32 resident hepatic cells. While there is no conclusive experimental evidence of a direct role for bone marrow-derived stem cells in hepato- carcinogenesis, some evidence exists to suggest that they contribute indirectly. There are reports showing that the fibrotic (desmoplastic) response seen in HCC is caused by bone marrow-derived stromal cells in the liver [69]. This desmoplastic reaction is thought to promote the tumor by secreting various growth factors. Despite the absence of strong support,the possibility that bone marrow-derived liver cells could be the target of a malignant transformation process cannot be completely discounted.
33 VI. References
1) Mishra L. Mouse knockout models of biliary epithelial cell formation and disease. In: Gianfranco Alpini DA, Marzioni M, LeSage G, LaRusso N,ed. The pathophysiology of biliary epithelia. Landes BioSciences, 2004; 363. 464.
2) Zhao R, Duncan SA. Embryonic development of the liver.
HEPATOLOGY 2005; 41:956-967.
3) Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 1999; 284:1998.
4) Rossi JM, DunnNR, HoganBL, ZaretKS. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 2001; 15:1998.
5) Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev 2004;14: 582-590.
6) Calmont A, Wandzioch E, Tremblay KD, Minowada G, Kaestner KH, Martin GR, et al. An FGF response pathway that mediates hepatic gene induction in embryonic endoderm cells. Dev Cell 2006; 11:339.
7) Monga SP, Tang Y, Candotti F, Rashid A, Wildner O, Mishra B, et al.
Expansion of hepatic and hematopoietic stem cells utilizing mouse embryonic liver explants. Cell Transplant 2001; 10:81-89.
8) ZaretKS. Genetic programming of liver and pancreas progenitors:
lessons for stem-cell differentiation. Nat Rev Genet 2008; 9:329.
34 9) McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome:
Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 2002; 129:1075-1082.
10) Alison MR: Liver stem cells: implications for hepatocarcinogenesis.
Stem Cell Rev 2005; 1:253–260.
11) Kinoshita T, Miyajima A. Cytokine regulation of liver development.
Biochim Biophys Acta. 2002; 1592(3):303–312.
12) Farber, E., Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res. 1956 Feb;16(2):142-8.
13) Theise, N.D., et al., The canals of Hering and hepatic stem cells in humans. Hepatology. 1999 Dec;30(6):1425-33.
14) Fausto, N., Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology. 2004 Jun;39(6):1477-87.
15) Kitisin K, Shetty K, Mishra L, Johnson LB: Hepatocellular stem cells. Cancer Biomark 2007; 3:251–262.
16) Cantz T, Manns M P, Ott M. Stem cells in liver regeneration and therapy. Cell Tissue Res, 2007.
17) RamadoriG, SaileB. Mesenchymal cells in the liver—one cell type or two? Liver, 2002, 22(4): 283–294
18) Bin Gao, Won-Il Jeong, and Zhigang Tian. Liver: An Organ with Predominant Innate Immunity HEPATOLOGY 2008; 47:729-736
19) Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276:60-66.
35 20) Roskams T. Liver stem cells and their implication in hepatocellular
and cholangiocarcinoma. Oncogene 2006; 25:3818-3822.
21) Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003:1301- 1311.
22) Dabeva MD, Alpini G, Hurston E, Shafritz DA: Models for hepatic progenitor cell activation. Proc Soc Exp Biol Med 1993, 204:242-252.
23) 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 U S A 2003, 100 Suppl 1:11881-11888.
24) Suzuki A, Zheng Y, Kondo R, Kusakabe M, Takada Y, Fukao K, Nakauchi H, Taniguchi H: Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology 2000, 32:1230-1239.
25) Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity.
Am J Pathol 1999; 154:537-541.
26) Libbrecht L, Desmet V, Damme BV, Roskams T. The immunohisto- chemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 2000; 33:76.
27) Theise ND, Nimmakayalu M, Gardner R, et al: Liver from bone marrow in humans. Hepatology 32: 11-16, 2000.
