Liver Matrix in Benign and Malignant Biliary Tract Disease

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 quantitative and qualitative modifications, which direct interactions among hepatic progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to generate the ductular reaction. Herein, we will give an overview of the main molecular factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we will discuss the structural alterations in terms of biochemical composition and physical stiffness featuring the “desmoplastic matrix” of cholangiocarcinoma along with their pro-oncogenic effects.

Keywords

basement membrane - cholangiocytes - ductular reaction - tumor reactive stroma - biliary fibrosis

Financial Support

L.F. was supported by Progetti di Ricerca di Dipartimento (PRID-DMM) 2017, University of Padua; M.S. was supported by the National Institutes of Health RO1DK096096I, by DK034989 Silvio O. Conte Digestive Diseases Research Core Center, and by PSC Partners Seeking a Cure; G.J.G. was supported by Chris M. Carlos and Catharine Nicole Jockisch Carlos Endowment Fund in Primary Sclerosing Cholangitis.

Publikationsverlauf

Artikel online veröffentlicht:
11. März 2020

• References

• 1 Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev 2016; 97: 4-27
• 2 Klaas M, Kangur T, Viil J. , et al. The alterations in the extracellular matrix composition guide the repair of damaged liver tissue. Sci Rep 2016; 6: 27398
• 3 Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 2011; 3 (12) a005058
• 4 Daley WP, Peters SB, Larsen M. Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci 2008; 121 (Pt 3): 255-264
• 5 Miller RT. Mechanical properties of basement membrane in health and disease. Matrix Biol 2017; 57-58: 366-373
• 6 Jayadev R, Sherwood DR. Basement membranes. Curr Biol 2017; 27 (06) R207-R211
• 7 Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 2003; 3 (06) 422-433
• 8 Marchand M, Monnot C, Muller L, Germain S. Extracellular matrix scaffolding in angiogenesis and capillary homeostasis. Semin Cell Dev Biol 2019; 89: 147-156
• 9 Insua-Rodríguez J, Oskarsson T. The extracellular matrix in breast cancer. Adv Drug Deliv Rev 2016; 97: 41-55
• 10 Burgstaller G, Oehrle B, Gerckens M, White ES, Schiller HB, Eickelberg O. The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease. Eur Respir J 2017; 50 (01) 1601805
• 11 Sonbol HS. Extracellular matrix remodeling in human disease. J Microsc Ultrastruct 2018; 6 (03) 123-128
• 12 Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med 2019; 65: 37-55
• 13 Mak KM, Mei R. Basement membrane type IV collagen and laminin: an overview of their biology and value as fibrosis biomarkers of liver disease. Anat Rec (Hoboken) 2017; 300 (08) 1371-1390
• 14 Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol 2011; 3 (01) a004978
• 15 Aycock RS, Seyer JM. Collagens of normal and cirrhotic human liver. Connect Tissue Res 1989; 23 (01) 19-31
• 16 Griffiths MR, Keir S, Burt AD. Basement membrane proteins in the space of Disse: a reappraisal. J Clin Pathol 1991; 44 (08) 646-648
• 17 Tunggal P, Smyth N, Paulsson M, Ott MC. Laminins: structure and genetic regulation. Microsc Res Tech 2000; 51 (03) 214-227
• 18 Kikkawa Y, Mochizuki Y, Miner JH, Mitaka T. Transient expression of laminin alpha1 chain in regenerating murine liver: restricted localization of laminin chains and nidogen-1. Exp Cell Res 2005; 305 (01) 99-109
• 19 Amenta PS, Harrison D. Expression and potential role of the extracellular matrix in hepatic ontogenesis: a review. Microsc Res Tech 1997; 39 (04) 372-386
• 20 Geerts A, Geuze HJ, Slot JW. , et al. Immunogold localization of procollagen III, fibronectin and heparan sulfate proteoglycan on ultrathin frozen sections of the normal rat liver. Histochemistry 1986; 84 (4-6): 355-362
• 21 Bachmann M, Kukkurainen S, Hytönen VP, Wehrle-Haller B. Cell adhesion by integrins. Physiol Rev 2019; 99 (04) 1655-1699
• 22 Schaefer L. Small leucine-rich proteoglycans in kidney disease. J Am Soc Nephrol 2011; 22 (07) 1200-1207
