EpCAM and the biology of hepatic stem/progenitor cells

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 308, Issue 4, 2015, Pages G233-G250

  Dollé, Laurent ^a   Theise, Neil D ^b   Schmelzer, Eva ^c   Boulter, Luke ^d   Gires, Olivier ^e   Van Grunsven, Leo A ^a  

^a VRIJE UNIVERSITEIT BRUSSEL   (Belgium)

^b ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^c UNIVERSITY OF PITTSBURGH   (United States)

^d UNIVERSITY OF EDINBURGH   (United Kingdom)

^e LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

EpCAM; Hepatic stem progenitor cell; Liver differentiation; Liver regeneration; Signaling

Indexed keywords

EPITHELIAL CELL ADHESION MOLECULE; CELL ADHESION MOLECULE; TUMOR ANTIGEN; TUMOR-ASSOCIATED ANTIGEN GA733;

ARTICLE; CANCER RESEARCH; CELL ADHESION; HEPATIC STEM CELL; HEPATOBILIARY SYSTEM; HUMAN; LIVER CELL CARCINOMA; NONALCOHOLIC FATTY LIVER; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN GLYCOSYLATION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; REGENERATIVE MEDICINE; STEM CELL; WNT SIGNALING PATHWAY; ANIMAL; CELL DIFFERENTIATION; CELL LINEAGE; CELL PROLIFERATION; GENE EXPRESSION REGULATION; GENETICS; LIVER; LIVER CELL; LIVER DISEASE; LIVER REGENERATION; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ANTIGENS, NEOPLASM; CELL ADHESION MOLECULES; CELL DIFFERENTIATION; CELL LINEAGE; CELL PROLIFERATION; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HEPATOCYTES; HUMANS; LIVER; LIVER DISEASES; LIVER REGENERATION; SIGNAL TRANSDUCTION; STEM CELLS;

EID: 84922943712     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00069.2014     Document Type: Article

References (155)

1. Anderson R, Schaible K, Heasman J, Wylie C. Expression of the homophilic adhesion molecule, Ep-CAM, in the mammalian germ line. J Reprod Fertil 116: 379–384, 1999.
2. Aupet S, Simone G, Heyd B, Bachellier P, Vidal I, Richert L, Martin H. Isolation of viable human hepatic progenitors from adult livers is possible even after 48 hours of cold ischemia. Tissue Eng Part C Methods 19: 497–506, 2013.
3. Baeuerle PA, Gires O. EpCAM (CD326) finding its role in cancer. Br J Cancer 96: 417–423, 2007.
4. Balzar M, Briaire-de Bruijn IH, Rees-Bakker HA, Prins FA, Hel-frich W, de Leij L, Riethmuller G, Alberti S, Warnaar SO, Fleuren GJ, Litvinov SV. Epidermal growth factor-like repeats mediate lateral and reciprocal interactions of Ep-CAM molecules in homophilic adhesions. Mol Cell Biol 21: 2570–2580, 2001.
5. Balzar M, Winter MJ, de Boer CJ, Litvinov SV. The biology of the 17-1A antigen (Ep-CAM). J Mol Med (Berl) 77: 699–712, 1999.
6. Best J, Dollé L, Manka P, Coombes J, van Grunsven LA, Syn WK. Role of liver progenitors in acute liver injury. Front Physiol 4: 258, 2013.
7. Bird TG, Lu WY, Boulter L, Gordon-Keylock S, Ridgway RA, Williams MJ, Taube J, Thomas JA, Wojtacha D, Gambardella A, Sansom OJ, Iredale JP, Forbes SJ. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc Natl Acad Sci USA 110: 6542–6547, 2013.
8. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 18: 572–579, 2012.
9. Boulter L, Lu WY, Forbes SJ. Differentiation of progenitors in the liver: a matter of local choice. J Clin Invest 123: 1867–1873, 2013.
10. Bryan RT, Shimwell NJ, Wei W, Devall AJ, Pirrie SJ, James ND, Zeegers MP, Cheng KK, Martin A, Ward DG. Urinary EpCAM in urothelial bladder cancer patients: characterisation and evaluation of biomarker potential. Br J Cancer 110: 679–685, 2014.
11. Cardinale V, Wang Y, Carpino G, Alvaro D, Reid L, Gaudio E. Multipotent stem cells in the biliary tree. Ital J Anat Embryol 115: 85–90, 2010.
