The roles of transforming growth factor-β, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours (review)

International Journal of Oncology

Volumn 44, Issue 4, 2014, Pages 1015-1022

  Bogaerts, Eliene ^a   Heindryckx, Femke ^b   Vandewynckel, Yves Paul ^a   Van Grunsven, Leo A ^c   Van Vlierberghe, Hans ^a  

^a GHENT UNIVERSITY HOSPITAL   (Belgium)

^b UPPSALA UNIVERSITY   (Sweden)

^c VRIJE UNIVERSITEIT BRUSSEL   (Belgium)

Author keywords

Cancer stem cells; Hepatic cancer; Hypoxia inducible factor 1; Liver progenitor cell; Notch receptors; Tgf ; Wnt receptors

Indexed keywords

NOTCH RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

BILE DUCT CARCINOMA; BILE DUCT TUMOR; CELL DIFFERENTIATION; CELL HYPOXIA; CELL TRANSFORMATION; CYTOLOGY; HUMAN; INTRAHEPATIC BILE DUCT; LIVER; LIVER CELL CARCINOMA; LIVER TUMOR; METABOLISM; PATHOLOGY; PHYSIOLOGY; STEM CELL; WNT SIGNALING PATHWAY;

BILE DUCT NEOPLASMS; BILE DUCTS, INTRAHEPATIC; CARCINOMA, HEPATOCELLULAR; CELL DIFFERENTIATION; CELL HYPOXIA; CELL TRANSFORMATION, NEOPLASTIC; CHOLANGIOCARCINOMA; HUMANS; LIVER; LIVER NEOPLASMS; RECEPTORS, NOTCH; STEM CELLS; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEINS; WNT SIGNALING PATHWAY;

EID: 84894422475     PISSN: 10196439     EISSN: 17912423     Source Type: Journal    
DOI: 10.3892/ijo.2014.2286     Document Type: Review

References (97)

