The Extracellular Matrix in Cancer: Comparison
Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Hans Henrik Raskov.

As the core component of all organs, the extracellular matrix (ECM) is an interlocking macromolecular meshwork of proteins, glycoproteins, and proteoglycans that provides mechanical support to cells and tissues. In cancer, the ECM can be remodelled in response to environmental cues, and it controls a plethora of cellular functions, including metabolism, cell polarity, migration, and proliferation, to sustain and support oncogenesis. The biophysical and biochemical properties of the ECM, such as its structural arrangement and being a reservoir for bioactive molecules, control several intra- and intercellular signalling pathways and induce cytoskeletal changes that alter cell shapes, behaviour, and viability.

  • extracellular matrix
  • composition
  • cancer
  • desmoplasia
  • therapeutical targets

1. Introduction

All cells synthesise, secrete, and degrade the extracellular matrix (ECM) occupying the space between them. Apart from being passive mechanical support for cells, the ECM is an extraordinarily complex and highly dynamic macromolecular meshwork of proteins, glycoproteins, proteoglycans, water, minerals, and a multitude of bioactive molecules that determine the phenotypes and molecular functions of the cells it surrounds (Figure 1). The interaction between ECM components, ECM-bound factors and cell surface receptors plays a crucial role in mediating cell adhesion and signalling that regulates multiple biological processes. Additionally, the ECM caters to the three-dimensional architectural structures of organs.
Figure 1. Schematic overview of the ECM structure and its components. The ECM is a complex environment and highly organised support network comprised of multiple proteins such as collagens, fibronectin, proteoglycans, integrins, growth factors and metalloproteinases, which provide cell anchorage. The ECM regulates a plethora of functions to maintain homeostasis. Each matrix protein consists of specific properties that define structural, mechanical, and chemical characteristics. In the figure, a fibronectin molecule is linked to a transmembranous integrin dimer, which is attached to a collagen molecule and thus creates a connection between the cytoskeleton and the ECM. Moreover, laminin complexes are attached to integrins, glycoproteins, and glycolipids through the linker/anchor region (LG domain) on the membrane, creating a dynamic link between cells and the ECM. Syndecans associate with integrins, growth factor receptors, as well as other ECM glycoproteins and collagens. The extracellular domains of syndecans are important for cell–cell and cell–matrix interactions via the glycosaminoglycan sidechains.
Serving as a reservoir for growth factors (GF) and other morphogenic proteins such as matrix metalloproteinases (MMP) originating from tumour cells and non-malignant stromal cells in the microenvironment, the ECM provides positional information to cells and facilitates cell proliferation, differentiation, signalling, and migration. The bidirectional flow of information between cells and the ECM regulates changes in ECM morphology and composition that involves the recruitment and recycling of large numbers of bioactive molecules (reviewed in [1])
The structural scaffolding, mechanical strength, and organisation of ECM components maintain the viability and motility of cells through cell surface contact points that connect the ECM to the cytoskeleton [2,3,4][2][3][4]. The ECM regulates the ability to transport cargo and resist deformation [5,6][5][6].
Through cytoskeleton/ECM adhesions and cytoskeleton contractions, cells can sense the spatial context and mechanical properties of the surrounding ECM. Mechanical stimuli convey downstream signalling (mechano-transduction) that regulates gene transcription [7] and continuously remodel the deposition, degradation, and modification of ECM components. The basement membrane (BM) is part of the ECM that separates epithelial cells from the deeper layers of connective tissues where bioactive molecules moving in and out of cells get filtered. The BM is a pericellular matrix structure that functions as a physical barrier and maintains cellular phenotypes without conferring any structural stability to the cell.
In cancer, tumour cells actively remodel their surrounding ECM through a variety of mechanisms, including the secretion of ECM-degrading enzymes and the synthesis of ECM proteins. The resulting dysregulation induces a range of biophysical and biochemical changes, including excess matrix deposition, rigidity, and fibrosis of the stroma [8]. These changes affect the three-dimensional spatial topology of the matrix around cells as well as cell fate promoting tumour growth, tumour cell migration, metastasis and resistance to anticancer therapies [9,10][9][10]. Understanding the relationship between cell motility and the characteristics of the extracellular matrix (ECM) is of great importance in cancer research, highlighting the necessity of mapping the intricate biological structures of both the ECM and the tumour microenvironment (TME) during the onset and progression of cancer. As wresearchers continue to make significant advancements in exploring intrastromal communication, it is possible that we may o soon witness the implementation of cancer therapies that target specific stromal alterations.

