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The Extracellular Matrix: an Accomplice in Gastric Cancer Development and Progression

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cells Review The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression Ana Margarida Moreira 1,2,3, Joana Pereira 1,2,4, Soraia Melo 1,2,4 , Maria Sofia Fernandes 1,2, Patrícia Carneiro 1,2 , Raquel Seruca 1,2,4 and Joana Figueiredo 1,2,* 1 Epithelial Interactions in Cancer Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; [email protected] (A.M.M.); [email protected] (J.P.); [email protected] (S.M.); [email protected] (M.S.F.); [email protected] (P.C.); [email protected] (R.S.) 2 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal 3 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal 4 Medical Faculty, University of Porto, 4200-319 Porto, Portugal * Correspondence: jfi[email protected]; Tel.: +351-220408800; Fax: +351-225570799 Received: 15 January 2020; Accepted: 6 February 2020; Published: 8 February 2020 Abstract: The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though the detailed mechanisms underlying cell-ECM crosstalk are yet to unravel, it is well established that ECM deregulation accompanies the development of many pathological conditions, such as gastric cancer. Notably, gastric cancer remains a worldwide concern, representing the third most frequent cause of cancer-associated deaths. Despite increased surveillance protocols, patients are usually diagnosed at advanced disease stages, urging the identification of novel diagnostic biomarkers and efficient therapeutic strategies. In this review, we provide a comprehensive overview regarding expression patterns of ECM components and cognate receptors described in normal gastric epithelium, pre-malignant lesions, and gastric carcinomas. Important insights are also discussed for the use of ECM-associated molecules as predictive biomarkers of the disease or as potential targets in gastric cancer. Keywords: gastric cancer; extracellular matrix; integrin; cell-ECM interaction; ECM deregulation; ECM targeting; ECM biomarkers 1. Introduction The extracellular matrix (ECM) is a complex assembly of fibrous proteins, proteoglycans and other molecules, namely cytokines, growth factors and hormones, whose precise composition varies from tissue to tissue [1]. A tight ECM regulation provides for proper architecture, as well as essential cues for mechanosensing and signaling during tissue development and maintenance [1,2]. Indeed, cellular processes such as growth, differentiation, survival, and morphogenesis are highly dependent on the cell-ECM interplay [3,4]. The reciprocal relationship between cells and the ECM is mainly mediated by cell receptors for ECM components, the so-called integrins. Integrins work as bi-directional molecules that transduce physical and biochemical inputs from the surrounding microenvironment to the cell and vice-versa: transforming intracellular signals into different interactions with their ECM ligands [5,6]. Abnormal ECM and integrin profiles are frequently reported in cancer corroborating the functional relevance and the specificity of both ECM Cells 2020, 9, 394; doi:10.3390/cells9020394 www.mdpi.com/journal/cells Cells 2020, 9, 394 2 of 23 Cells 2020, 9, 394 2 of 23 are frequently reported in cancer corroborating the functional relevance and the specificity of both ECM and integrins. Several studies have provided evidence that the ECM contributes to cancer andpathogenesis integrins. Severalby (i) studies stimulating have provided integrin-dependent evidence that thesignaling ECM contributes that promotes to cancer invasion pathogenesis and byproliferation; (i) stimulating (ii) integrin-dependent promoting an advantageous signaling that microenvironmental promotes invasion and niche proliferation; for metastatic (ii) promoting cells; (iii) anserving advantageous as a reservoir microenvironmental of growth factor niche and for metastaticcytokines; cells;(iv) interfering (iii) serving with as a reservoirthe communication of growth factorbetween and cancer cytokines; and (iv)immune interfering cells; withand (v) the forming communication a physical between barrier cancer to anti-cancer and immune agents cells; (Figure and (v)1) forming[4,6]. a physical barrier to anti-cancer agents (Figure1)[4,6]. FigureFigure 1. 