28) Rowe PM: Chronic Lyme disease: the debate goes on. Lancet 355:
1436, 2000.
36 29) Alison M R, Poulsom R, Jeffery R, Dhillon A P, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright N A. Hepatocytes from non-hepatic adult stem cells. Nature, 2000, 406(6793): 257
30) Herzog E L, Chai L, Krause D S. Plasticity of marrow-derived stem cells. Blood, 2003, 102(10): 3483–3493.
31) Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman I L, Grompe M. Purified hematopoietic stem cells can differentiate into hepa- tocytes in vivo.
Nat Med, 2000, 6(11): 1229–1234
32) Levicar N, Dimarakis I, Flores C, Tracey J, Gordon M Y, Habib N A.
Stem cells as a treatment for chronic liver disease and diabetes. Handb Exp Pharmacol, 2007, (180): 243–262
33) Herr I, Groth A, Schemmer P, Buchler M W. Adult stem cells in progression and therapy of hepatocellular carcinoma. Int J Cancer, 2007, 121(9): 1875–1882
34) Wu X Z, Yu X H. Bone marrow cells: the source of hepato- cellular carcinoma? Med Hypotheses, 2007, 69(1): 36–42
35) OhSH, WitekRP,BaeSH,ZhengD,JungY,PiscagliaAC, Petersen B E.
Bone marrow-derived hepatic oval cells differ- entiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Gastroenterology, 2007, 132(3): 1077–1087
36) Petersen B E, Bowen W C, Patrene K D, Mars W M, Sullivan A K, Murase N, Boggs S S, Greenberger J S, Goff J P. Bone marrow as a potential source of hepatic oval cells. Science, 1999, 284(5417): 1168–
1170
37 37) Fiegel H C, Lange C, Kneser U, Lambrecht W, Zander A R, Rogiers X, Kluth D. Fetal and adult liver stem cells for liver regeneration and tissue engineering. J Cell Mol Med, 2006, 10(3): 577–58
38) Jang Y Y, Collector M I, Baylin S B, Diehl A M, Sharkis S J.
Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol, 2004, 6(6): 532–539
39) ZhanY, WangY, WeiL, ChenH, CongX, FeiR,GaoY,Liu F.
Differentiation of hematopoietic stem cells into hepatocytes in liver fibrosis in rats. Transplantat Proc, 2006, 38(9): 3082– 3085
40) Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006, 44(1): 240-251.
41) Xu XL, Xing BC, Han HB, Zhao W, Hu MH, Xu ZL, Li JY, Xie Y, Gu J, Wang Y, Zhang ZQ. The properties of tumor-initiating cells from a hepatocellular carcinoma patient’s primary and recurrent tumor.
Carcinogenesis 2010; 31: 167-174.
42) El-Serag, H.B.; Rudolph, K.L. Hepatocellular carcinoma:
Epidemiology and molecular carcinogenesis. Gastroenterology 2007, 132, 2557–2576.
43) Donato MF, Arosio E, Monti V, et al. Proliferating cell nuclear antigen assessed by a computer-assisted image analysis system in patients with chronic viral hepatitis and cirrhosis. Dig Liver Dis. 2002;
34:197–203.
44) Freeman A, Hamid S, Morris L, et al. Improved detection of hepatocyte proliferation using antibody to the pre-replication complex:
38 an association with hepatic fibrosis and viral replication in chronic hepatitis C virus infection. J Viral Hepat. 2003; 10:345–350.
45) Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC, McDade H. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA. 1996; 93:4398–4402.
46) Mu X, Espanol-Suner R, Mederacke I, et al. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J Clin Invest 2015; 125:3891–3903.
47) Shin S, Wangensteen KJ, Teta-Bissett M, et al. Genetic lineage tracing analysis of the cell of origin of March 2017 Liver Cancer Cell of Origin and Classes 757 REVIEWS AND PERSPECTIVES hepatotoxin-induced liver tumors in mice. Hepatology 2016; 64:1163–
1177.
48) Font-Burgada J, Shalapour S, Ramaswamy S, et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer.