2. Components of ECM

ECM is a composite of cell-secreted macromolecules that include fibrous proteins providing the tissues tensile strength and glycoproteins and proteoglycans providing resistance to compression and deformation. Importantly, these molecules participate in multiple signalling pathways and are described in the subsequent section.

3. Fibrous ECM Proteins

3.1. Collagen

Collagen is a polypeptide structure produced by fibroblasts. Except for the brain, collagen is the most abundant protein throughout the human body and the most significant protein in the ECM [11]. Collagen is the major component of most connective tissues supporting and contributing to the three-dimensional from of organs. In addition, collagen plays an important role in various physiologic processes that include angiogenesis, haemostasis, and mineralisation, as well as in common pathologies such as cancer, fibrosis, and cardiovascular diseases [12]. In solid cancers, collagen deposition not only creates a barrier for cytotoxic immune cells and increases therapy resistance but also provides a rich source of exploitable metabolic fuels for cancer cells [13]. Following synthesis and assembly in the endoplasmic reticulum, the precursor peptide procollagen is packaged and exocytosed into the extracellular space. In the extracellular space, propeptide domains at the carboxy- and amino terminals of the procollagen are cleaved off by MMPs to modify the fibril shape and prevent lateral growth. The formation of the mature collagen microfibril requires binding to the N-terminus of fibronectin [14]. Each collagen fibre is made up of several subtypes. Defined by their bonds and amino acid repeats, twenty-eight different types of collagen composed of at least 46 distinct α-chains have been identified in humans [15]. Nearly 50% of amino acids incorporated into collagens are proline and glycine, which have important roles in the regulation of energy production, protein synthesis, redox balance, and intracellular signalling [16]. Collagen can be divided into fibrillar collagens type 1, 2, 3, 5, 11, 24, and 27 and non-fibrillar collagen type 4 (basement membrane); 6 (beaded filaments); 7 (anchor fibres); 8, 10 (short chain); 9, 12, and 14 (fibril-associated collagens with interrupted helices or FACIT); and type 13 (transmembrane collagen). The most abundant is collagen type 1, found in the skin, bones, and tendons [17]. Mutations in collagens 1, 2, 3, 9, 10, and 11 result in a broad range of ailments affecting cartilage, bones, and blood vessels, including osteogenesis imperfecta, various types of chondrodysplasia, Ehlers–Danlos syndrome types 4 and 7, and some cases of osteoarthritis, osteoporosis, and familial aneurysms [18].

3.2. Elastin

Elastin is a fibrillar hydrophobic matrix protein that, in contrast to collagen, is able to stretch eight times its resting length [19]. Elastin provides flexibility to blood vessels, skin, lungs, and ligaments. It is synthesised by fibroblasts, vascular smooth muscle cells [20], smooth muscle cells, and several types of epithelial cells. Being the primary ECM protein in arteries, where it amounts to ~50% of the weight [21], it has an impressive ability to withstand the mechanical stress of more than 3 billion expansions and contractions during an 80-year life cycle. The precursor protein, tropoelastin, is secreted with a chaperone molecule that facilitates the correct folding of the protein before it is incorporated into the highly flexible elastin strands. Similar to other ECM proteins, such as collagens, mature elastin is extensively cross-linked with other elastin molecules to form sheets and fibres [22]. Elastic fibres are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins. Due to its unique structure, extensive cross-linking and durability, elastin does not undergo significant turnover in healthy tissues where it has a half-life of more than 70 years [23]. It is primarily deposited during prenatal development and childhood and is rarely synthesised during adulthood [24]. Aberrant expression of elastases and degradation of elastin trigger the release of elastokines (fragments of matrix proteins with cytokine-like properties) that promote angiogenesis and regulate cell adhesion, chemotaxis, migration, and proliferation. Much of the elastokine effects are mediated by membrane elastin receptor complexes [23] that trigger signalling pathways involving the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and serine/threonine-protein kinase (AKT) activation [25]. Elastases belong to the enzyme classes of MMP, aspartic proteases, serine proteases, and cysteine proteases. The destruction of elastin promotes the development and progression of different pathological conditions, including chronic obstructive pulmonary disease, atherosclerosis, vascular aneurysms, and cancer. In lung and colon cancer, the degradation of the matrix and fragmentation of elastin was found mainly to occur at the invasive front, and the expression levels of MMP also correlated to the metastatic potential of these cancers [26,27][26][27].