• 23 Anderson LR, Owens TW, Naylor MJ. Structural and mechanical functions of integrins. Biophys Rev 2014; 6 (02) 203-213
• 24 Salanueva IJ, Cerezo A, Guadamillas MC, del Pozo MA. Integrin regulation of caveolin function. J Cell Mol Med 2007; 11 (05) 969-980
• 25 Harburger DS, Calderwood DA. Integrin signalling at a glance. J Cell Sci 2009; 122 (Pt 2): 159-163
• 26 Zemskov EA, Loukinova E, Mikhailenko I, Coleman RA, Strickland DK, Belkin AM. Regulation of platelet-derived growth factor receptor function by integrin-associated cell surface transglutaminase. J Biol Chem 2009; 284 (24) 16693-16703
• 27 Schnittert J, Bansal R, Storm G, Prakash J. Integrins in wound healing, fibrosis and tumor stroma: high potential targets for therapeutics and drug delivery. Adv Drug Deliv Rev 2018; 129: 37-53
• 28 Popov Y, Patsenker E, Stickel F. , et al. Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 2008; 48 (03) 453-464
• 29 Cannito S, Milani C, Cappon A, Parola M, Strazzabosco M, Cadamuro M. Fibroinflammatory liver injuries as preneoplastic condition in cholangiopathies. Int J Mol Sci 2018; 19 (12) E3875
• 30 Yasoshima M, Tsuneyama K, Harada K, Sasaki M, Gershwin ME, Nakanuma Y. Immunohistochemical analysis of cell-matrix adhesion molecules and their ligands in the portal tracts of primary biliary cirrhosis. J Pathol 2000; 190 (01) 93-99
• 31 Washington K, Clavien PA, Killenberg P. Peribiliary vascular plexus in primary sclerosing cholangitis and primary biliary cirrhosis. Hum Pathol 1997; 28 (07) 791-795
• 32 Arriazu E, Ruiz de Galarreta M, Cubero FJ. , et al. Extracellular matrix and liver disease. Antioxid Redox Signal 2014; 21 (07) 1078-1097
• 33 Forsten-Williams K, Chu CL, Fannon M, Buczek-Thomas JA, Nugent MA. Control of growth factor networks by heparan sulfate proteoglycans. Ann Biomed Eng 2008; 36 (12) 2134-2148
• 34 Somasundaram R, Ruehl M, Tiling N. , et al. Collagens serve as an extracellular store of bioactive interleukin 2. J Biol Chem 2000; 275 (49) 38170-38175
• 35 Van Hul NK, Abarca-Quinones J, Sempoux C, Horsmans Y, Leclercq IA. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 2009; 49 (05) 1625-1635
• 36 Roskams TA, Theise ND, Balabaud C. , et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 2004; 39 (06) 1739-1745
• 37 Fabris L, Spirli C, Cadamuro M, Fiorotto R, Strazzabosco M. Emerging concepts in biliary repair and fibrosis. Am J Physiol Gastrointest Liver Physiol 2017; 313 (02) G102-G116
• 38 Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. III. Implications for liver pathology. Virchows Arch 2011; 458 (03) 271-279
• 39 Hao C, Cui Y, Owen S, Li W, Cheng S, Jiang WG. Human osteopontin: potential clinical applications in cancer (Review). Int J Mol Med 2017; 39 (06) 1327-1337
• 40 Whitington PF, Malladi P, Melin-Aldana H, Azzam R, Mack CL, Sahai A. Expression of osteopontin correlates with portal biliary proliferation and fibrosis in biliary atresia. Pediatr Res 2005; 57 (06) 837-844
• 41 Lorena D, Darby IA, Gadeau AP. , et al. Osteopontin expression in normal and fibrotic liver. altered liver healing in osteopontin-deficient mice. J Hepatol 2006; 44 (02) 383-390
• 42 Fickert P, Stöger U, Fuchsbichler A. , et al. A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am J Pathol 2007; 171 (02) 525-536
• 43 Wang X, Lopategi A, Ge X. , et al. Osteopontin induces ductular reaction contributing to liver fibrosis. Gut 2014; 63 (11) 1805-1818
• 44 Coombes JD, Swiderska-Syn M, Dollé L. , et al. Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut 2015; 64 (07) 1120-1131
• 45 Xiao X, Gang Y, Gu Y. , et al. Osteopontin contributes to TGF-β1 mediated hepatic stellate cell activation. Dig Dis Sci 2012; 57 (11) 2883-2891
• 46 Fickert P, Thueringer A, Moustafa T. , et al. The role of osteopontin and tumor necrosis factor alpha receptor-1 in xenobiotic-induced cholangitis and biliary fibrosis in mice. Lab Invest 2010; 90 (06) 844-852