12. Cardinale V, Wang Y, Carpino G, Cui CB, Gatto M, Rossi M, Berloco PB, Cantafora A, Wauthier E, Furth ME, Inverardi L, Dominguez-Bendala J, Ricordi C, Gerber D, Gaudio E, Alvaro D, Reid L. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology 54: 2159–2172, 2011.
13. Cardinale V, Wang Y, Carpino G, Mendel G, Alpini G, Gaudio E, Reid LM, Alvaro D. The biliary tree—a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol 9: 231–240, 2012.
14. Carpenter G, Red Brewer M. EpCAM: another surface-to-nucleus missile. Cancer Cell 15: 165–166, 2009.
15. Carpentier R, Suner RE, van Hul N, Kopp JL, Beaudry JB, Cordi S, Antoniou A, Raynaud P, Lepreux S, Jacquemin P, Leclercq IA, Sander M, Lemaigre FP. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141: 1432–1438; 1438.e1–1438.e4, 2011.
16. Carpino G, Cardinale V, Gentile R, Onori P, Semeraro R, Franchitto A, Wang Y, Bosco D, Iossa A, Napoletano C, Cantafora A, D’Argenio G, Nuti M, Caporaso N, Berloco P, Venere R, Oikawa T, Reid L, Alvaro D, Gaudio E. Evidence for multipotent endodermal stem/progenitor cell populations in human gallbladder. J Hepatol 60: 1194–1202, 2014.
17. Carpino G, Cardinale V, Onori P, Franchitto A, Berloco PB, Rossi M, Wang Y, Semeraro R, Anceschi M, Brunelli R, Alvaro D, Reid LM, Gaudio E. Biliary tree stem/progenitor cells in glands of extrahe-patic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat 220: 186–199, 2012.
18. Chaves-Perez A, Mack B, Maetzel D, Kremling H, Eggert C, Har-reus U, Gires O. EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene 32: 641–650, 2013.
19. Cheng K, Benten D, Bhargava K, Inada M, Joseph B, Palestro C, Gupta S. Hepatic targeting and biodistribution of human fetal liver stem/progenitor cells and adult hepatocytes in mice. Hepatology 50: 1194–1203, 2009.
20. Chong JM, Speicher DW. Determination of disulfide bond assignments and N-glycosylation sites of the human gastrointestinal carcinoma antigen GA733-2 (CO17-1A, EGP, KS1-4, KSA, and Ep-CAM). J Biol Chem 276: 5804–5813, 2001.
21. Cirulli V, Crisa L, Beattie GM, Mally MI, Lopez AD, Fannon A, Ptasznik A, Inverardi L, Ricordi C, Deerinck T, Ellisman M, Reis-feld RA, Hayek A. KSA antigen Ep-CAM mediates cell-cell adhesion of pancreatic epithelial cells: morphoregulatory roles in pancreatic islet development. J Cell Biol 140: 1519–1534, 1998.
22. Claas C, Wahl J, Orlicky DJ, Karaduman H, Schnölzer M, Kempf T, Zöller M. The tetraspanin D6.1A and its molecular partners on rat carcinoma cells. Biochem J 389: 99–110, 2005.
23. de Boer CJ, van Krieken JH, Janssen-van Rhijn CM, Litvinov SV. Expression of Ep-CAM in normal, regenerating, metaplastic, and neo-plastic liver. J Pathol 188: 201–206, 1999.
24. Denzel S, Maetzel D, Mack B, Eggert C, Barr G, Gires O. Initial activation of EpCAM cleavage via cell-to-cell contact. BMC Cancer 9: 402, 2009.
25. Diehl AM. Neighborhood watch orchestrates liver regeneration. Nat Med 18: 497–499, 2012.
26. Dollé L, Best J, Empsen C, Mei J, Van Rossen E, Roelandt P, Snykers S, Najimi M, Al Battah F, Theise ND, Streetz K, Sokal E, Leclercq IA, Verfaillie C, Rogiers V, Geerts A, van Grunsven LA. Successful isolation of liver progenitor cells by aldehyde dehydrogenase activity in naive mice. Hepatology 55: 540–552, 2012.
27. Dollé L, Best J, Mei J, Al Battah F, Reynaert H, van Grunsven LA, Geerts A. The quest for liver progenitor cells: a practical point of view. J Hepatol 52: 117–129, 2010.