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global Cancer Statistics. CA Cancer J Clin 61: 69-90, 2011.
2. Braillon A: Hepatocellular carcinoma. Lancet 380: 469, 2012.
3. Heindryckx F, Bogaerts E, Coulon SH, Devlies H, Geerts AM, Libbrecht L, Stassen JM, et al: Inhibition of the placental growth factor decreases burden of cholangiocarcinoma and hepatocellular carcinoma in a transgenic mouse model. Eur J Gastroenterol Hepatol 24: 1020-1032, 2012.
4. de Lope CR, Tremosini S, Forner A, Reig M and Bruix J: Management of HCC. J Hepatol 56: S75-S87, 2012.
5. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, et al: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15: 220-231, 2009.
6. Zen C, Zen Y, Mitry RR, Corbeil D, Karbanova J, O'Grady J, Karani J, et al: Mixed phenotype hepatocellular carcinoma after transarterial chemoembolization and liver transplantation. Liver Transplant 17: 943-954, 2011.
7. Heindryckx F, Kuchnio A, Casteleyn C, Coulon S, Olievier K, Colle I, Geerts A, et al: Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice. J Hepatol 57: 61-68, 2012.
8. Tong CM, Ma S and Guan XY: Biology of hepatic cancer stem cells. J Gastroenterol Hepatol 26: 1229-1237, 2011.
9. Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 414: 105-111, 2001.
10. Forbes S, Vig P, Poulsom R, Thomas H and Alison M: Hepatic stem cells. J Pathol 197: 510-518, 2002.
11. Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C and Dabeva MD: Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology 47: 636-647, 2008.
12. Espanol-Suner R, Carpentier R, Van Hul N, Legry V, Achouri Y, Cordi S, Jacquemin P, et al: Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143: 1564-1575, 2012.
13. Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, Smirnova O, et al: Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev 25: 1185-1192, 2011.
14. Roskams T: Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25: 3818-3822, 2006.
15. Ma S, Chan KW, Hu L, Lee TKW, Wo JYH, Ng IL, Zheng BJ, et al: Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132: 2542-2556, 2007.
16. Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, Tanaka S, et al: Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 94: 851-857, 2003.
17. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, et al: A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12: 410-416, 2006.
18. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, et al: The canals of Hering and hepatic stem cells in humans. Hepatology 30: 1425-1433, 1999.
19. Dolle L, Best J, Mei J, Al Battah F, Reynaert H, van Grunsven LA and Geerts A: The quest for liver progenitor cells: a practical point of view. J Hepatol 52: 117-129, 2010.
20. Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E and Theise ND: The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 47: 1994-2002, 2008.
21. Zhang W, Chen XP, Zhang WG, Zhang F, Xiang SA, Dong HH and Zhang L: Hepatic non-parenchymal cells and extracellular matrix participate in oval cell-mediated liver regeneration. World J Gastroenterol 15: 552-560, 2009.
22. Van Hul N, Lanthier N, Suner RE, Quinones JA, van Rooijen N and Leclercq I: Kupffer cells influence parenchymal invasion and phenotypic orientation, but not the proliferation, of liver progenitor cells in a murine model of liver injury. Am J Pathol 179: 1839-1850, 2011.
23. Pintilie DG, Shupe TD, Oh SH, Salganik SV, Darwiche H and Petersen BE: Hepatic stellate cells' involvement in progenitor-mediated liver regeneration. Lab Invest 90: 1199-1208, 2010.
24. Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, et al: Liver stem cells and hepatocellular carcinoma. Hepatology 49: 318-329, 2009.
25. Villanueva A, Newell P, Chiang DY, Friedman SL and Llovet JM: Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 27: 55-76, 2007.
26. Chiba T, Kamiya A, Yokosuka O and Iwama A: Cancer stem cells in hepatocellular carcinoma: recent progress and perspective. Cancer Lett 286: 145-153, 2009.
27. Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS, Fox AJ, Smirnova O, et al: Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 25: 1193-1203, 2011.
28. Dolle L, Best J, Empsen C, Mei J, Van Rossen E, Roelandt P, Snykers S, et al: Successful isolation of liver progenitor cells by aldehyde dehydrogenase activity in naive mice. Hepatology 55: 540-552, 2012.
29. Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M, Sato T, et al: In vitro expansion of single Lgr5(+) liver stem cells induced by Wnt-driven regeneration. Nature 494: 247-250, 2013.
30. Coulouarn C, Cavard C, Rubbia-Brandt L, Audebourg A, Dumont F, Jacques S, Just PA, et al: Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGF signaling pathways. Carcinogenesis 33: 1791-1796, 2012.
31. Shimada M, Sugimoto K, Iwahashi S, Utsunomiya T, Morine Y, Imura S and Ikemoto T: CD133 expression is a potential prognostic indicator in intrahepatic cholangiocarcinoma. J Gastroenterol 45: 896-902, 2010.
32. Yin SY, Li JJ, Hu C, Chen XH, Yao M, Yan MX, Jiang GP, et al: CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120: 1444-1450, 2007.