• 47 Yang M, Ramachandran A, Yan HM. , et al. Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice. Toxicol Lett 2014; 224 (02) 186-195
• 48 Lenga Y, Koh A, Perera AS, McCulloch CA, Sodek J, Zohar R. Osteopontin expression is required for myofibroblast differentiation. Circ Res 2008; 102 (03) 319-327
• 49 Arriazu E, Ge X, Leung TM. , et al. Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 2017; 66 (06) 1123-1137
• 50 Ramazani Y, Knops N, Elmonem MA. , et al. Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol 2018; 68-69: 44-66
• 51 Pi L, Robinson PM, Jorgensen M. , et al. Connective tissue growth factor and integrin αvβ6: a new pair of regulators critical for ductular reaction and biliary fibrosis in mice. Hepatology 2015; 61 (02) 678-691
• 52 Peng ZW, Ikenaga N, Liu SB. , et al. Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis. Hepatology 2016; 63 (01) 217-232
• 53 Locatelli L, Cadamuro M, Spirlì C. , et al. Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. Hepatology 2016; 63 (03) 965-982
• 54 Spirli C, Locatelli L, Morell CM. , et al. Protein kinase A-dependent pSer(675)-β-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 2013; 58 (05) 1713-1723
• 55 Guicciardi ME, Trussoni CE, Krishnan A. , et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol 2018; 69 (03) 676-686
• 56 Liu SB, Ikenaga N, Peng ZW. , et al. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J 2016; 30 (04) 1599-1609
• 57 Ikenaga N, Peng ZW, Vaid KA. , et al. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 2017; 66 (09) 1697-1708
• 58 Pollheimer MJ, Racedo S, Mikels-Vigdal A. , et al. Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis. J Hepatol 2018; 69 (02) 368-377
• 59 Muir AJ, Levy C, Janssen HLA. , et al; GS-US-321-0102 Investigators. Simtuzumab for primary sclerosing cholangitis: phase 2 study results with insights on the natural history of the disease. Hepatology 2019; 69 (02) 684-698
• 60 Tsuchiya A, Lu WY, Weinhold B. , et al. Polysialic acid/neural cell adhesion molecule modulates the formation of ductular reactions in liver injury. Hepatology 2014; 60 (05) 1727-1740
• 61 Fabris L, Strazzabosco M, Crosby HA. , et al. Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations. Am J Pathol 2000; 156 (05) 1599-1612
• 62 Strazzabosco M, Fabris L. Neural cell adhesion molecule and polysialic acid in ductular reaction: the puzzle is far from completed, but the picture is becoming more clear. Hepatology 2014; 60 (05) 1469-1472
• 63 Tanimizu N, Miyajima A, Mostov KE. Liver progenitor cells develop cholangiocyte-type epithelial polarity in three-dimensional culture. Mol Biol Cell 2007; 18 (04) 1472-1479
• 64 Tanimizu N, Kikkawa Y, Mitaka T, Miyajima A. α1- and α5-containing laminins regulate the development of bile ducts via β1 integrin signals. J Biol Chem 2012; 287 (34) 28586-28597
• 65 Yasoshima M, Sato Y, Furubo S. , et al. Matrix proteins of basement membrane of intrahepatic bile ducts are degraded in congenital hepatic fibrosis and Caroli's disease. J Pathol 2009; 217 (03) 442-451
• 66 Kourouklis AP, Kaylan KB, Underhill GH. Substrate stiffness and matrix composition coordinately control the differentiation of liver progenitor cells. Biomaterials 2016; 99: 82-94
• 67 Yanai M, Tatsumi N, Hasunuma N, Katsu K, Endo F, Yokouchi Y. FGF signaling segregates biliary cell-lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro. Dev Dyn 2008; 237 (05) 1268-1283
• 68 Kaylan KB, Ermilova V, Yada RC, Underhill GH. Combinatorial microenvironmental regulation of liver progenitor differentiation by Notch ligands, TGFβ, and extracellular matrix. Sci Rep 2016; 6: 23490
• 69 Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012; 196 (04) 395-406
• 70 Brivio S, Cadamuro M, Strazzabosco M, Fabris L. Tumor reactive stroma in cholangiocarcinoma: the fuel behind cancer aggressiveness. World J Hepatol 2017; 9 (09) 455-468
• 71 Fabris L, Perugorria MJ, Mertens J. , et al. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int 2019; 39 (Suppl. 01) 63-78