28. Dollé L, Streetz KL, van Grunsven LA. Sharpen your look on liver progenitor cells. Hepatology 55: 319–321, 2012.
29. Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS, Fox AJ, Smirnova O, Duncan AW, Finegold MJ, Sander M, Kaestner KH, Grompe M. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 25: 1193–1203, 2011.
30. Driemel C, Kremling H, Schumacher S, Will D, Wolters J, Linden-lauf N, Mack B, Baldus SA, Hoya V, Pietsch JM, Panagiotidou P, Raba K, Vay C, Vallbohmer D, Harreus U, Knoefel WT, Stoecklein NH, Gires O. Context-dependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene 33: 4904–4915, 2014.
31. Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology 137: 466–481, 2009.
32. Eisenwort G, Jurkin J, Yasmin N, Bauer T, Gesslbauer B, Strobl H. Identification of TROP2 (TACSTD2), an EpCAM-like molecule, as a specific marker for TGF-beta1-dependent human epidermal Langerhans cells. J Invest Dermatol 131: 2049–2057, 2011.
33. Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P. Adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol 27: 1941–1947, 2009.
34. Fong D, Moser P, Kasal A, Seeber A, Gastl G, Martowicz A, Wurm M, Mian C, Obrist P, Mazzoleni G, Spizzo G. Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer. Histopathology 64: 683–692, 2014.
35. Fong D, Seeber A, Terracciano L, Kasal A, Mazzoleni G, Lehne F, Gastl G, Spizzo G. Expression of EpCAM(MF) and EpCAM(MT) variants in human carcinomas. J Clin Pathol 67: 408–414, 2014.
36. Gaudio E, Carpino G, Cardinale V, Franchitto A, Onori P, Alvaro D. New insights into liver stem cells. Dig Liver Dis 41: 455–462, 2009.
37. Gires O. EpCAM in hepatocytes and their progenitors. J Hepatol 56: 490–492, 2012.
38. Gires O, Bauerle PA. EpCAM as a target in cancer therapy. J Clin Oncol 28: e239–e240; author reply e241–e232, 2010.
39. Gires O, Klein CA, Baeuerle PA. On the abundance of EpCAM on cancer stem cells. Nat Rev Cancer 9: 143, 2009.
40. Gires O, Stoecklein NH. Dynamic EpCAM expression on circulating and disseminating tumor cells: causes and consequences. Cell Mol Life Sci 71: 4393–4402, 2014.
41. Gonzalez B, Denzel S, Mack B, Conrad M, Gires O. EpCAM is involved in maintenance of the murine embryonic stem cell phenotype. Stem Cells 27: 1782–1791, 2009.
42. Gouw AS, Clouston AD, Theise ND. Ductular reactions in human liver: diversity at the interface. Hepatology 54: 1853–1863, 2011.
43. Govaere O, Komuta M, Berkers J, Spee B, Janssen C, de Luca F, Katoonizadeh A, Wouters J, van Kempen LC, Durnez A, Verslype C, De Kock J, Rogiers V, van Grunsven LA, Topal B, Pirenne J, Vankelecom H, Nevens F, van den Oord J, Pinzani M, Roskams T. Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut 63: 674–685, 2014.
44. Gridelli B, Vizzini G, Pietrosi G, Luca A, Spada M, Gruttadauria S, Cintorino D, Amico G, Chinnici C, Miki T, Schmelzer E, Conaldi PG, Triolo F, Gerlach JC. Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell-based therapy and case report on cell transplantation. Liver Transpl 18: 226–237, 2012.
45. Guerra E, Lattanzio R, La Sorda R, Dini F, Tiboni GM, Piantelli M, Alberti S. mTrop1/Epcam knockout mice develop congenital tufting enteropathy through dysregulation of intestinal E-cadherin/beta-catenin. PLoS One 7: e49302, 2012.
46. Guillemot JC, Naspetti M, Malergue F, Montcourrier P, Galland F, Naquet P. Ep-CAM transfection in thymic epithelial cell lines triggers the formation of dynamic actin-rich protrusions involved in the organization of epithelial cell layers. Histochem Cell Biol 116: 371–378, 2001.
47. Gumbiner BM, Kim NG. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci 127: 709–717, 2014.
48. Hachmeister M, Bobowski KD, Hogl S, Dislich B, Fukumori A, Eggert C, Mack B, Kremling H, Sarrach S, Coscia F, Zimmermann W, Steiner H, Lichtenthaler SF, Gires O. Regulated intramembrane proteolysis and degradation of murine epithelial cell adhesion molecule mEpCAM. PLoS One 29: e71836, 2013.