4. The Glycoproteins

Glycomics is an important new frontier in life science research. Similar to proteoglycans, glycoproteins are composed of proteins with attached saccharide chains; however, the glycoprotein side chains are much shorter than the saccharide chains in proteoglycans. They contain no (or few) repeating units and are usually branched. The two most important ECM glycoproteins are fibronectin and laminin. Glycoproteins often act as connecting molecules that bind other ECM molecules, GF, and receptors. They have N-linked and O-linked saccharide sidechains, with the N-linked chains being connected to -NH2 on asparagine residues in the protein and O-linked chains to the -OH on the serine/threonine residues. N-linked and O-linked glycoproteins are mainly located on the cell membrane, where they play crucial roles in the cell–cell communication, adhesion, migration, proliferation and healing processes; they may also exist as secreted proteins.

4.1. Fibronectin

Within the body, fibronectin exists as soluble plasma glycoproteins (synthesised by hepatocytes and secreted into the blood) and as insoluble cellular fibronectin (a fibrillar cross-linked structure on the cell membranes). It is responsible for cell adhesion, proliferation, migration, and the deposition of ECM proteins [28]. The basic structural unit of fibronectin is a dimer composed of two nearly identical polypeptide chains linked by a pair of disulphide bonds. Fibronectin fibrils serve as mechanical links between the cytoskeleton and the surrounding ECM. It primarily binds to actin-anchored integrins on the cell membrane (Figure 1). Mediating the adhesion of BM components to ECM structures, integrins are heterodimeric (α and β subunits) cell-surface receptors and bi-directional transducers of biochemical signals and mechanical forces acting on the ECM. The α and β subunits both have a cytoplasmic tail, a transmembrane domain, and a large extracellular domain that bind numerous ECM ligands. The anchorage to the ECM is required for normal cells to enter the S phase, even in the presence of GF. If cells detach from their integrin ligation points and lose the sense of their mechanical environment, they undergo a specific type of apoptosis, anoikis (Greek for homeless). Resistance to anoikis is a characteristic feature of tumour cells that enables them to survive under non-adherent conditions [29,30,31][29][30][31]. The connection between the ECM and cytoskeleton stimulates cell proliferation and angiogenesis through pathways that include ERK 1/2 phosphorylation, dysregulation of the HIPPO (tumour suppressor) pathway, and suppression of apoptosis through the nuclear factor kappa B (NF-κB) or the phosphoinositide 3-kinase (PI3kinase)/AKT pathway [32]. Fibronectin fibrillogenesis is initiated by cytoskeleton-derived tensional forces transmitted across transmembrane integrins, typically α5β1 [33]. During this process, soluble molecular fibronectin is irreversibly assembled into insoluble fibrils that stretch up to four times their resting length, which implies domain unfolding and subsequent ECM remodelling [34]. Fibronectin fibres are proposed to be held together by hydrogen and disulphide bonds; however, catalytic agents such as thermolysin, plasmin, thrombin, trypsin, cathepsin D, and chymotrypsin can cleave them. Fibronectin fibrillogenesis and collagen fibrillogenesis have a complex relationship, with fibronectin regulating the assembly of collagen and vice versa [35]. How the production, organisation and matrix deposition of fibronectin are regulated by tumour cells is less understood as the turnover of fibronectin is largely unexplored [36]. Interacting with other ECM proteins, including GF, glycosaminoglycans, cell surface receptors and other fibronectin structures, fibronectin provides key mechanical and chemical signals to induce differentiation and epithelial-mesenchymal transition (EMT) [37]. Transforming growth factor β (TGFβ), fibroblast growth factor (FGR), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) have multiple binding sites within fibronectin. The binding of TGFβ1 to fibronectin fibrils was shown to upregulate EMT [37], whereas dysregulation of fibronectin promoted tumorigenesis and fibrosis, with the expression levels of fibronectin being significant prognostic factors in several cancers [38,39][38][39]. Hypoxia-induced factors upregulated in tumour cells stimulate endogenous FN synthesis. Intercellular signalling between tumour cells and protumorigenic stromal cells, such as tumour-associated macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells drive persistent FN deposition and remodelling of the ECM that facilitate growth and dissemination [40,41,42][40][41][42].

4.2. Laminin

Laminins are one of the major glycoproteins in the basement membranes that glue cells and tissues together and regulate cellular activities and signalling pathways. Structurally, laminins are cross-shaped, trimeric glycoproteins of 400–800 kDa in size and composed of a few distinct domains, of which 16 different combinations have been identified. Primarily involved in tissue repair and wound healing [43[43][44][45],44,45], all laminin complexes have a high affinity for GF through their heparin-binding domains; thus, apart from contributing to the anchoring of cells, laminin is a storage facility for GF whose release determines cell differentiation, survival, shape, and motility [46]. In hepatocellular carcinoma, laminin was found to be involved in EMT and disease progression [47]. The association between ECM proteins and GF is shown in Table 1.
Table 1.
Growth factors and their association with ECM proteins.

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