Liver Matrix in Benign and Malignant Biliary Tract Disease

Liver Matrix in Benign and Malignant Biliary Tract Disease Luca Fabris, MD, PhD1,2 Massimiliano Cadamuro, PhD1 Silvia Cagnin, MD1 Mario Strazzabosco, MD, PhD2 Gregory J. Gores, MD, PhD3 1 Department of Molecular Medicine, University of Padua, Padua, Italy Address for correspondence Luca Fabris, MD, PhD, Department of 2 Liver Center, Department of Medicine, Yale University, New Haven, Molecular Medicine, University of Padua, Via A. Gabelli 63, Connecticut Padua 35121, Italy (e-mail: [email protected]). 3 Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Michigan Semin Liver Dis Abstract The extracellular matrix is a highly reactive scaffold formed by a wide array of multifunctional molecules, encompassing collagens and noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and polysaccharides. Besides outlining the tissue borders, the extracellular matrix profoundly regulates the behavior of resident cells by transducing mechanical signals, and by integrating multiple cues derived from the microenvironment. Evidence is mounting that changes in the biostructure of the extracellular matrix are instrumental for biliary repair. Following biliary damage and eventually, malignant transformation, the extracellular matrix undergoes several Keywords quantitative and qualitative modifications, which direct interactions among hepatic ► basement membrane progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to ► cholangiocytes generate the ductular reaction. Herein, we will give an overview of the main molecular ► ductular reaction factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we ► tumor reactive will discuss the structural alterations in terms of biochemical composition and physical stroma stiffness featuring the “desmoplastic matrix” of cholangiocarcinoma along with their ► biliary fibrosis pro-oncogenic effects. Architectural organization of organs is based on a three- The ECM can be divided into two main components, the dimensional scaffold holding together different cell types basement membrane (BM) and the interstitial matrix, which and enabling them to communicate. This extracellular matrix variably support cell polarization and migration. The BM is a (ECM) is not a simple inert substrate, but rather, a highly finely assembled membrane, underlining tubular structures, dynamic biostructure composed by a complex meshwork of such as blood and lymphatic vessels, and ductal epithelia. multifunctional molecules, formed by cross-linked proteins The BM mediates cell attachment and adhesion, and pro- (collagens and noncollagenous glycoproteins), proteoglycans, motes polarization and transport activities.6,7 The interstitial glycosaminoglycans, and polysaccharides. The ECM defines matrix is the main component of the stroma, which fills the tissue boundaries, but also regulates cell behavior.1,2 Indeed, space among the resident mesenchymal cell types, and besides providing structural anchorage for the attachment of instructs their contribution to several fundamental tissue – parenchymal cells, and transducing mechanical signals,3 5 functions, such as development, regeneration and repair, and ECM can play a range of functions, including presentation of angiogenesis.8 Although changes in ECM composition are growth factors to their cognate receptors, storage of soluble considered relevant to the progression of several chronic factors, cytokines and chemokines, thereby integrating multi- diseases including those of the biliary epithelium (also called ple cues released in the microenvironment.2 “cholangiopathies”), in recent years this topic has received Copyright © by Thieme Medical DOI https://doi.org/ Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0040-1705109. New York, NY 10001, USA. ISSN 0272-8087. Tel: +1(212) 760-0888. Liver Matrix in Benign and Malignant Biliary Tract Disease Fabris et al. – less attention.9 12 Thus, the aim of the present review is to associated large heparan sulfate proteoglycan (HSPG) express- reawaken interest in the role of the biliary ECM, first by ing several binding domains for laminins and collagens, acts as discussing ECM structure and composition in the normal a bridge between these structural molecules. In the normal liver, and then addressing ECM remodeling as it occurs in liver, small leucine-rich proteoglycans such as decorin and benign and malignant diseases of the biliary tract. biglycan are contained in the space of Disse, likely acting as antifibrotic agents due to their ability to bind and neutralize β 22 ECM in the Normal Liver biologically active transforming growth factor (TGF)- 1. On the other hand, proteoglycans can serve as co-receptors for In the normal liver, the ECM is localized in the portal