Liver tumor-initiating cells as a therapeutic target for hepatocellular carcinoma

Cancer Letters

Volumn 338, Issue 1, 2013, Pages 101-109

  Lee, Terence Kin Wah ^a,b   Cheung, Vincent Chi Ho ^a,b   Ng, Irene Oi Lin ^a,b  

^a THE UNIVERSITY OF HONG KONG   (Hong Kong)

^b UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

ALDH; Chemoresistance; CSCs; EpCAM; GEP; HCC; HIF 1 ; HNF 4 ; OSM; PTEN; ROS; Self renewal; SP; T IC; TGF ; Tumor initiating cells; Tumorigenicity

Indexed keywords

ANTINEOPLASTIC AGENT; AURISTATIN F CD133 ANTIBODY; BESTATIN; BETA CATENIN; BMI1 PROTEIN; CD133 ANTIGEN; CD24 ANTIGEN; CD3 ANTIBODY; CD44 ANTIBODY; CELL MARKER; CYTOKINE; DELTA LIKE 1 HOMOLOG; EPITHELIAL CELL ADHESION MOLECULE; EPITHELIAL CELL ADHESION MOLECULE CD3 ANTIBODY; FLUOROURACIL; GRANULIN EPITHELIN PRECURSOR ANTIBODY; HERMES ANTIGEN; MICROSOMAL AMINOPEPTIDASE; NOTCH RECEPTOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROGRANULIN; PROTEIN OSM; PROTEIN OV6; SONIC HEDGEHOG PROTEIN; STAT3 PROTEIN; THY 1 ANTIGEN; TRANSFORMING GROWTH FACTOR BETA; TUMOR MARKER; UNCLASSIFIED DRUG; WNT PROTEIN;

APOPTOSIS; CANCER CHEMOTHERAPY; CANCER GROWTH; CANCER INHIBITION; CANCER RESISTANCE; CANCER STEM CELL; CELL DIFFERENTIATION; CELL RENEWAL; CELL TYPE; CHEMOSENSITIVITY; EVIDENCE BASED MEDICINE; GENE SILENCING; HUMAN; INTRACELLULAR SIGNALING; LIVER CELL CARCINOMA; MOLECULAR INTERACTION; NONHUMAN; NOTCH SIGNALING; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; RADIOSENSITIVITY; RNA INTERFERENCE; SHORT SURVEY; SIDE POPULATION CELL; SIGNAL TRANSDUCTION; SONIC HEDGEHOG SIGNALING; STAT3 SIGNALING; TUMOR INITIATING CELL; TUMOR VASCULARIZATION; WNT SIGNALING PATHWAY;

EID: 84882822844     PISSN: 03043835     EISSN: 18727980     Source Type: Journal    
DOI: 10.1016/j.canlet.2012.05.001     Document Type: Review

References (75)

