Stem Cells in Hepatocarcinogenesis: Evidence from Genomic Data

Jens U Marquardt; Snorri S Thorgeirsson

doi:10.1055/s-0030-1247130

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2010; 30(1): 026-034
DOI: 10.1055/s-0030-1247130

Stem Cells in Hepatocarcinogenesis: Evidence from Genomic Data

Jens U. Marquardt¹ , Snorri S. Thorgeirsson¹

¹Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Abstract

ABSTRACT

Increasing evidence suggests that many, perhaps all solid tumors contain a subset of cells that possess functional properties similar to the normal tissue stem cells, including self-renewal, unlimited proliferative capacity, and pluripotency. The hierarchical cancer model that places a cancer stem cell (CSC) population at the apex of tumor formation is based on this notion. The cancer stem cell hypothesis posits that CSCs are responsible not only for tumor initiation, but also generation of metastasis and local recurrence after therapy. Current definitions of the CSC are based only on functional properties regardless of potential cellular origin. Histopathology investigations of chronic liver diseases and experimental studies support the existence of CSCs in liver cancer. In particular, recent advances in microarray technologies utilizing integrative comparative genomic analysis of human hepatocellular carcinoma specimens, cancer cell lines, and transgenic models establish the molecular similarities between CSC and normal tissue stem cells and highlight the importance of CSC for the prognosis of liver cancer patients. The results have also uncovered the key “stemness” and oncogenic pathways frequently disrupted during hepatocarcinogenesis providing the basis for identifying novel therapeutic targets against CSC.

KEYWORDS

Hepatocellular carcinoma - stem/ progenitor cells - oval cells - comparative functional genomics - cancer stem cells - hepatocarcinogenesis

