor effects mediated by ADAMTS metalloproteases. These effects have been mainly described for ADAMTS-1. ADAMTSs can be produced by stromal or tumor cells, and exert antitumor properties inhibiting angiogenic or lymphangiogenic processes, or blocking tumor-promoting signaling pathways in tumor cells. These effects may be both dependent (degradation of extracellular components such as thrombospondin-1 and -2, and nidogen-1 and -2), or independent (VEGF sequestration) of the catalytic activity. Several ADAMTS genes are silenced through epigenetic modification in tumors from different origins. Structural domains of ADAMTSs are indicated. spacer-2 region between the fourth and fifth TS1 motifs ADAMTSs as a new family of secreted metallopro- in ADAMTS-7 and ADAMTS-12; the GON-1 domain at teases [6–8]. Phylogenetic analysis of the 19 human the carboxy-terminal end of ADAMTS-9 and ADAMTSs allowed their classification into different ADAMTS-20; the PLAC domain in ADAMTS-2, -3, subfamilies of closely related members [4,5]. -6, -7, -10, -12, -14, -15, -16, -17 and -19; and the CUB Functional characterization of different ADAMTSs domains in ADAMTS-13 [5]. These structural domains revealed that they were involved in key biological could influence protease activity and led to consider processes. For instance, ADAMTS-2, ADAMTS-3 and ADAMTS proteases and cancer 79 Induction of cell migration ADAMTS gene Tumor cells mutated ADAMTS18 gene EGF-like growth factors release Fibroblasts ADAMTS recruitment n Induction of angiogenesis ADAMTS-1, ADAMTS-4, ADAMTS-5 Degradation of proteoglycans Blood vessel Pro-domain Thrombospondin Type I domain Catalytic domain Cysteine-rich domain Disintegrin domain Spacer Fig. 2. Schematic representation of the protumor effects mediated by ADAMTS metalloproteases. ADAMTSs may cleave or induce the release or activation of pro-angiogenic factors (HB-EGF, amphiregulin, IGFBP2), and digest extracellular matrix components (proteoglycans) to facilitate tumor cell spreading and metastasis. Protumor effects elicited by ADAMTSs are protease-dependent. Additionally, ADAMTSs can induce the recruitment of fibroblasts involved in tumor growth. Genetic alterations of ADAMTS genes can also induce protumor effects. Structural domains of ADAMTSs are indicated. ADAMTS-14 are procollagen N-proteinases [9–11], ADAMTS17 gene [16]. In this case, affected individuals and loss-of-function mutations in ADAMTS2 cause exhibit some of the symptoms of Weill–Marchesani Ehlers–Danlos syndrome VIIC, a connective tissue syndrome, but they show no signs of brachydactyly or disorder characterized by severe skin fragility [12]. decreased joint flexibility. ADAMTS-13 is the enzyme ADAMTS-4 and ADAMTS-5/11 are responsible for responsible for the cleavage of large multimers of von aggrecan degradation in osteoarthritic diseases Willebrand factor [17], and defects in the gene encoding [13,14]. ADAMTS10 mutations underlie Weill– this metalloprotease cause thrombotic thrombocytope- Marchesani syndrome [15], an acromelic dysplasia nic purpura, a life-threatening hematologic disease associated with short stature, eye abnormalities, characterized by the inability of blood to clot normally brachydactyly and joint stiffness. A Weill–Marchesani- [18]. Adamts20 ismutatedinbeltedmice,whichlack like syndrome is caused by mutations in the pigment in the belt-like region of the trunk as a result of a 80 ADAMTS proteases and cancer defect in melanocyte development [19]. These exam- essential to promote angio-inhibitory capacity. Contrary ples illustrate the functional relevance of ADAMTSs not to ADAMTS-1, ADAMTS-9 does not cleave thrombos- only in normal biological events but also in pathological pondins 1 and 2 and does not bind VEGF165 [34]. conditions. However, ADAMTS-4 is also able to capture and ADAMTSs have also been associated with cancer inactivate VEGF and, additionally, to inhibit phosphor- as their expression was found to be altered in tumors ylation of VEGF receptor 2 (VEGFR2) [29]. An early from different origins, similarly to what happened report by Iruela-Arispe et al. showed that ADAMTS-1 with the founder member of the family ADAMTS-1 in can also inactivate VEGFR2 in human aortic endothe- colon cancer cachexia [8]. However a growing lial cells [38]. More recently it has also been found that number of studies have also highlighted the tumor- ADAMTS-1 is able to block VEGFR3 phosphorylation protective effects of ADAMTSs [20,21]. Different in human dermal lymphatic microvascular endothelial mechanisms have been linked to the protumor or cells HMVEC-dLy, leading to an inhibition of lymphan- antitumor activities of these metalloproteases, giogenesis [39]. These findings point out the impor- including regulation of angiogenesis, cell prolifera- tance of ADAMTSs as modulators of both angiogenic tion, adhesion and migration, as well as degradation and lymphangiogenic responses (Fig. 1). or interaction with extracellular matrix
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