1. Jemal A., Siegel R., Ward E., Hao Y., Xu Y., Murray T., Thun M.J. Cancer statistics. CA Cancer J. Clin. 2008, 58:71-96.
2. Carr B.I. Hepatocellular carcinoma: current management and future trends. Gastroenterology 2004, 127:218-224.
3. Llovet J.M., Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003, 37:429-442.
4. Ma S., Chan K.W., Hu L., Lee T.K., Wo J.Y., Ng I.O., Zheng B.J., Guan X.Y. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 2007, 132:2542-2556.
5. + HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 2008, 27:1749-1758.
6. + liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett. 2012, 315:129-137.
7. Ma S., Chan K.W., Lee T.K., Tang K.H., Wo J.Y., Zheng B.J., Guan X.Y. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell population. Mol. Cancer Res. 2008, 27:1749-1758.
8. Tang K.H., Ma S., Lee T.K., Chan Y.P., Kwan P.S., Tong C.M., Ng I.O., Man K., To K.F., Lai P.B., Lo C.M., Guan X.Y., Chan K.W. CD133(+) liver tumor initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology 2012, 55:807-820.
9. Kohga K., Tatsumi T., Takehara T., Tsunematsu H., Shimizu S., Yamamoto M., Sasakawa A., Miyagi T., Hayashi N. Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J. Hepatol. 2010, 52:872-879.
10. Yao J., Zhang T., Ren J., Yu M., Wu G. Effect of CD133/prominin-1 antisense oligodeoxynucleotide on in vitro growth characteristics of Huh-7 human hepatocarcinoma cells and U251 human glioma cells. Oncol. Rep. 2009, 22:781-787.
11. + population in hepatocellular carcinoma. Int. J. Cancer 2010, 126:2067-2078.
12. Smith L.M., Nesterova A., Ryan M.C., Duniho S., Jonas M., Anderson M., Zabinski R.F., Sutherland M.K., Gerber H.P., Van Orden K.L., Moore P.A., Ruben S.M., Carter P.J. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br. J. Cancer 2008, 99:100-109.
13. + cancer stem cells in human liver cancer. Cancer Cell 2008, 13:153-166.
14. Yang Z.F., Ngai P., Ho D.W., Yu W.C., Ng M.N., Lau C.K., Li M.L., Tam K.H., Lam C.T., Poon R.T., Fan S.T. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008, 47:919-928.
15. Yovchev M.I., Grozdanov P.N., Zhou H., Racheria H., Guha C., Dabeva M.D. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology 2008, 47:636-647.
16. Yamashita T., Forgues M., Wang W., Kim J.W., Ye Q., Jia H., Budhu A., Zanetti K.A., Chen Y., Qin L.X., Tang Z.Y., Wang X.W. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008, 68:1451-1461.
17. Yamashita T., Ji J., Budhu A., Forgues M., Yang W., Wang H.Y., Jia H., Ye Q., Qin L.X., Wauthier E., Reid L.M., Minato H., Honda M., Kaneko S., Tang Z.Y., Wang X.W. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009, 136:1012-1024.
18. + cell population in hepatocellular carcinoma cell lines. Cancer Sci. 2010, 101:2145-2155.
19. Groth A., Salnikov A.V., Ottinger S., Gladkich J., Liu L., Kallifatidis G., Salnikova O., Ryschich E., Giese N., Giese T., Momburg F., Büchler M.W., Moldenhauer G., Herr I. New gene-immunotherapy combining TRAIL-lymphocytes and EpCAMxCD3 biospecific antibody for tumor targeting. Clin. Cancer Res. 2012, 18:1028-1038.
20. Xie Z., Choong P.F., Poon L.F., Zhou J., Khng J., Jasinghe V.J., Palaniyandi S., Chen C.S. Inhibition of CD44 expression in hepatocellular carcinoma cells enhances apoptosis, chemosensitivity, and reduces tumorigenesis and invasion. Cancer Chemother. Pharmacol. 2008, 62:949-957.
21. Haraguchi N., Ishii H., Mimori K., Tanaka F., Ohkuma M., Kim H.M., Akita H., Takiuchi D., Hatano H., Nagano H., Barnard G.F., Doki Y., Mori M. CD13 is a therapeutic target in human liver cancer stem cells. J. Clin. Invest. 2010, 120:3326-3339.