area, cytokines and growth factors, as betaglycan does for TGF-β1, around the central veins and in the thin space surrounding and syndecans for basic fibroblast growth factor (FGF). The role liver sinusoids (space of Disse). The liver sinusoids lack a BM, of ECM as reservoir for proinflammatory cytokines andgrowth but some ECM components are contained in the space of factors able to regulate profibrotic responses will be discussed Disse. The normal constituents of the hepatic ECM in both in the following study. rodents and humans include collagens, laminins, fibronectin, Interactions of ECM components with cells are mediated by nidogens (or entactin), and perlecan, which distribute vari- specific cell membrane receptors, among which integrins are ably in the BM and in the interstitial matrix.2,13 best studied. Integrins are transmembrane heterodimers Collagens are the major constituents in the ECM; 28 differ- formed by α and β subunits, variably combined in more than ent types of collagens have been identified so far, and are 20 members, with binding domains located in their globular categorized into “fibrillar-forming” and “network-forming” portion constituted by an Arg-Gly-Asp (RGD) sequence with collagens.14 In the normal liver, the most represented member affinity for both ECM components (collagens, laminins, fibro- of the collagen family is collagen-IV, a network-forming colla- nectin) and cell adhesion molecules.23 Besides providing gen.15 It is expressed in the BM lining of the bile ducts, as well adhesive functions, integrins modulate several signaling path- as in the interstitial matrix of the portal tracts, where it ways by recruiting adaptor molecules (caveolin, paxillin)24,25 assembles with the fibrillary-forming collagens -III, -V, and and tyrosinekinases (platelet-derivedgrowth factors [PDGF]-β -I (though less abundantly expressed), to generate anchoring receptors)26 to form focal adhesion complexes. In the normal sites for cells. Notably, collagen-IV is also expressed in the liver, integrin receptors are expressed, though at low levels, by space of Disse.16 hepatocytes (α1β1, α5β1, α9β1) and hepatic stellate cells Laminins are a large family of noncollagenousglycoproteins (α1β1, α2β1, α5β1, α6β4). Studies in mouse models of liver highly expressed in the BM, composed of α (1–5), β (1–4), and γ fibrosis have shown that laminin-binding (α6β1, α2β1) and (1–3) disulfide-linked chains, with structural and functional fibronectin-binding (α5β1, αvβ6) integrins are upregulated.27 roles.17 Laminins affect cell differentiation, adhesion, and In particular, upregulation of integrin αvβ6 in the biliary migration. In the mouse liver, the most abundant is the β2 epithelium is a hallmark of biliary fibrosis, as discussed later.28 laminin, which is a constitutive BM component in the bile ►Table 1 outlines the structural components characteriz- ducts, and in portal vessels.18 By combining with collagen type ing the “healthy” ECM phenotype in the liver. Noteworthy, IV, laminin generates a BM around the hepatic sinusoid, an these macromolecules are normally secreted at low levels by element of the so-called “capillarization” of sinusoids, typical stromal cells usually present in the hepatic microenvironment of cirrhosis.13 (hepatic stellate cells and portal fibroblasts). Following biliary Another major component of the hepatic ECM is fibronec- damage and eventually malignant transformation, other cell tin, a high molecular weight (around 440 kDa) glycoprotein elements, including hepatic progenitor cells (HPCs), reactive largely expressed in the interstitial matrix surrounding the ductular cells, activated myofibroblasts and macrophages, gain portal vein and in the BM of the bile ducts in rodent the ability to secrete pre-existing or new ECM components, models.19,20 Thanks to its pronounced binding ability to leading to quantitative and qualitative changes which are several ligands (collagens, heparin, fibrin) and cell surface instrumental for ECM remodeling, as discussed in the follow- receptors, in particular with integrins, fibronectin undergoes ing sections.29 polymerization and stabilizes fibrils, serving as a hook for the attachment of several cell types to the ECM, to regulate cell fl 21 ECM Remodeling in In ammatory adhesion and cytoskeletal organization. Cholangiopathies Nidogens (also called “entactins”) are a class of noncollagenous glycoproteins expressed by the BM. Two forms, ECM remodeling is a functional hallmark of liver repair and nidogen-1 and nidogen-2, have been described, and are fibrogenesis. Some of the major changes of ECM during fibro- critically involved in the development of BM by providing genesis are an increased expression of collagen-I

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