Cell 2015; 162:766–779.
49) Jors S, Jeliazkova P, Ringelhan M, et al. Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest 2015;
125:2445–2457.
50) He G, Dhar D, Nakagawa H, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013;155: 384–396.
51) Marquardt JU. Deconvolution of the cellular origin in hepatocellular carcinoma: Hepatocytes take the center stage. Hepatology 2016;
64:1020–1023.
39 52) Tarlow BD, Pelz C, Naugler WE, et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes.
Cell Stem Cell 2014; 15:605–618.
53) Gournay J, Auvigne I, Pichard V, Ligeza C, Bralet MP and Ferry N:
In vivo cell lineage analysis during chemical hepatocarcinogenesis in rats using retroviral-mediated gene transfer: evidence for dedifferentiation of mature hepatocytes. Lab Invest 82: 781-788, 2002.
30.
54) Bralet MP, Pichard V and Ferry N: Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethyl nitrosamine-treated rats. Hepatology 36: 623-630, 2002.
55) Kitade M, Factor VM, Andersen JB, et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling.
Genes Dev 2013; 27:1706–1717.
56) Chiba T, Zheng YW, Kita K, et al. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation.
Gastroenterology 2007; 133:937–950.
57) Tschaharganeh DF, Xue W, Calvisi DF, et al. p53- dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer.
Cell 2014; 158:579–592.
58) Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS: A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006, 12:410-416.
40 59) Libbrecht L, Roskams T. Hepatic progenitor cells in human liver
diseases. Semin Cell Dev Biol 2002; 13:389 –396.
60) Fang CH, Gong JQ, Zhang W: Function of oval cells in hepatocellular carcinoma in rats. World J Gastroenterol 2004, 10:2482-2487.
61) Gordon GJ, Coleman WB, Hixson DC, Grisham JW: Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol 2000, 156:607-619.
62) Dumble ML, Croager EJ, Yeoh GC, Quail EA: Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis 2002, 23:435-445.
63) Becker R, Luthgens B, Oesch F, Dienes HP, Steinberg P:
Ha-rasVal12 but not p53Ser247 leads to a significant neoplastic transformation rate of the putative rat liver stem cells (oval cell).
Carcinogenesis 1996, 17:2635-2640.
64) Yaswen P, Goyette M, Shank PR, Fausto N: Expression of c-Ki-ras, c-Ha-ras, and c-myc in specific cell types during hepatocarcinogenesis.
Mol Cell Biol 1985, 5:780-786.
65) Sell S, Dunsford HA. Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol 1989;
134:1347–1363.
66) Sell S, Leffert HL. An evaluation of cellular lineages in the pathogenesis of experimental hepatocellular carcinoma. Hepatology 1982; 2:77– 86.
41 67) Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y, Zeng
SS, Hayashi T, Kondo M, Takatori H, Ya- mashita T, Mizukoshi E, Ikeda H, Zen Y, Takamura H, Wang XW, Kaneko S: Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology 2013; 57:1484–1497.
68) Yang Z, Ho DW, Ng MN, et al. Significance of CD90? cancer stem cells in human liver cancer. Cancer Cell. 2008; 13:153–166.
69) Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenter- ology.
2007; 132:2542–2556.
70) Zhang, F.; Chen, X.P.; Zhang, W.; Dong, H.H.; Xiang, S.; Zhang, W.G.; Zhang, B.X. Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: Immunohistochemical and double-fluorescence immunostaining
evidence. Histopathology 2008, 52, 224–232.
71) Yamashita, T.; Wang, X.W. Cancer stem cells in the development of liver cancer. J. Clin. Invest. 2013, 123, 1911–1918.
72) He, G.; Dhar, D.; Nakagawa, H.; Font-Burgada, J.; Ogata, H.; Jiang, Y.; Shalapour, S.; Seki, E.; Yost, S.E.; Jepsen, K.; et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013, 155, 384–396.
73) Wu, K.; Ding, J.; Chen, C.; Sun, W.; Ning, B.F.; Wen, W.; Huang, L.; Han, T.; Yang, W.; Wang, C. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 2012, 56, 2255–2267.
