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The Adhesome Network: Key Components Shaping the Tumour Stroma

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The Adhesome Network: Key Components Shaping the Tumour Stroma cancers Review The Adhesome Network: Key Components Shaping the Tumour Stroma Pinelopi A. Nikolopoulou † , Maria A. Koufaki † and Vassiliki Kostourou * Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Bioinnovation, 34 Fleming Str., 16672 Vari-Athens, Greece; nikolopoulou@fleming.gr (P.A.N.); koufaki@fleming.gr (M.A.K.) * Correspondence: kostourou@fleming.gr; Tel.: +30-210-965-4465 † These authors contributed equally to this work. Simple Summary: Tumours are not formed only by malignant cells but contain many other cell types, including endothelial and mural cells of blood vessels, immune cells and cancer-associated fibroblasts. These host cells, together with extracellular matrix, form the tumour stroma. Tumour growth and metastasis depends on interactions between cancer cells and tumour stroma. Cell adhesion to extracellular matrix is essential for tissue growth and homeostasis and is deregulated in many pathological conditions, including cancer. This review highlights the vital role of cell adhesion in malignancy and describes how adhesion components regulate tumour stroma responses and control cancer development. Abstract: Beyond the conventional perception of solid tumours as mere masses of cancer cells, ad- vanced cancer research focuses on the complex contributions of tumour-associated host cells that are known as “tumour microenvironment” (TME). It has been long appreciated that the tumour stroma, composed mainly of blood vessels, cancer-associated fibroblasts and immune cells, together with Citation: Nikolopoulou, P.A.; the extracellular matrix (ECM), define the tumour architecture and influence cancer cell properties. Koufaki, M.A.; Kostourou, V. The Besides soluble cues, that mediate the crosstalk between tumour and stroma cells, cell adhesion to Adhesome Network: Key ECM arises as a crucial determinant in cancer progression. In this review, we discuss how adhesome, Components Shaping the Tumour the intracellular protein network formed at cell adhesions, regulate the TME and control malignancy. Stroma. Cancers 2021, 13, 525. The role of adhesome extends beyond the physical attachment of cells to ECM and the regulation of https://doi.org/10.3390/ cytoskeletal remodelling and acts as a signalling and mechanosensing hub, orchestrating cellular cancers13030525 responses that shape the tumour milieu. Academic Editors: Nikos Karamanos Keywords: tumour microenvironment; adhesome; focal adhesion sites; endothelial cells; mural cells; and Zoi Piperigkou cancer-associated fibroblasts; immune cells; tumour stroma Received: 23 December 2020 Accepted: 25 January 2021 Published: 30 January 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Malignant cells are the main driving force of tumour formation and growth, yet published maps and institutional affil- they do not manifest the disease single-handed. It is now increasingly accepted that iations. noncancerous cells located in the tumour niche are involved in the hallmark capabilities of cancer [1]. Key cellular players in the tumour stroma are vascular cells comprising blood and lymphatic vessels (endothelial cells and mural cells), cancer-associated fibroblasts (CAFs), and infiltrating immune cells. Additional stromal cell types of solid tumours Copyright: © 2021 by the authors. include mesenchymal stem cells, adipocytes and neurons [2,3]. The complex contributions Licensee MDPI, Basel, Switzerland. of these allegedly normal, constituent cells together with noncellular components, namely This article is an open access article the extracellular matrix (ECM) and soluble factors, are collectively known as the tumour distributed under the terms and microenvironment (TME) (Figure1). conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Cancers 2021, 13, 525. https://doi.org/10.3390/cancers13030525 https://www.mdpi.com/journal/cancers CancersCancers 20212021,, 1313,, x 525 1 2of of 36 38 FigureFigure 1. 1. TumourTumour microenviro microenvironmentnment (TME).