49. Hass MR, Sato C, Kopan R, Zhao G. Presenilin: RIP and beyond. Semin Cell Dev Biol 20: 201–210, 2009.
50. Hassan K, Bhalla V, El Regal ME, A-Kader HH. Nonalcoholic fatty liver disease: a comprehensive review of a growing epidemic. World J Gastroenterol 20: 12082–12101, 2014.
51. Hayashida K, Bartlett AH, Chen Y, Park PW. Molecular and cellular mechanisms of ectodomain shedding. Anat Rec (Hoboken) 293: 925–937, 2010.
52. Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci USA 76: 1438–1442, 1979.
53. Huang HP, Chen PH, Yu CY, Chuang CY, Stone L, Hsiao WC, Li CL, Tsai SC, Chen KY, Chen HF, Ho HN, Kuo HC. Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor-mediated pluripotency reprogramming. J Biol Chem 286: 33520–33532, 2011.
54. Imrich S, Hachmeister M, Gires O. EpCAM and its potential role in tumor-initiating cells. Cell Adh Migr 6: 30–38, 2012.
55. Itoh T, Miyajima A. Liver regeneration by stem/progenitor cells. Hepa-tology 59: 1617–1626, 2014.
56. Ji H, Greening DW, Barnes TW, Lim JW, Tauro BJ, Rai A, Xu R, Adda C, Mathivanan S, Zhao W, Xue Y, Xu T, Zhu HJ, Simpson RJ. Proteome profiling of exosomes derived from human primary and met-astatic colorectal cancer cells reveal differential expression of key met-astatic factors and signal transduction components. Proteomics 13: 1672–1686, 2013.
57. Johnson CP, Fujimoto I, Rutishauser U, Leckband DE. Direct evidence that neural cell adhesion molecule (NCAM) polysialylation increases intermembrane repulsion and abrogates adhesion. J Biol Chem 280: 137–145, 2005.
58. Jozefczuk J, Stachelscheid H, Chavez L, Herwig R, Lehrach H, Zeilinger K, Gerlach JC, Adjaye J. Molecular characterization of cultured adult human liver progenitor cells. Tissue Eng Part C Methods 16: 821–834, 2010.
59. Kasper M, Behrens J, Schuh D, Muller M. Distribution of E-cadherin and Ep-CAM in the human lung during development and after injury. Histochem Cell Biol 103: 281–286, 1995.
60. Khan AA, Parveen N, Mahaboob VS, Rajendraprasad A, Ravin-draprakash HR, Venkateswarlu J, Rao P, Pande G, Narusu ML, Khaja MN, Pramila R, Habeeb A, Habibullah CM. Management of hyperbilirubinemia in biliary atresia by hepatic progenitor cell transplantation through hepatic artery: a case report. Transplant Proc 40: 1153–1155, 2008.
61. Khan AA, Rajendraprasad A, Parveen N, Shaik MV, Tiwari SK, Srinivas G, Raj TA, Habeeb MA, Pande G, Habibullah CM. In vitro insulin production and analysis of pancreatic transcription factors in induced human hepatic progenitor cells. Diabetes Technol Ther 12: 373–378, 2010.
62. Khan AA, Shaik MV, Parveen N, Rajendraprasad A, Aleem MA, Habeeb MA, Srinivas G, Raj TA, Tiwari SK, Kumaresan K, Ven-kateswarlu J, Pande G, Habibullah CM. Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis. Cell Transplant 19: 409–418, 2010.
63. Kiefer JC. Primer and interviews: the dynamic stem cell niche. Dev Dyn 240: 737–743, 2011.
64. Kim NG, Koh E, Chen X, Gumbiner BM. E-Cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci USA 108: 11930–11935, 2011.
65. Kinoshita T, Sekiguchi T, Xu MJ, Ito Y, Kamiya A, Tsuji K, Nakahata T, Miyajima A. Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis. Proc Natl Acad Sci USA 96: 7265–7270, 1999.
66. Klein CE, Cordon-Cardo C, Soehnchen R, Cote RJ, Oettgen HF, Eisinger M, Old LJ. Changes in cell surface glycoprotein expression during differentiation of human keratinocytes. J Invest Dermatol 89: 500–506, 1987.
67. Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, Theise ND. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 47: 1994–2002, 2008.