22. Lee T.K., Castilho A., Cheung V.C., Tang K.H., Ma S., Ng I.O. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 2011, 9:50-63.
23. Roskams T., Dr Vos R., Van Eyken P., Myazaki H., Van Damme B., Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J. Hepatol. 1998, 29:455-463.
24. Yang W., Yan H.X., Chen L., Liu Q., He Y.Q., Yu L.X., Zhang S.H., Huang D.D., Tang L., Kong X.N., Chen C., Liu S.Q., Wu M.C., Wang H.Y. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008, 68:4287-4295.
25. Cheung S.T., Wong S.Y., Leung K.L., Chen X., So S., Ng I.O., Fan S.T. Granulin-epithelin precursor overexpression promotes growth and the invasion of hepatocellular carcinoma. Clin. Cancer Res. 2004, 10:7629-7636.
26. Cheung S.T., Cheung P.F., Cheng C.K., Wong N.C., Fan S.T. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance. Gastroenterology 2011, 140:344-355.
27. Cheung P.F., Cheng C.K., Wong N.C., Ho J.C., Yip C.W., Lui V.C., Cheung A.N., Fan S.T., Cheung S.T. Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells. PLoS One 2011, 6:e28246.
28. Ho J.C., Ip Y.C., Cheung S.T., Lee Y.T., Chan K.F., Wong S.Y., Fan S.T. Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma. Hepatology 2008, 47:1524-1532.
29. Chiba T., Kita K., Zheng Y.W., Yokosuka O., Saisho H., Iwama A., Nakauchi H., Taniguchi H. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006, 44:240-251.
30. Chiba T., Miyagi S., Saraya A., Aoki R., Seki A., Morita Y., Yonemitsu Y., Yokosuka O., Taniguchi H., Nakauchi H., Iwama A. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res. 2008, 68:7742-7749.
31. Hu C., Li H., Li J., Zhu Z., Yin S., Hao X., Yao M., Zheng S., Gu J. Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling. Carcinogenesis 2008, 29:2289-2297.
32. Huang J., Zhang X., Zhang M., Zhu J.D., Zhang Y.L., Lin Y., Wang K.S., Qi X.F., Zhang Q., Liu G.Z., Yu J., Cui Y., Yang P.Y., Wang Z.Q., Han Z.G. Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcimoma. Carcinogenesis 2007, 28:1094-1103.
33. Xu X., Liu R.F., Zhang X., Huang L.Y., Chen F., Fei Q.L., Han Z.G. DLK as a potential target against cancer stem/progenitor cells of hepatocellular carcinoma. Mol. Cancer Ther. 2012, 11:629-638.
34. Yu F., Hao X., Zhao H., Ge C., Yao M., Yang S., Li J. Delta-like 1 contributes to cell growth by increasing the interferon-inducible protein 16 expression in hepatocellular carcinoma. Liver Int. 2010, 30:85-92.
35. Chiba T., Zheng Y.W., Kita K., Yokosuka O., Saisho H., Onodera M., Miyoshi H., Nakano M., Zen Y., Nakanuma Y., Nakauchi H., Iwama A., Taniguchi H. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 2007, 133:937-950.
36. Chiba T., Seki A., Aoki R., Ichikawa H., Negishi M., Miyagi S., Oguro H., Saraya A., Kamiya A., Nakauchi H., Okosuka O., Iwama A. Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and in-dependent manners in mice. Hepatology 2010, 52:1111-1123.
37. Effendi K., Mori T., Komuta M., Masugi Y., Du W., Sakamoto M. Bmi-1 gene is upregulated in early-stage hepatocellular carcinoma and correlates with ATP-binding cassette transporter B1 expression. Cancer Sci. 2010, 101:666-672.
38. You H., Ding W., Rountree C.B. Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology 2010, 51:1635-1644.
39. Baek H.J., Pishvaian M.J., Tang Y., Kim T.H., Yang S., Zouhairi M.E., Mendelson J., Shetty K., Kallakury B., Berry D.L., Shin K.H., Mishra B., Reddy E.P., Kim S.S., Mishra L. Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer. Hepatology 2011, 53:1676-1684.