33. Yin X, Zhang BH, Qiu SJ, Ren ZG, Zhou J, Chen XH, Zhou Y, et al: Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features, treatment modalities, and prognosis. Ann Surg Oncol 19: 2869-2876, 2012.
34. Gottschling S, Schnabel PA, Herth FJF and Herpel E: Are we missing the target? Cancer stem cells and drug resistance in non-small cell lung cancer. Cancer Genomics Proteomics 9: 275-286, 2012.
35. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, et al: Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 18: 572-579, 2012.
36. Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E and Roskams T: Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut 59: 247-257, 2010.
37. Wendt MK, Tian MZ and Schiemann WP: Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell Tissue Res 347: 85-101, 2012.
38. Seok JY, Na DC, Woo HG, Roncalli M, Kwon SM, Yoo JE, Ahn EY, et al: A fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition. Hepatology 55: 1776-1786, 2012.
39. MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17: 9-26, 2009.
40. Polakis P: Wnt signaling and cancer. Genes Dev 14: 1837-1851, 2000.
41. Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, et al: Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68: 4287-4295, 2008.
42. Yamashita T, Budhu A, Forgues M and Wang XW: Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 67: 10831-10839, 2007.
43. Apte U, Thompson MD, Cui SS, Liu B, Cieply B and Monga SPS: Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 47: 288-295, 2008.
44. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, et al: EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136: 1012-1024, 2009.
45. Abdullah LN and Chow EK: Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2: 3, 2013.
46. Noda T, Nagano H, Takemasa I, Yoshioka S, Murakami M, Wada H, Kobayashi S, et al: Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma. Br J Cancer 100: 1647-1658, 2009.
47. DeMorrow S, Francis H, Gaudio E, Venter J, Franchitto A, Kopriva S, Onori P, et al: The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol 295: G1150-G1158, 2008.
48. Toyama T, Lee HC, Koga H, Wands JR and Kim M: Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration. Mol Cancer Res 8: 254-265, 2010.
49. Yuzugullu H, Benhaj K, Ozturk N, Senturk S, Celik E, Toylu A, Tasdemir N, et al: Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells. Mol Cancer 8: 90, 2009.
50. Mishra L, Jogunoori W, Johnson L, Tang Y, Katuri V, Shetty K and Mishra B: TGF-beta-signaling is required for ductal progenitor cell survival and epithelial cell differentiation in normal liver. Gastroenterology 128: A353-A353, 2005.
51. Conidi A, Cazzola S, Beets K, Coddens K, Collart C, Cornelis F, Cox L, et al: Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFβ/BMP signaling in vivo. Cytokine Growth Factor Rev 22: 287-300, 2011.
52. van Grunsven LA, Verstappen G, Huylebroeck D and Verschueren K: Smads and chromatin modulation. Cytokine Growth Factor Rev 16: 495-512, 2005.
53. Mu Y, Gudey SK and Landström M: Non-Smad signaling pathways. Cell Tissue Res 347: 11-20, 2011.
54. Drabsch Y and ten Dijke P: TGF-beta signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev 31: 553-568, 2012.
55. Fausto N: Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39: 1477-1487, 2004.
56. Ikegami T: Transforming growth factor-beta signaling and liver cancer stem cell. Hepatol Res 39: 847-849, 2009.
57. Caja L, Bertran E, Campbell J, Fausto N and Fabregat I: The transforming growth factor-beta (TGF-β) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J Cell Physiol 226: 1214-1223, 2011.
58. Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7: 131-142, 2006.
59. Zulehner G, Mikula M, Schneller D, van Zijl F, Huber H, Sieghart W, Grasl-Kraupp B, et al: Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. Am J Pathol 176: 472-481, 2010.
60. Thenappan A, Li Y, Kitisin K, Rashid A, Shetty K, Johnson L and Mishra L: Role of transforming growth factor beta signaling and expansion of progenitor cells in regenerating liver. Hepatology 51: 1373-1382, 2010.
61. Fortini ME: Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16: 633-647, 2009.
62. Zong YW, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F and Stanger BZ: Notch signaling controls liver development by regulating biliary differentiation. Development 136: 1727-1739, 2009.
63. Yin L, Velazquez OC and Liu ZJ: Notch signaling: emerging molecular targets for cancer therapy. Biochem Pharmacol 80: 690-701, 2010.
64. Qi RZ, An HZ, Yu YZ, Zhang MH, Liu SX, Xu HM, Guo ZH, et al: Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res 63: 8323-8329, 2003.
65. Lim SO, Park YM, Kim HS, Quan X, Yoo JE, Park YN, Choi GH, et al: Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma. Hepatology 53: 1352-1362, 2011.
66. Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin CW, Zmoos AF, et al: Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med 208: 1963-1976, 2011.
67. Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong YW, Toffanin S, Rodriguez-Carunchio L, et al: Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143: 1660-1669, 2012.