68. Ladwein M, Pape UF, Schmidt DS, Schnolzer M, Fiedler S, Langbein L, Franke WW, Moldenhauer G, Zoller M. The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein clau-din-7. Exp Cell Res 309: 345–357, 2005.
69. Lal M, Caplan M. Regulated intramembrane proteolysis: signaling pathways and biological functions. Physiology (Bethesda) 26: 34–44, 2011.
70. Lanzoni G, Oikawa T, Wang Y, Cui CB, Carpino G, Cardinale V, Gerber D, Gabriel M, Dominguez-Bendala J, Furth ME, Gaudio E, Alvaro D, Inverardi L, Reid LM. Clinical programs of stem cell therapies for liver and pancreas. Stem Cells 31: 2047–2060, 2013.
71. Le Naour F, Zoller M. The tumor antigen EpCAM: tetraspanins and the tight junction protein claudin-7, new partners, new functions. Front Biosci 13: 5847–5865, 2008.
72. Lei Z, Maeda T, Tamura A, Nakamura T, Yamazaki Y, Shiratori H, Yashiro K, Tsukita S, Hamada H. EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. Dev Biol 371: 136–145, 2012.
73. Lichtenthaler SF, Haass C, Steiner H. Regulated intramembrane pro-teolysis—lessons from amyloid precursor protein processing. J Neuro-chem 117: 779–796, 2011.
74. Lin CW, Liao MY, Lin WW, Wang YP, Lu TY, Wu HC. Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. J Biol Chem 287: 39449–39459, 2012.
75. Litvinov SV, Bakker HA, Gourevitch MM, Velders MP, Warnaar SO. Evidence for a role of the epithelial glycoprotein 40 (Ep-CAM) in epithelial cell-cell adhesion. Cell Adhes Commun 2: 417–428, 1994.
76. Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, Fleuren GJ, Warnaar SO. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol 139: 1337–1348, 1997.
77. Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO. Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 125: 437–446, 1994.
78. Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P, Dooley S. Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol 304: G449–G468, 2013.
79. Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K, Aucott R, Clayton E, Andreone P, Bernardi M, Golding M, Alison MR, Iredale JP, Forbes SJ. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 59: 645–654, 2010.
80. Lozoya OA, Wauthier E, Turner RA, Barbier C, Prestwich GD, Guilak F, Superfine R, Lubkin SR, Reid LM. Regulation of hepatic stem/progenitor phenotype by microenvironment stiffness in hydrogel models of the human liver stem cell niche. Biomaterials 32: 7389–7402, 2011.
81. Lu H, Ma J, Yang Y, Shi W, Luo L. EpCAM is an endoderm-specific Wnt derepressor that licenses hepatic development. Dev Cell 24: 543–553, 2013.
82. Lu TY, Lu RM, Liao MY, Yu J, Chung CH, Kao CF, Wu HC. Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. J Biol Chem 285: 8719–8732, 2010.
83. Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, Kieu C, Papior P, Baeuerle PA, Munz M, Gires O. Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 11: 162–171, 2009.
84. Maghzal N, Kayali HA, Rohani N, Kajava AV, Fagotto F. EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC. Dev Cell 27: 263–277, 2013.
85. Maghzal N, Vogt E, Reintsch W, Fraser JS, Fagotto F. The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling. J Cell Biol 191: 645-659, 2010.
86. Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 9: 197-208, 2010.
87. McClelland R, Wauthier E, Tallheden T, Reid LM, Hsu E. In situ labeling and magnetic resonance imaging of transplanted human hepatic stem cells. Mol Imaging Biol 13: 911-922, 2011.
88. Medina M, Dotti CG. RIPped out by presenilin-dependent gamma-secretase. Cell Signal 15: 829-841, 2003.
89. Michalopoulos GK. Advances in liver regeneration. Expert Rev Gastroenterol Hepatol 8: 897-907, 2014.
90. Miyajima A, Kinoshita T, Tanaka M, Kamiya A, Mukouyama Y, Hara T. Role of oncostatin M in hematopoiesis and liver development. Cytokine Growth Factor Rev 11: 177-183, 2000.
91. Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14: 561-574, 2014.
92. Momburg F, Moldenhauer G, Hammerling GJ, Moller P. Immuno-histochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues. Cancer Res 47: 2883-2891, 1987.
93. Mueller JL, McGeough MD, Pena CA, Sivagnanam M. Functional consequences of EpCam mutation in mice and men. Am J Physiol Gastrointest Liver Physiol 306: G278-G288, 2014.
94. Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 69: 5627-5629, 2009.
95. Munz M, Fellinger K, Hofmann T, Schmitt B, Gires O. Glycosylation is crucial for stability of tumour and cancer stem cell antigen EpCAM. Front Biosci 13: 5195-5201, 2008.
96. Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23: 5748-5758, 2004.
97. Munz M, Murr A, Kvesic M, Rau D, Mangold S, Pflanz S, Lumsden J, Volkland J, Fagerberg J, Riethmuller G, Ruttinger D, Kufer P, Baeuerle PA, Raum T. Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies. Cancer Cell Int 10: 44, 2010.
98. Nagao K, Zhu J, Heneghan MB, Hanson JC, Morasso MI, Tessarollo L, Mackem S, Udey MC. Abnormal placental development and early embryonic lethality in EpCAM-null mice. PLoS One 4: e8543, 2009.
99. Ng VY, Ang SN, Chan JX, Choo AB. Characterization of epithelial cell adhesion molecule as a surface marker on undifferentiated human embryonic stem cells. Stem Cells 28: 29-35, 2010.
100. Nubel T, Preobraschenski J, Tuncay H, Weiss T, Kuhn S, Ladwein M, Langbein L, Zoller M. Claudin-7 regulates EpCAM-mediated functions in tumor progression. Mol Cancer Res 7: 285-299, 2009.
101. Okabe M, Tsukahara Y, Tanaka M, Suzuki K, Saito S, Kamiya Y, Tsujimura T, Nakamura K, Miyajima A. Potential hepatic stem cells reside in EpCAM + cells of normal and injured mouse liver. Development 136: 1951-1960, 2009.
102. Osterreicher CH, Trauner M. Animal models of biliary tract injury. Curr Opin Gastroenterol 28: 239-243, 2012.
103. Patriarca C, Macchi RM, Marschner AK, Mellstedt H. Epithelial cell adhesion molecule expression (CD326) in cancer: a short review. Cancer Treat Rev 38: 68-75, 2012.
104. Pauli C, Munz M, Kieu C, Mack B, Breinl P, Wollenberg B, Lang S, Zeidler R, Gires O. Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett 193: 25-32, 2003.
105. Puppi J, Strom SC, Hughes RD, Bansal S, Castell JV, Dagher I, Ellis EC, Nowak G, Ericzon BG, Fox IJ, Gomez-Lechon MJ, Guha C, Gupta S, Mitry RR, Ohashi K, Ott M, Reid LM, Roy-Chowdhury J, Sokal E, Weber A, Dhawan A. Improving the techniques for human hepatocyte transplantation: report from a consensus meeting in London. Cell Transplant 21: 1-10, 2012.
106. Raju R, Chau D, Verfaille C, Hu WS. The road to regenerative liver therapies: the triumphs, trials and tribulations. Biotechnol Adv 31: 1085-1093, 2013.
107. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 434: 843-850, 2005.
108. Rountree CB, Barsky L, Ge S, Zhu J, Senadheera S, Crooks GM. A CD133-expressing murine liver oval cell population with bilineage potential. Stem Cells 25: 2419–2429, 2007.
109. Sackett SD, Gao Y, Shin S, Esterson YB, Tsingalia A, Hurtt RS, Brondell K, Kaestner KH, Greenbaum LE. Foxl1 promotes liver repair following cholestatic injury in mice. Lab Invest 89: 1387–1396, 2009.
110. Sankpal NV, Willman MW, Fleming TP, Mayfield JD, Gillanders WE. Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion. Cancer Res 69: 753–757, 2009.
111. Schmelzer E, Reid LM. EpCAM expression in normal, non-pathological tissues. Front Biosci 13: 3096–3100, 2008.
112. Schmelzer E, Wauthier E, Reid LM. The phenotypes of pluripotent human hepatic progenitors. Stem Cells 24: 1852–1858, 2006.
113. Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, Moss N, Melhem A, McClelland R, Turner W, Kulik M, Sherwood S, Tallheden T, Cheng N, Furth ME, Reid LM. Human hepatic stem cells from fetal and postnatal donors. J Exp Med 204: 1973–1987, 2007.
114. Schmidt DS, Klingbeil P, Schnolzer M, Zoller M. CD44 variant isoforms associate with tetraspanins and EpCAM. Exp Cell Res 297: 329–347, 2004.
115. Schnell U, Cirulli V, Giepmans BN. EpCAM: structure and function in health and disease. Biochim Biophys Acta 1828: 1989–2001, 2013.