42 74) Kawai, T.; Yasuchika, K.; Ishii, T.; Katayama, H.; Yoshitoshi, E.Y.;
Ogiso, S.; Kita, S.; Yasuda, K.; Fukumitsu, K.; Mizumoto, M.; et al.
Keratin 19, a Cancer Stem Cell Marker in Human Hepatocellular Carcinoma. Clin. Cancer Res. 2015, 21, 3081–3091
43
Chapter III
A Novel Model of Liver Cancer Stem Cells Developed from Induced
Pluripotent Stem Cells
44 I. Introduction
According to the World Cancer Report, the incidence was globally 6% and the mortality burden was 9% in liver cancer [1]. The number of deaths being estimated 746,000 in 2012, liver cancer is the second leading cause of cancer mortality in the world. The liver cancer in men is described as the fifth most common cancer (554,000 new cases, 8% of the total) and that in women the ninth (228,000 cases, 3% of the total). Among the primary liver cancers, HCC is the major histological subtype [2].
Hepatocarcinogenesis could be explained by a complexed multistep process at molecular level giving various diagnostic observations in cells and histology. Although the molecular mechanism of the liver cancer development has been studied for many years, these studies focused only on the cancer cells, which are present in the cancer tissues, but not the origin of these cancer cells, which are known as the liver CSCs. Liver CSCs were described with the capacity of self-renewal, differentiation [3].
Liver CSCs are currently considered as a specific subpopulation with significant tumorigenic potential, which should contribute to the development and recurrence of HCC [4]. Taking the presence of original cells granted, we support the idea that the liver CSCs could be originated by the transformation of liver stem/progenitor cells [5]. Actually, liver CSCs are identified by self-renewal and pluripotency and classified with normal liver stem cell markers.
Generally, CSCs are defined by self-renewal, pluripotency and tumorigenicity, which play a critical role in the growth of primary tumors with heterogeneity [6]. Considering that CSCs are responsible for the
45 malignant tumorigenic potential providing the heterogeneity [7], CSCs could be the cells at the top of the hierarchy undergoing differentiation into cancer cells with diverse phenotypes with limited proliferative potential in many cancers as found in the hierarchy of normal stem cells in normal tissues. Incredible efforts have been made to understand where the CSCs come from. Due to the recent rapid progress in the stem cell research, cancer is widely accepted as a stem cell disease [8]. Also, some scientists suggested that hierarchically organized tumors originated from normal stem cells [9], which opened the possibility of the liver stem cell to be the origin of liver CSCs [10]. Stem cells were hypothesized to dwell in a specific microenvironment called a “stem cell niche,” which plays an essential role to regulate stem cell maintenance and self-renewal by secreting various factors [11]. A similar concept of niche also is considered present and applies to CSCs which is so called “CSC niche”. And the interactions of CSCs with this niche should be essential to maintain the CSC population [12]. Cells within the CSC niche secrete factors, which stimulate CSC self-renewal, induce the differentiation such as angiogenesis [13] and recruit immune cells and other stromal cells, which secrete additional factors to promote tumor cell invasion and metastasis [14]. The niche for liver CSCs has not yet been elucidated and still obscure, but the mechanisms similar to the niche of the normal stem cells should exist to control cell proliferation, migration, invasion and apoptosis resistance [15].
Recently, stem cells, including embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), have gathered great attention in the field of medicine because of the development of novel therapy of tissue regeneration. On the other hand, the development of CSCs or cancer cells
46 could be possible when normal stem cells are affected by the tumor microenvironment although the mechanism of development is not clear yet.
Our group hypothesize that the CSCs may appear from the normal stem cells affected by the cancer-inducing niche defined as chronic inflammation [16]. This mechanistic insight, which converts stem cells into liver CSCs, will significantly be important to uncover the molecular mechanisms lying in liver CSC development. In the present study, we tried to develop liver CSCs using miPSCs using the CM of HCC cell lines mimicking chronic liver disease.