1.The The extracellular extracellular matrix matrix (ECM) (ECM) contribution contribution to cancer to cancer pathogenesis. pathogenesis. The ECM The mediates ECM mediates cancer developmentcancer development through through several mechanisms,several mechanisms, including incl formationuding formation of a physical of a physical barrier tobarrier anti-cancer to anti- drugscancer (A), drugs provision (A), provision of growth of factor grow andth factor cytokines and cytokines reserves (B), reserves alteration (B), ofalteration immune of cell immune responses cell (C),responses stimulation (C), stimulation of integrin-dependent of integrin-dependent signaling that signaling promotes that invasionpromotes and invasion proliferation and proliferation (D), and establishment(D), and establishment of an advantageous of an advantageous niche for metastaticniche for metastatic cells (E). cells (E). InIn gastricgastric cancer,cancer, thethe rolerole of of the the ECM ECM has has been been undeniably undeniably demonstrated demonstrated inin allall stepssteps ofof thethe disease,disease, from from initiation initiation to metastases.to metastases. For instance,For instance, increased increased expression expression of tenascin of tenascin has been has detected been indetected pre-malignant in pre-malignant and malignant and malignant gastric epithelia gastric ep [7ithelia], whereas [7], whereas collagens collagens have been have shown been shown to be deregulatedto be deregulated in more in advanced more advanced stages [8 stages–10]. Notably, [8–10]. Notably, a subset ofa collagensubset of genes collagen have genes been suggestedhave been assuggested powerful as independent powerful independent prognostic markers prognostic and are markers able to and distinguish are able pre-malignant to distinguish from pre-malignant malignant lesionsfrom malignant [8–10]. It islesions thus foreseen [8–10]. It that is ECMthus foreseen components that andECM interactors components hold and great interactors clinical potential hold great as prognosticclinical potential biomarkers as prognostic and pharmacological biomarkers and targets pharmacological in gastric cancer. targets in gastric cancer. ThisThis review review comprises comprises a comprehensive a comprehensive analysis analysis of the mainof the studies main concerning studies ECMconcerning remodeling ECM andremodeling integrin alterationsand integrin during alterations gastric during cancer gastric development. cancer development. In particular, In we particular, highlight we the highlight current understandingthe current understanding of key ECM of components key ECM components and adhesion and molecules adhesion thatmolecules mediate that aberrant mediate cell-ECM aberrant crosstalkcell-ECM and crosstalk postulate and their postulate future their application future application in innovative in innovative gastric cancer gastric therapies. cancer therapies. 2.2. TheThe BiologicalBiological RelevanceRelevance of of the the ECM ECM in in Normal Normal Gastric Gastric Tissue Tissue TheThe ECMECM isis aa complex complex three-dimensional three-dimensional network,network, ubiquitouslyubiquitously presentpresent inin thethe non-cellularnon-cellular compartmentcompartment ofof tissues,tissues, providingproviding structuralstructural supportsupport andand maintainingmaintaining normalnormal tissuetissue architecture,architecture, whilstwhilst modulatingmodulating intercellularintercellular crosstalkcrosstalk [4[4,11,12].,11,12]. AsAs partpart ofof everyevery cell’scell’s microenvironment,microenvironment, thethe ECMECM isis producedproduced andand released released by by local local cells cells such such as as tissue-specific tissue-specific cells, cells, fibroblasts, fibroblasts, and and immune immune cellscells [ 1[1,13,14].,13,14]. Structurally,Structurally, thethe ECMECM isis anan organizedorganized scascaffoldffold assemblingassembling aa vastvast numbernumber ofof didifferentfferent macromolecules,macromolecules, namely namely collagen collagen type-I, type-I, -II, -III,-II, -III, -V, and -V, -XI,and fibronectin, -XI, fibronectin, laminin, laminin, vitronectin, vitronectin, elastin, andelastin, growth and factors,growth cytokines, factors, cytokines, and matrix and metalloproteinases matrix metalloproteinases (MMPs), for(MMPs), which for the which ECM actsthe ECM as a reservoiracts as a controlling reservoir controlling their distribution their distribution and availability and [availability12,15]. A complete [12,15]. listA complete of ECM components, list of ECM Cells 2020, 9, 394 3 of 23 their structure, and function are reviewed elsewhere [1,15,16]. Additionally, there are two specialized forms of ECM, the basement membrane, which links the cells to the interstitial matrix, and the interstitial matrix itself, a scaffold in the form of a hydrated gel [11]. It is now well established that the type of components, their proportions, and their
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