116. Schnell U, Kuipers J, Giepmans BN. EpCAM proteolysis: new fragments with distinct functions? Biosci Rep 33: e00030, 2013.
117. Shin S, Upadhyay N, Greenbaum LE, Kaestner KH. Ablation of Foxl1-Cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury. Gastroenterology pii: S0016–5085: 01193–01197, 2014.
118. Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, Smirnova O, Dorrell C, Erker L, Chu AS, Wells RG, Grompe M, Greenbaum LE, Kaestner KH. Foxl1-Cre-marked adult hepatic progenitors have clono-genic and bilineage differentiation potential. Genes Dev 25: 1185–1192, 2011.
119. Simon M, Stefan N, Pluckthun A, Zangemeister-Wittke U. Epithelial cell adhesion molecule-targeted drug delivery for cancer therapy. Expert Opin Drug Deliv 10: 451–468, 2013.
120. Slanchev K, Carney TJ, Stemmler MP, Koschorz B, Amsterdam A, Schwarz H, Hammerschmidt M. The epithelial cell adhesion molecule EpCAM is required for epithelial morphogenesis and integrity during zebrafish epiboly and skin development. PLoS Genet 5: e1000563, 2009.
121. Spizzo G, Gastl G, Obrist P, Fong D, Haun M, Grunewald K, Parson W, Eichmann C, Millinger S, Fiegl H, Margreiter R, Amberger A. Methylation status of the Ep-CAM promoter region in human breast cancer cell lines and breast cancer tissue. Cancer Lett 246: 253–261, 2007.
122. Stachelscheid H, Urbaniak T, Ring A, Spengler B, Gerlach JC, Zeilinger K. Isolation and characterization of adult human liver progenitors from ischemic liver tissue derived from therapeutic hepatectomies. Tissue Eng Part A 15: 1633–1643, 2009.
123. Strazzabosco M, Fabris L. The balance between Notch/Wnt signaling regulates progenitor cells’ commitment during liver repair: mystery solved? J Hepatol 58: 181–183, 2013.
124. Suzuki A, Sekiya S, Onishi M, Oshima N, Kiyonari H, Nakauchi H, Taniguchi H. Flow cytometric isolation and clonal identification of self-renewing bipotent hepatic progenitor cells in adult mouse liver. Hepatology 48: 1964–1978, 2008.
125. Tanaka M, Okabe M, Suzuki K, Kamiya Y, Tsukahara Y, Saito S, Miyajima A. Mouse hepatoblasts at distinct developmental stages are characterized by expression of EpCAM and DLK1: drastic change of EpCAM expression during liver development. Mech Dev 126: 665–676, 2009.
126. Tanimizu N, Mitaka T. Re-evaluation of liver stem/progenitor cells. Organogenesis 10: 208–215, 2014.
127. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM. The canals of Hering and hepatic stem cells in humans. Hepatology 30: 1425–1433, 1999.
128. Trzpis M, Bremer E, McLaughlin PM, de Leij LF, Harmsen MC. EpCAM in morphogenesis. Front Biosci 13: 5050–5055, 2008.
129. Trzpis M, McLaughlin PM, de Leij LM, Harmsen MC. Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule. Am J Pathol 171: 386–395, 2007.
130. Trzpis M, McLaughlin PM, Popa ER, Terpstra P, van Kooten TG, de Leij LM, Harmsen MC. EpCAM homologues exhibit epithelial-specific but different expression patterns in the kidney. Transgenic Res 17: 229–238, 2008.
131. Trzpis M, Popa ER, McLaughlin PM, van Goor H, Timmer A, Bosman GW, de Leij LM, Harmsen MC. Spatial and temporal expression patterns of the epithelial cell adhesion molecule (EpCAM/EGP-2) in developing and adult kidneys. Nephron Exp Nephrol 107: e119–e131, 2007.
132. Tsuchiya A, Lu WY, Weinhold B, Boulter L, Stutchfield BM, Williams MJ, Guest RV, Minnis-Lyons SE, MacKinnon AC, Schwarzer D, Ichida T, Nomoto M, Aoyagi Y, Gerardy-Schahn R, Forbes SJ. Polysialic acid/neural cell adhesion molecule modulates the formation of ductular reactions in liver injury. Hepatology 60: 1727–1740, 2014.
133. Turner R, Gerber D, Reid L. The future of cell transplant therapies: a need for tissue grafting. Transplantation 90: 807–810, 2010.
134. Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G, Mendel G, Wauthier E, Barbier C, Alvaro D, Reid LM. Human hepatic stem cell and maturational liver lineage biology. Hepatology 53: 1035–1045, 2011.
135. Turner RA, Mendel G, Wauthier E, Barbier C, Reid LM. Hyaluro-nan-supplemented buffers preserve adhesion mechanisms facilitating cryopreservation of human hepatic stem/progenitor cells. Cell Transplant 21: 2257–2266, 2012.
136. Turner RA, Wauthier E, Lozoya O, McClelland R, Bowsher JE, Barbier C, Prestwich G, Hsu E, Gerber DA, Reid LM. Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts. Hepatology 57: 775–784, 2013.
137. Turner WS, Schmelzer E, McClelland R, Wauthier E, Chen W, Reid LM. Human hepatoblast phenotype maintained by hyaluronan hydrogels. J Biomed Mater Res B Appl Biomater 82: 156–168, 2007.
138. van der Gun BT, de Groote ML, Kazemier HG, Arendzen AJ, Terpstra P, Ruiters MH, McLaughlin PM, Rots MG. Transcription factors and molecular epigenetic marks underlying EpCAM overexpres-sion in ovarian cancer. Br J Cancer 105: 312–319, 2011.
139. van der Gun BT, Melchers LJ, Ruiters MH, de Leij LF, McLaughlin PM, Rots MG. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis 31: 1913–1921, 2010.
140. Verhulst S, Best J, van Grunsven LA, Dollé L. Advances in hepatic stem/progenitor cell biology. EXCLI J. In press.
141. Voog J, Jones DL. Stem cells and the niche: a dynamic duo. Cell Stem Cell 6: 103–115, 2010.
142. Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 100, Suppl 1: 11881–11888, 2003.
143. Wang Y, Cui CB, Yamauchi M, Miguez P, Roach M, Malavarca R, Costello MJ, Cardinale V, Wauthier E, Barbier C, Gerber DA, Alvaro D, Reid LM. Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds. Hepatology 53: 293–305, 2011.
144. Wang Y, Lanzoni G, Carpino G, Cui CB, Dominguez-Bendala J, Wauthier E, Cardinale V, Oikawa T, Pileggi A, Gerber D, Furth ME, Alvaro D, Gaudio E, Inverardi L, Reid LM. Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis. Stem Cells 31: 1966–1979, 2013.
145. Wauthier E, Schmelzer E, Turner W, Zhang L, LeCluyse E, Ruiz J, Turner R, Furth ME, Kubota H, Lozoya O, Barbier C, McClelland R, Yao HL, Moss N, Bruce A, Ludlow J, Reid LM. Hepatic stem cells and hepatoblasts: identification, isolation, and ex vivo maintenance. Methods Cell Biol 86: 137–225, 2008.
146. Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S. Frequent EpCam protein expression in human carcinomas. Hum Pathol 35: 122–128, 2004.
147. Wu CJ, Mannan P, Lu M, Udey MC. Epithelial cell adhesion molecule (EpCAM) regulates claudin dynamics and tight junctions. J Biol Chem 288: 12253–12268, 2013.
148. Xie X, Wang CY, Cao YX, Wang W, Zhuang R, Chen LH, Dang NN, Fang L, Jin BQ. Expression pattern of epithelial cell adhesion molecule on normal and malignant colon tissues. World J Gastroenterol 11: 344–347, 2005.
149. Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellu-lar carcinoma. Cancer Res 67: 10831–10839, 2007.
150. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, Budhu A, Zanetti KA, Chen Y, Qin LX, Tang ZY, Wang XW. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepa-tocellular carcinoma. Cancer Res 68: 1451–1461, 2008.
151. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gas-troenterology 136: 1012–1024, 2009.
152. Yoon SM, Gerasimidou D, Kuwahara R, Hytiroglou P, Yoo JE, Park YN, Theise ND. Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Hepa-tology 53: 964–973, 2011.
153. Yovchev MI, Grozdanov PN, Joseph B, Gupta S, Dabeva MD. Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology 45: 139–149, 2007.
154. Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD. Identification of adult hepatic progenitor cells capable of repopu-lating injured rat liver. Hepatology 47: 636–647, 2008.
155. Zhang L, Theise N, Chua M, Reid LM. The stem cell niche of human livers: symmetry between development and regeneration. Hepatology 48: 1598–1607, 2008.