Full Text

References

REFERENCES

1 Bergsagel D E, Valeriote F A. Growth characteristics of a mouse plasma cell tumor. Cancer Res. 1968; 28(11) 2187-2196
2 Heppner G H. Tumor heterogeneity. Cancer Res. 1984; 44(6) 2259-2265
3 Weisenthal L M, Lippman M E. Clonogenic and nonclonogenic in vitro chemosensitivity assays. Cancer Treat Rep. 1985; 69(6) 615-632
4 Hewitt H B. Studies of the dissemination and quantitative transplantation of a lymphocytic leukaemia of CBA mice. Br J Cancer. 1958; 12(3) 378-401
5 Southam C M, Brunschwig A. Quantitative studies of autotransplantation of human cancer. Preliminary report. Cancer. 1961; 14(5) 971-978
6 Hamburger A W, Salmon S E. Primary bioassay of human tumor stem cells. Science. 1977; 197(4302) 461-463
7 Reya T, Morrison S J, Clarke M F, Weissman I L. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414(6859) 105-111
8 Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997; 3(7) 730-737
9 Campbell L L, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution?. Cell Cycle. 2007; 6(19) 2332-2338
10 Nowell P C. The clonal evolution of tumor cell populations. Science. 1976; 194(4260) 23-28
11 Clarke M F, Dick J E, Dirks P B et al.. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006; 66(19) 9339-9344
12 Jordan C T, Guzman M L, Noble M. Cancer stem cells. N Engl J Med. 2006; 355(12) 1253-1261
13 Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005; 5(4) 275-284
14 Ganguly R, Puri I K. Mathematical model for chemotherapeutic drug efficacy in arresting tumour growth based on the cancer stem cell hypothesis. Cell Prolif. 2007; 40(3) 338-354
15 Zajicek G. Resistance to cancer chemotherapy. Med Hypotheses. 1986; 19(2) 103-112
16 Polyak K, Weinberg R A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009; 9(4) 265-273
17 Farazi P A, DePinho R A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006; 6(9) 674-687
18 Ramaswamy S. Translating cancer genomics into clinical oncology. N Engl J Med. 2004; 350(18) 1814-1816
19 Couinaud C. Le Foie: Études Anatomiques et Chirurgicales. Paris; Masson et Cie 1957: 187-208
20 Desmet V J. Organizational principles in the liver: biology and pathobiology. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Shafritz DA The Liver: Biology and Pathobiology. 3rd ed. New York; Raven Press 1994: 3-14
21 Duncan A W, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009; 137(2) 466-481
22 Overturf K, al-Dhalimy M, Ou C N, Finegold M, Grompe M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol. 1997; 151(5) 1273-1280
23 Roskams T. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene. 2006; 25(27) 3818-3822
24 Farber E. Carcinoma of the liver in rats fed ethionine. AMA Arch Pathol. 1956; 62(6) 445-453
25 Opie E L. The pathogenesis of tumors of the liver produced by butter yellow. J Exp Med. 1944; 80(3) 231-246
26 Evarts R P, Nagy P, Marsden E, Thorgeirsson S S. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis. 1987; 8(11) 1737-1740
27 Popper H, Schaffner F. The liver and its diseases. Gastroenterology. 1961; 40 536-552
28 Ruben L N, Balls M. Genetic disparity and cancer induction by normal tissue implants in amphibia. Science. 1964; 146 1321-1322
29 Roskams T, Desmet V. Ductular reaction and its diagnostic significance. Semin Diagn Pathol. 1998; 15(4) 259-269
30 Hsia C C, Thorgeirsson S S, Tabor E. Expression of hepatitis B surface and core antigens and transforming growth factor-alpha in “oval cells” of the liver in patients with hepatocellular carcinoma. J Med Virol. 1994; 43(3) 216-221
31 Hsia C C, Evarts R P, Nakatsukasa H, Marsden E R, Thorgeirsson S S. Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology. 1992; 16(6) 1327-1333
32 Thorgeirsson S S, Grisham J W. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology. 2006; 43(1) 2-8
33 Fiegel H C, Lioznov M V, Cortes-Dericks L et al.. Liver-specific gene expression in cultured human hematopoietic stem cells. Stem Cells. 2003; 21(1) 98-104
34 Fukuda K, Sugihara A, Nakasho K et al.. The origin of biliary ductular cells that appear in the spleen after transplantation of hepatocytes. Cell Transplant. 2004; 13(1) 27-33
35 Minguet S, Cortegano I, Gonzalo P et al.. A population of c-Kit(low)(CD45/TER119)- hepatic cell progenitors of 11-day postcoitus mouse embryo liver reconstitutes cell-depleted liver organoids. J Clin Invest. 2003; 112(8) 1152-1163
36 Lagasse E, Connors H, Al-Dhalimy M et al.. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000; 6(11) 1229-1234
37 Willenbring H, Bailey A S, Foster M et al.. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med. 2004; 10(7) 744-748
38 Coleman W B, Wennerberg A E, Smith G J, Grisham J W. Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment. Am J Pathol. 1993; 142(5) 1373-1382
39 Dumble M L, Croager E J, Yeoh G C, Quail E A. Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis. 2002; 23(3) 435-445
40 Garfield S, Huber B E, Nagy P, Cordingley M G, Thorgeirsson S S. Neoplastic transformation and lineage switching of rat liver epithelial cells by retrovirus-associated oncogenes. Mol Carcinog. 1988; 1(3) 189-195
41 Tsao M S, Grisham J W. Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed cultured rat liver epithelial cells. A light- and electron-microscopic analysis. Am J Pathol. 1987; 127(1) 168-181
42 Braun L, Mikumo R, Fausto N. Production of hepatocellular carcinoma by oval cells: cell cycle expression of c-myc and p53 at different stages of oval cell transformation. Cancer Res. 1989; 49(6) 1554-1561
43 Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic “progenitor cells” correlates with parenchymal inflammation in chronic viral hepatitis: can “progenitor cells” migrate?. J Pathol. 2000; 192(3) 373-378