68. Zender S, Nickeleit I, Wuestefeld T, Sorensen I, Dauch D, Bozko P, El-Khatib M, et al: A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 23: 784-795, 2013.
69. Harris A: Resistance to anti-angiogenic therapy induced by hypoxia and notch signalling. EJC (Suppl) 8: 183-184, 2010.
70. Li JL, Sainson RCA, Oon CE, Turley H, Leek R, Sheldon H, Bridges E, et al: DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res 71: 6073-6083, 2011.
71. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, et al: Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279: 38458-38465, 2004.
72. Van Steenkiste C, Ribera J, Geerts A, Pauta M, Tugues S, Casteleyn C, Libbrecht L, et al: Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice. Hepatology 53: 1629-1640, 2011.
73. Heindryckx F, Coulon S, Terrie E, Casteleyn C, Stassen JM, Geerts A, Libbrecht L, Allemeersch J, Carmeliet P, Colle I and Van Vlierberghe H: The placental growth factor as a target against hepatocellular carcinoma in an orthotopic mouse model. J Hepatol 58: 319-328, 2012.
74. Alison MR, Lin WR, Lim SML and Nicholson LJ: Cancer stem cells: in the line of fire. Cancer Treat Rev 38: 589-598, 2012.
75. Mathieu J, Zhang Z, Zhou WY, Wang AJ, Heddleston JM, Pinna CMA, Hubaud A, et al: HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 71: 4640-4652, 2011.
76. Liang YJ, Zheng TS, Song RP, Wang JB, Yin DL, Wang LL, Liu HT, et al: Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinomaa. Hepatology 57: 1847-1857, 2013.
77. Lehwald N, Tao GZ, Jang KY, Sorkin M, Knoefel WT and Sylvester KG: Wnt-β-catenin signaling protects against hepatic ischemia and reperfusion injury in mice. Gastroenterology 141: 707-718, 2011.
78. Zhang Q, Bai XL, Chen W, Ma T, Hu QD, Liang C, Xie SZ, et al: Wnt/beta-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1 alpha signaling. Carcinogenesis 34: 962-973, 2013.
79. Chen YX, Wong PP, Sjeklocha L, Steer CJ and Sahin MB: Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture. Hepatology 55: 563-574, 2012.
80. Matsuoka J, Yashiro M, Doi Y, Fuyuhiro Y, Kato Y, Shinto O, Noda S, et al: Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFbeta signaling. PLoS One 8: e62310, 2013.
81. Copple BL: Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int 30: 669-682, 2010.
82. Matsuno Y, Coelho AL, Jarai G, Westvvick J and Hogaboam CM: Notch signaling mediates TGF-beta 1-induced epithelial-mesenchymal transition through the induction of Snail. Int J Biochem Cell Biol 44: 776-789, 2012.
83. Sahlgren C, Gustafsson MV, Jin S, Poellinger L and Lendahl U: Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105: 6392-6397, 2008.
84. Lim SO, Kim HS, Quan X, Ahn SM, Kim H, Hsieh D, Seong JK, et al: Notch1 binds and induces degradation of Snail in hepatocellular carcinoma. BMC Biol 9: 83, 2011.
85. Goodman ZD, Ishak KG, Langloss JM, Sesterhenn IA and Rabin L: Combined hepatocellular-cholangiocarcinoma - a histologic and immunohistochemical study. Cancer 55: 124-135, 1985.
86. Lau CK, Yang ZF, Ho DW, Ng MN, Yeoh GCT, Poon RTP and Fan ST: An Akt/hypoxia-inducible factor-1alpha/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells. Clin Cancer Res 15: 3462-3471, 2009.
87. Lee JI, Lee JW, Kim JM, Kim JK, Chung HJ and Kim YS: Prognosis of hepatocellular carcinoma expressing cytokeratin 19: comparison with other liver cancers. World J Gastroenterol 18: 4751-4757, 2012.
88. Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, Laleman W, et al: Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. Hepatology 55: 1876-1888, 2012.
89. Tickoo SK, Zee SY, Obiekwe S, Xiao H, Koea J, Robiou C, Blumgart LH, et al: Combined hepatocellular-cholangiocarcinoma - a histopathologic, immunohistochemical, and in situ hybridization study. Am J Surg Pathol 26: 989-997, 2002.
90. Wang XQ, Ongkeko WM, Chen L, Yang ZF, Lu P, Chen KK, Lopez JP, et al: Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology 52: 528-539, 2010.
91. Chu PGG, Ishizawa S, Wu E and Weiss LM: Hepatocyte antigen as a marker of hepatocellular carcinoma - an immunohistochemical comparison to carcinoembryonic antigen, CD10, and alpha-fetoprotein. Am J Surg Pathol 26: 978-988, 2002.
92. Omori N, Evarts RP, Omori M, Hu ZY, Marsden ER and Thorgeirsson SS: Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab Invest 75: 15-24, 1996.
93. Carpentier R, Suner RE, van Hul N, Kopp JL, Beaudry JB, Cordi S, Antoniou A, et al: Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141: 1432-1438, 2011.
94. Ma S, Lee TK, Zheng BJ, Chan K and Guan XY: CD133(+) HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27: 1749-1758, 2008.
95. Fan LN, He FR, Liu HX, Zhu J, Liu YX, Yin ZY, Wang L, et al: CD133: a potential indicator for differentiation and prognosis of human cholangiocarcinoma. BMC Cancer 11: 320, 2011.
96. Hou Y, Zou QF, Ge RL, Shen F and Wang YZ: The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers. Cell Res 22: 259-272, 2012.
97. Knight B, Tirnitz-Parker JEE and Olynyk JK: C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits liver tumor formation in mice. Gastroenterology 135: 969-979, 2008.