• 72 Özdemir BC, Pentcheva-Hoang T, Carstens JL. , et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014; 25 (06) 719-734
• 73 Kim EJ, Sahai V, Abel EV. , et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res 2014; 20 (23) 5937-5945
• 74 Khoshchehreh R, Totonchi M, Carlos Ramirez J. , et al. Epigenetic reprogramming of primary pancreatic cancer cells counteracts their in vivo tumourigenicity. Oncogene 2019; 38 (34) 6226-6239
• 75 Terada T, Okada Y, Nakanuma Y. Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. Hepatology 1996; 23 (06) 1341-1344
• 76 Prakobwong S, Yongvanit P, Hiraku Y. , et al. Involvement of MMP-9 in peribiliary fibrosis and cholangiocarcinogenesis via Rac1-dependent DNA damage in a hamster model. Int J Cancer 2010; 127 (11) 2576-2587
• 77 Glentis A, Oertle P, Mariani P. , et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat Commun 2017; 8 (01) 924
• 78 Aishima S, Taguchi K, Terashi T, Matsuura S, Shimada M, Tsuneyoshi M. Tenascin expression at the invasive front is associated with poor prognosis in intrahepatic cholangiocarcinoma. Mod Pathol 2003; 16 (10) 1019-1027
• 79 Utispan K, Thuwajit P, Abiko Y. , et al. Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker. Mol Cancer 2010; 9: 13
• 80 Sirica AE, Almenara JA, Li C. Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications. Exp Mol Pathol 2014; 97 (03) 515-524
• 81 Huang Y, Liu W, Xiao H. , et al. Matricellular protein periostin contributes to hepatic inflammation and fibrosis. Am J Pathol 2015; 185 (03) 786-797
• 82 Utispan K, Sonongbua J, Thuwajit P. , et al. Periostin activates integrin α5β1 through a PI3K/AKT–dependent pathway in invasion of cholangiocarcinoma. Int J Oncol 2012; 41 (03) 1110-1118
• 83 Zeng J, Liu Z, Sun S. , et al. Tumor-associated macrophages recruited by periostin in intrahepatic cholangiocarcinoma stem cells. Oncol Lett 2018; 15 (06) 8681-8686
• 84 Zhou W, Ke SQ, Huang Z. , et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 2015; 17 (02) 170-182
• 85 Mino M, Kanno K, Okimoto K. , et al. Periostin promotes malignant potential by induction of epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. Hepatol Commun 2017; 1 (10) 1099-1109
• 86 Midwood KS, Chiquet M, Tucker RP, Orend G. Tenascin-C at a glance. J Cell Sci 2016; 129 (23) 4321-4327
• 87 Lowy CM, Oskarsson T. Tenascin C in metastasis: a view from the invasive front. Cell Adhes Migr 2015; 9 (1-2): 112-124
• 88 De Wever O, Nguyen QD, Van Hoorde L. , et al. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J 2004; 18 (09) 1016-1018
• 89 Degen M, Brellier F, Kain R. , et al. Tenascin-W is a novel marker for activated tumor stroma in low-grade human breast cancer and influences cell behavior. Cancer Res 2007; 67 (19) 9169-9179
• 90 Degen M, Brellier F, Schenk S. , et al. Tenascin-W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients. Int J Cancer 2008; 122 (11) 2454-2461
• 91 Hendrix MJ, Seftor EA, Hess AR, Seftor RE. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 2003; 3 (06) 411-421
• 92 Zhao H, Chen Q, Alam A. , et al. The role of osteopontin in the progression of solid organ tumour. Cell Death Dis 2018; 9 (03) 356
• 93 Loosen SH, Roderburg C, Kauertz KL. , et al. Elevated levels of circulating osteopontin are associated with a poor survival after resection of cholangiocarcinoma. J Hepatol 2017; 67 (04) 749-757
• 94 Zheng Y, Zhou C, Yu XX. , et al. Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of β-Catenin. Cell Death Dis 2018; 9 (02) 179
• 95 Sulpice L, Rayar M, Desille M. , et al. Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma. Hepatology 2013; 58 (06) 1992-2000
• 96 Banales JM, Cardinale V, Carpino G. , et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016; 13 (05) 261-280
• 97 Armstrong T, Packham G, Murphy LB. , et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res 2004; 10 (21) 7427-7437
• 98 Barcus CE, O'Leary KA, Brockman JL. , et al. Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells. Breast Cancer Res 2017; 19 (01) 9