40. Tang Y., Kitisin K., Jogunoori W., Li C., Deng C.X., Mueller S.C., Ressom H.W., Rashid A., He A.R., Mendelson J.S., Jessup J.M., Shetty K., Zasloff M., Mishra B., Reddy E.P., Johnson L., Mishra L. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling. Proc. Natl. Acad. Sci. USA 2008, 105:2445-2450.
41. Lin L., Amin R., Gallicano G.I., Glasgow E., Jogunoori W., Jessup J.M., Zasloff M., Marshall J.L., Shetty K., Johnson L., Mishra L., He A.R. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGC-beta signaling. Oncogene 2009, 28:961-972.
42. X.Q. Wang, W. Zhang, E.L. Lui, Y. Zhu, P. Lu, X. Yu, J. Sun, S. Yang, R.T. Poon, S.T. Fan, Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma, Int. J. Cancer (2011).
43. Nishina S., Shiraha H., Nakanishi Y., Tanaka S., Matsubara M., Takaoka N., Uemura M., Horiguchi S., Kataoka J., Iwamuro M., Yagi T., Yamamoto K. Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling. Oncol. Rep. 2011, 26:523-531.
44. Viatour P., Ehmer U., Saddic L.A., Dorrell C., Andersen J.B., Lin C., Zmoos A.F., Mazur P.K., Schaffer B.E., Ostermeier A., Vogel H., Sylvester K.G., Thorgeirsson S.S., Grompe M., Sage J. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J. Exp. Med. 2011, 208:1963-1976.
45. Sicklick J.K., Li Y.X., Jayaraman A., Kannangai R., Qi Y., Vivekanandan P., Ludlow J.W., Owzar K., Chen W., Torbenson M.S., Diehl A.M. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 2006, 27:748-757.
46. Pereira Tde A., Witek R.P., Syn W.K., Choi S.S., Bradrick S., Karaca G.F., Agboola K.M., Jung Y., Omenetti A., Moylan C.A., Yang L., Fernandez-Zapico M.E., Jhaveri R., Shah V.H., Pereira F.E., Diehl A.M. Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Invest. 2010, 90:1690-1703.
47. Chen X., Lingala S., Khoobyari S., Nolta J., Zern M.A., Wu J. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J. Hepatol. 2011, 55:838-845.
48. Tian F., Mysliwietz J., Ellwart J., Gamarra F., Huber R.M., Bergner A. Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin. Exp. Med. 2012, 12:25-30.
49. Guryanova O.A., Wu Q., Cheng L., Lathia J.D., Huang Z., Yang J., MacSwords J., Eyler C.E., McLendon R.E., Heddleston J.M., Shou W., Hambardzumyan D., Lee J., Hjelmeland A.B., Sloan A.E., Bredel M., Stark G.R., Rich J.N., Bao S. Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell 2011, 19:498-511.
50. Wang C., Yang W., Yan H.X., Luo T., Zhang J., Tang L., Wu F.Q., Zhang H.L., Yu L.X., Zheng L.Y., Li Y.Q., Dong W., He Y.Q., Liu Q., Zou S.S., Lin Y., Hu L., Li Z., Wu M.C., Wang H.Y. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology 2012, 55:108-120.
51. Stiles B., Wang Y., Stahl A., Bassilian S., Lee W.P., Kim Y.J., Sherwin R., Devaskar S., Lesche R., Magnuson M.A., Wu H. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity. Proc. Natl. Acad. Sci. USA 2004, 101:2082-2087.
52. Rountree C.B., Ding W., He L., Stiles B. Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensin homolog deleted on chromosome 10-deleted mice. Stem cells 2009, 27:290-299.
53. Galicia V.A., He L., Dang H., Kanel G., Vendryes C., French B.A., Zeng N., Bayan J.A., Ding W., Wang K.S., French S., Birnbaum M.J., Rountree C.B., Stiles B.L. Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology 2010, 139:2170-2182.
54. Lee T.K., Castilho A., Cheung V.C., Tang K.H., Ma S., Ng I.O. Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation. Hepatology 2011, 53:160-170.
55. Yamashita T., Honda M., Nio K., Nakamoto Y., Yamashita T., Takamura H., Tani T., Zen Y., Kaneko S. Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation. Cancer Res. 2010, 70:4687-4697.
56. Li J., Ning G., Duncan S. Mammalian hepatocyte differentiation requires the transcription factor HNF-4a. Genes Dev. 2000, 14:464-474.