(TME). BesidesBesides cancer cancer cells cells (depicted (depicted in in grey), grey), distinct distinct cell cell types typesand extracellular and extracellular matrix matrix (ECM) (ECM) constitute constitute the TME the that TME controls that control cancers developmentcancer development and progression. and progression.Abbreviations: Abbreviations: CAF, cancer-associated CAF, cancer fibroblast;-associated TAM, fibroblast; tumour-associated TAM, tumour macrophages;-associated macro- MDSCs, phages;myeloid-derived MDSCs, m suppressoryeloid-derived cells; suppressor NK cell, natural cells; killerNK cell cell;, natural EC, endothelial killer cell; cell; EC, DC, endothelial dendritic cell; cell; DC,TAN, dendritic tumour-associated cell; TAN, tumour neutrophils;-associated ECM, neutrophils extracellular; ECM, matrix. extracellular matrix. AsAs in in normal normal tissue, tissue, all all cells cells in in the the TME TME are are attached attached and and intera interactct with with ECM ECM at at specific specific sites,sites, called called cell cell–matrix–matrix adhesions. TheseThese structuresstructures are are composed composed by by the the integrin integrin family family of ofECM ECM receptors receptors and and an an intrigue intrigue protein protein network network called called adhesome adhesome that that is is directly directly linked linked to tothe the cell cell cytoskeleton cytoskeleton [4– [46].–6] Adhesion. Adhesion sites sites physically physically attach attach the the cell cell to its to microenvironmentits microenviron- mentand maintainand maintain cell homeostasis. cell homeostasis. Depending Depending on the on protein the protein composition composition and arrangementsand arrange- mentswithin within the adhesome, the adhesome, cell–matrix cell–matrix adhesions adhesions have have distinct distinct architecture, architecture localisation, localisation and andlifespan lifespan [7]. [ These7]. These dynamic dynamic characteristics characteristics enable enable adhesion adhesion sites sites to rapidly to rapidly change change cell cellmorphology morphology and and modulate modulate cell spreading cell spreading to facilitate to facilitate cell migration cell migration and invasion. and invasion. Further- Furthermore,more, cell–matrix cell– adhesionsmatrix adhesions co-ordinate co-ordinate cellular cellular responses responses to extracellular to extracellular stimuli throughstimuli throughcrosstalk crosstalk with intracellular with intracellular signal transduction signal transduction pathways, pathways, hence influencing hence influencing cell survival, cell survival,proliferation proliferation and differentiation. and differentiation. Emerging Emerging data highlight data highlight the role the of mechanicalrole of mechanical cues in cuesregulating in regulating cell function. cell function. In this In aspect, this aspect, adhesome adhesome proteins proteins constitute constitute critical critical players play- in ersboth insensing both sensing and transducing and transducing mechanical mechanical forces to forces cell cytoskeleton. to cell cytoskeleton. Adhesome Adhesome members membersinclude more include than more 232 adhesion-related than 232 adhesion proteins-related broadly proteins divided broadly into divided structural/adaptor into struc- α tural/adaptorproteins (such proteins as talin, (such vinculin, as talin, ILK-PINCH-parvin, vinculin, ILK-PINCH paxillin,-parvin, zyxin, paxillin, tensin, zyxin,-actinin, tensin, filamin and KANK) and signalling proteins (for example FAK, Pyk2, Src, RhoGTPases α-actinin, filamin and KANK) and signalling proteins (for example FAK, Pyk2, Src, RhoG- and myosin light chain kinase). These proteins could constitute intrinsic components of TPases and myosin light chain kinase). These proteins could constitute intrinsic compo- cell–matrix adhesions or transiently associate with the adhesion network, facilitating the nents of cell–matrix adhesions or transiently associate with the adhesion network, facili- coordination of cell behaviour [8–12]. Finally, adhesome components connect with different tating the coordination of cell behaviour [8–12]. Finally, adhesome components connect actin structures (stress fibres, cortical actin, lamellipodia, filopodia) and microtubules, to with different actin structures (stress fibres, cortical actin, lamellipodia, filopodia) and mi- stabilise cell shape and facilitate cell migration and invasion. crotubules, to stabilise cell shape and facilitate cell migration and invasion. Several experimental approaches, ranging from genomics, proteomics and bioinfor- Several experimental approaches, ranging from genomics, proteomics and bioinfor- matics, to classical biochemistry, cell biology and model organisms (fly, worm, mouse), matics, to classical biochemistry, cell biology and model organisms (fly, worm, mouse), have started to decipher both the composition and the role of adhesome members in or- have started to decipher both the composition and the role of adhesome members in or- chestrating cell function in physiology and pathology. In this review, we elaborate on the chestrating cell function in physiology and pathology. In this review, we elaborate on the functional impact of adhesome proteins in cancer, focusing on host cells located into the functionaltumour niche: impact endothelial of adhesome cells proteins (ECs), mural in cancer, cells, focusing CAFs and on immune host cells cells located (summarised into the tumourin Table
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