44 Libbrecht L, Desmet V, Van Damme B, Roskams T. The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol. 2000; 33(1) 76-84
45 Lowes K N, Brennan B A, Yeoh G C, Olynyk J K. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol. 1999; 154(2) 537-541
46 Durnez A, Verslype C, Nevens F et al.. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology. 2006; 49(2) 138-151
47 Wu P C, Lai V C, Fang J W, Gerber M A, Lai C L, Lau J Y. Hepatocellular carcinoma expressing both hepatocellular and biliary markers also expresses cytokeratin 14, a marker of bipotential progenitor cells. J Hepatol. 1999; 31(5) 965-966
48 Andersen J B, Loi R, Perra A et al.. Progenitor-derived hepatocellular carcinoma model in the rat. Hepatology. 2009; , December 4 (Epub ahead of print)
49 Tang Y, Kitisin K, Jogunoori W et al.. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling. Proc Natl Acad Sci U S A. 2008; 105(7) 2445-2450
50 Knight B, Tirnitz-Parker J E, Olynyk J K. C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits liver tumor formation in mice. Gastroenterology. 2008; 135(3) 969-979, 979, e1
51 Lee J S, Thorgeirsson S S. Genetic profiling of human hepatocellular carcinoma. Semin Liver Dis. 2005; 25(2) 125-132
52 Iizuka N, Oka M, Yamada-Okabe H et al.. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003; 361(9361) 923-929
53 Lee J S, Chu I S, Heo J et al.. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004; 40(3) 667-676
54 Yamashita T, Forgues M, Wang W et al.. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008; 68(5) 1451-1461
55 Ye Q H, Qin L X, Forgues M et al.. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003; 9(4) 416-423
56 Santoni-Rugiu E, Jelnes P, Thorgeirsson S S, Bisgaard H C. Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion. APMIS. 2005; 113(11-12) 876-902
57 Yang W, Yan H X, Chen L et al.. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008; 68(11) 4287-4295
58 Hoshida Y, Nijman S M, Kobayashi M et al.. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009; 69(18) 7385-7392
59 El-Serag H B, Rudolph K L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007; 132(7) 2557-2576
60 Villanueva A, Newell P, Chiang D Y, Friedman S L, Llovet J M. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007; 27(1) 55-76
61 Segal E, Friedman N, Koller D, Regev A. A module map showing conditional activity of expression modules in cancer. Nat Genet. 2004; 36(10) 1090-1098
62 Wong D J, Liu H, Ridky T W, Cassarino D, Segal E, Chang H Y. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell. 2008; 2(4) 333-344
63 Lee J S, Chu I S, Mikaelyan A et al.. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet. 2004; 36(12) 1306-1311
64 Shachaf C M, Kopelman A M, Arvanitis C et al.. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004; 431(7012) 1112-1117
65 Kaposi-Novak P, Libbrecht L, Woo H G et al.. Central role of c-Myc during malignant conversion in human hepatocarcinogenesis. Cancer Res. 2009; 69(7) 2775-2782
66 Lee J S, Thorgeirsson S S. Comparative and integrative functional genomics of HCC. Oncogene. 2006; 25(27) 3801-3809
67 Lee J S, Heo J, Libbrecht L et al.. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006; 12(4) 410-416
68 Chiba T, Kita K, Zheng Y W et al.. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology. 2006; 44(1) 240-251
69 Haraguchi N, Utsunomiya T, Inoue H et al.. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006; 24(3) 506-513
70 Ma S, Chan K W, Hu L et al.. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007; 132(7) 2542-2556
71 Yamashita T, Ji J, Budhu A et al.. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009; 136(3) 1012-1024
72 Yang Z F, Ho D W, Ng M N et al.. Significance of CD90 + cancer stem cells in human liver cancer. Cancer Cell. 2008; 13(2) 153-166
73 Ma S, Chan K W, Lee T K et al.. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res. 2008; 6(7) 1146-1153
74 Munz M, Baeuerle P A, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009; 69(14) 5627-5629
75 Shmelkov S V, Butler J M, Hooper A T et al.. CD133 expression is not restricted to stem cells, and both CD133 + and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest. 2008; 118(6) 2111-2120
76 Goodell M A, Brose K, Paradis G, Conner A S, Mulligan R C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996; 183(4) 1797-1806
77 Chiba T, Zheng Y W, Kita K et al.. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology. 2007; 133(3) 937-950
78 Chiba T, Miyagi S, Saraya A et al.. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res. 2008; 68(19) 7742-7749
79 Park I K, Qian D, Kiel M et al.. BMI-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003; 423(6937) 302-305
80 Marquardt J U, Raggi C, Andersen J B et al.. Gene expression signature of putative cancer stem cells predicts survival of HCC patients. Paper presented at: 61st AASLD Annual Meeting October 29–November 2, 2009 Boston, MA;
81 Klonisch T, Wiechec E, Hombach-Klonisch S et al.. Cancer stem cell markers in common cancers - therapeutic implications. Trends Mol Med. 2008; 14(10) 450-460
82 Shi G M, Xu Y, Fan J et al.. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol. 2008; 134(11) 1155-1163
83 Zhu Z, Hao X, Yan M et al.. Cancer stem/progenitor cells are highly enriched in CD133(+)CD44(+) population in hepatocellular carcinoma. Int J Cancer. 2009; , August 26 (Epub ahead of print)
84 Yang Z F, Ngai P, Ho D W et al.. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology. 2008; 47(3) 919-928

Snorri S ThorgeirssonM.D. Ph.D.

Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research

National Cancer Institute, NIH, 37 Convent Drive, Room 4146, Bethesda, MD 20892

Email: snorri_thorgeirsson@nih.gov