57. Ning B.F., Ding J., Yin C., Zhong W., Wu K., Zeng X., Yang W., Chen Y.X., Zhang J.P., Zhang X., Wang H.Y., Xie W.F. Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res. 2010, 70:7640-7651.
58. Yin C., Lin Y., Zhang X., Xhen Y.X., Zeng X., Yue H.Y., Hou J.L., Deng X., Zhang J.P., Han Z.G., Xie W.F. Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene. Hepatology 2008, 48:1528-1539.
59. Sun W., Ding J., Wu K., Ning B.F., Wen W., Sun H.Y., Han T., Huang L., Dong L.W., Yang W., Deng X., Li Z., Wu M.C., Feng G.S., Xie W.F., Wang H.Y. Gankyrin-mediated dedifferentiation facilitates the tumorigenicity of rat hepatocytes and hepatoma cells. Hepatology 2011, 54:1259-1572.
60. Wang X.Q., Ongkeko W.M., Chen L., Yang Z.F., Lu P., Chen K.K., Lopez J.P., Poon R.T., Fan S.T. Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology 2010, 52:528-539.
61. Yekta S., Shih I.H., Bartel D.P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 2004, 304:594-596.
62. Calin C.A., Croce C.M. MicroRNA-cancer connection: the beginning of a newtale. Cancer Res. 2006, 66:7390-7394.
63. Ji J., Yamashita T., Budhu A., Forgues M., Jia H.L., Li C., Deng C., Wauthier E., Reid L.M., Ye Q.H., Qin L.X., Yang W., Wang H.Y., Tang Z.Y., Croce C.M., Wang X.W. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 2009, 50:472-480.
64. Ma S., Tang K.H., Chan Y.P., Lee T.K., Kwan P.S., Castilho A., Ng I., Man K., Wong N., To K.F., Zheng B.J., Lai P.B., Lo C.M., Chan K.W., Guan X.Y. MiR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 2010, 7:694-707.
65. Shimono Y., Zabala M., Cho R.W., Lobo N., Dalerba P., Qian D., Diehn M., Liu H., Panula S.P., Chiao E., Dirbas F.M., Somlo G., Pera R.A., Lao K., Clarke M.F. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009, 138:592-603.
66. Zhang J., Luo N., Luo Y., Peng Z., Zhang T., Li S. MicroRNA-150 inhibits human CD133-positive liver cancer stem cells through negative regulation of the transcription factor c-Myb. Int. J. Oncol. 2012, 40:747-756.
67. Jung C.J., Iyengar S., Blahnik K.R., Ajuha T.P., Jiang J.X., Farnham P.J., Zern M. Epigenetic modulation of miR-122 facilitates human embryonic stem cell self-renewal and hepatocellular carcinoma proliferation. PLoS One 2011, 6:e27740.
68. Kaur B., Brat D.J., Devi N.S., Van Meir E.G. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 2005, 24:3632-3642.
69. Yang X.R., Xu Y., Yu B., Zhou J., Qiu S.J., Shi G.M., Zhang B.H., Wu W.Z., Shi Y.H., Wu B., Yamg H.H., Ji Y., Fan J. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010, 59:953-962.
70. Rosmorduc O., Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin. Liver Dis. 2010, 30:258-267.
71. Patsenker E., Popov Y., Stickel F., Schneider V., Ledermann M., Sägesser H., Niedobitek G., Goodman S.L., Schuppan D. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 2009, 50:1501-1511.
72. Lau C.K., Yang Z.F., Ho D.W., Ng M.N., Yeoh G.C., Poon R.T., Fan S.T. An Akt/hypoxia-inducible factor-1 alpha/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells. Clin. Cancer Res. 2009, 15:3462-3471.
73. Yilmaz O.H., Valdez R., Theisen B.K., Guo W., Ferguson D.O., Wu H., Morrison S.J. Pten dependence distinguishes haematopoietic stem cells from leukemia-initiating cells. Nature 2005, 441:475-482.
74. Mistra L., Banker T., Murray J., Byers S., Thenappan A., He A.R., Shetty K., Johnson L., Reddy E.P. Liver stem cells and hepatocellular carcinoma. Hepatology 2009, 49:318-329.
75. Hou Y., Zou Q.F., Ge R.L., Shen F., Wang Y.Z. The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers. Cell Res. 2012, 22:259-272.