Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

Hindawi Disease Markers Volume 2019, Article ID 2304931, 15 pages https://doi.org/10.1155/2019/2304931 Review Article Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis Carlo Smirne ,1 Cristina Rigamonti ,1 Carla De Benedittis,1 Pier Paolo Sainaghi ,1,2,3 Mattia Bellan ,1,2,3 Michela Emma Burlone,1 Luigi Mario Castello,1 and Gian Carlo Avanzi1,3 1 Internal Medicine Division, Maggiore della Carità Hospital, Department of Translational Medicine, Università del Piemonte Orientale (UPO), Novara, Italy 2 Immunorheumatology Unit, CAAD (Center for Autoimmune and Allergic Diseases), “Maggiore della Carità” Hospital, Novara, Italy 3 IRCAD (Interdisciplinary Research Center of Autoimmune Diseases), Novara, Italy Correspondence should be addressed to Carlo Smirne; Received 5 April 2019; Revised 20 June 2019; Accepted 12 August 2019; Published 8 September 2019 Academic Editor: Michele Malaguarnera Copyright © 2019 Carlo Smirne et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity. 1. Introduction 1.1. Hepatic Fibrosis: Pathophysiology and Clinical Importance. All hepatologists wish they had a crystal ball in their clinic to enable them to determine whether or not their immediate patient has liver fibrosis or not. This is because liver fibrosis is a predominate key component of essentially all chronic liver diseases. It is the formation of scar tissue in response to parenchymal injuries such as chronic hepatitis B (CHB) and C (CHC), nonalcoholic fatty liver disease (NAFLD), or alcoholism (ALD). The continuous and progressive replacement of hepatocytes by the extracellular matrix and fibrous tissue eventually leads to liver cirrhosis, which in turn may lead to liver failure or promote a conducive microenvironment for cancer development, in particular hepatocellular carcinoma (HCC) [1, 2]. Whatever the etiology of liver injury, it is the activation of hepatic stellate cells (HSCs) that is responsible for liver fibrosis, being HSCs the main collagen-producing cells in the damaged liver [3, 4]. HSCs transform during chronic liver injuries from a quiescent state into a myofibroblast-like phenotype (HSCs/MFBs), which proliferate and migrate towards areas of necrosis and regeneration [5, 6]. The main action of HSCs/MFBs consists in a profound alteration of the extracellular matrix (ECM) composition due to the upregulation of proteins such as αsmooth muscle actin (α-SMA), interstitial collagens such as 2 collagen 1A1, and matrix metalloproteinases (MMPs) such as MMP9 as well as tissue inhibitors of metalloproteinases (TIMPs), and proteoglycans. Activated HSCs also generate hepatic cytokines such as transforming growth factor-β, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factor, hepatocyte growth factor, and vascular endothelial growth factor and recruit inflammatory mono- and polymorphonuclear leukocytes that produce chemokines, including monocyte chemotactic protein(MCP-) 1, regulated on activation normal T cell expressed and secreted (RANTES), chemokine (C-C motif) ligand 21 (CCL21), and C-C chemokine receptor type 5 (CCR5). Although HSCs’ critical role in liver fibrosis was proposed nearly two decades ago [7], more recent data demonstrate that, regardless of the underlying etiology of liver disease, the majority of myofibroblasts comes from the liverresident HSC population [8]. While liver fibrosis was once broadly thought of as an irreversible process, there is now substantial evidence that, at least from a speculative point of view, a near-normal hepatic architecture can be restored upon cessation of injury [9]. However, these promising findings must be offset by the fact that, after cessation of the fibrotic triggering insult, around half of the activated HSCs survive in an apparently quiescent state, as they are primed to quickly reactivate into myofibroblasts in response to fibrogenic stimuli [10, 11]. This leaves room for doubt that antifibrotic therapies meant to inhibit activated HSCs, although beneficial to prevent ECM deposition, may be sufficient to revert fibrosis permanently. In any case, accurately defining the current fibrosis stage reached by a patient along the course of his/her disease is, as previously mentioned, of quintessential clinical importance, since crucial decisions, such as starting monitoring for complications (e.g., esophageal varices or HCC), depend on it. Moreover, the presence and extent of liver fibrosis help to predict prognosis and to prompt treatment decisions in various chronic liver diseases. For instance, different international treatment guidelines mention that the severity of liver fibrosis should be considered, regardless of serum alanine aminotransferase level, for starting antiviral treatment for CHB [12, 13]. In conclusion, there are a multiplicity of reasons for which it is crucial to diagnose and assess the extent of liver fibrosis. 1.2. Liver Biopsy for Staging of Fibrosis. Liver biopsy is still considered as the gold standard method to assess liver fibrosis; moreover, it provides useful information about diagnosis as well as other damaging processes such as necrosi (...truncated)