• 99 Menke A, Philippi C, Vogelmann R. , et al. Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res 2001; 61 (08) 3508-3517
• 100 Nissen NI, Karsdal M, Willumsen N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J Exp Clin Cancer Res 2019; 38 (01) 115
• 101 Veenstra VL, Damhofer H, Waasdorp C. , et al. Stromal SPOCK1 supports invasive pancreatic cancer growth. Mol Oncol 2017; 11 (08) 1050-1064
• 102 Bradshaw AD. The role of SPARC in extracellular matrix assembly. J Cell Commun Signal 2009; 3 (3-4) 239-246
• 103 Karsdal MA, Manon-Jensen T, Genovese F. , et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2015; 308 (10) G807-G830
• 104 Matsumoto S, Yamamoto K, Nagano T. , et al. Immunohistochemical study on phenotypical changes of hepatocytes in liver disease with reference to extracellular matrix composition. Liver 1999; 19 (01) 32-38
• 105 Lamireau T, Le Bail B, Boussarie L. , et al. Expression of collagens type I and IV, osteonectin and transforming growth factor beta-1 (TGFbeta1) in biliary atresia and paucity of intrahepatic bile ducts during infancy. J Hepatol 1999; 31 (02) 248-255
• 106 Whitby T, Schroeder D, Kim HS. , et al. Modifications in integrin expression and extracellular matrix composition in children with biliary atresia. Klin Padiatr 2015; 227 (01) 15-22
• 107 Iordanskaia T, Koeck E, Rossi C. , et al. Integrin β-8, but not β-5 or -6, protein expression is increased in livers of children with biliary atresia. J Pediatr Gastroenterol Nutr 2014; 59 (06) 679-683
• 108 Harada K, Ozaki S, Sudo Y, Tsuneyama K, Ohta H, Nakanuma Y. Osteopontin is involved in the formation of epithelioid granuloma and bile duct injury in primary biliary cirrhosis. Pathol Int 2003; 53 (01) 8-17
• 109 Koukoulis GK, Koso-Thomas AK, Zardi L, Gabbiani G, Gould VE. Enhanced tenascin expression correlates with inflammation in primary sclerosing cholangitis. Pathol Res Pract 1999; 195 (11) 727-731
• 110 Noguchi H, Yoshida H, Takamatsu H, Akiyama H. Immunohistochemical studies on tenascin in extrahepatic bile duct remnants of biliary atresia. In Vivo 2000; 14 (06) 715-720
• 111 Honsawek S, Udomsinprasert W, Vejchapipat P, Chongsrisawat V, Phavichitr N, Poovorawan Y. Elevated serum periostin is associated with liver stiffness and clinical outcome in biliary atresia. Biomarkers 2015; 20 (02) 157-161
• 112 Bordeleau F, Mason BN, Lollis EM. , et al. Matrix stiffening promotes a tumor vasculature phenotype. Proc Natl Acad Sci U S A 2017; 114 (03) 492-497
• 113 Salmon H, Franciszkiewicz K, Damotte D. , et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 2012; 122 (03) 899-910
• 114 Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell 2016; 29 (06) 783-803
• 115 Domínguez-Calderón A, Ávila-Flores A, Ponce A. , et al. ZO-2 silencing induces renal hypertrophy through a cell cycle mechanism and the activation of YAP and the mTOR pathway. Mol Biol Cell 2016; 27 (10) 1581-1595
• 116 Wang G, Lu X, Dey P. , et al. Targeting YAP-dependent mdsc infiltration impairs tumor progression. Cancer Discov 2016; 6 (01) 80-95
• 117 Kim W, Khan SK, Liu Y. , et al. Hepatic hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 2018; 67 (09) 1692-1703
• 118 Chang L, Azzolin L, Di Biagio D. , et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 2018; 563 (7730): 265-269
• 119 Zou S, Li J, Zhou H. , et al. Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 2014; 5: 5696
• 120 Chakraborty S, Njah K, Pobbati AV. , et al. Agrin as a mechanotransduction signal regulating YAP through the hippo pathway. Cell Rep 2017; 18 (10) 2464-2479
• 121 Schuppan D, Ashfaq-Khan M, Yang AT, Kim YO. Liver fibrosis: direct antifibrotic agents and targeted therapies. Matrix Biol 2018; 68-69: 435-451
• 122 Macias RIR, Kornek M, Rodrigues PM. , et al. Diagnostic and prognostic biomarkers in cholangiocarcinoma. Liver Int 2019; 39 (Suppl. 01) 108-122
• 123 Ramanathan RK, McDonough SL, Philip PA. , et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol 2019; 37 (13) 1062-1069