Abstract
The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. Here we address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Parkin, D.M., Bray, F., Ferlay, J. & Pisani, P. Estimating the world cancer burden: Globocan 2000. Int. J. Cancer 94, 153–156 (2001).
El Serag, H.B. & Mason, A.C. Rising incidence of hepatocellular carcinoma in the United States. N. Engl. J. Med. 340, 745–750 (1999).
Bruix, J., Boix, L., Sala, M. & Llovet, J.M. Focus on hepatocellular carcinoma. Cancer Cell 5, 215–219 (2004).
Llovet, J.M. et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 29, 62–67 (1999).
Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Alizadeh, A.A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).
Ross, D.T. et al. Systematic variation in gene expression patterns in human cancer cell lines. Nat. Genet. 24, 227–235 (2000).
Roskams, T.A., Libbrecht, L. & Desmet, V.J. Progenitor cells in diseased human liver. Semin. Liver Dis. 23, 385–396 (2003).
Lee, J.S. et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat. Genet. 36, 1306–1311 (2004).
Lee, J.S., Grisham, J.W. & Thorgeirsson, S.S. Comparative functional genomics for identifying models of human cancer. Carcinogenesis 26, 1013–1020 (2005).
Petkov, P.M. et al. Gene expression pattern in hepatic stem/progenitor cells during rat fetal development using complementary DNA microarrays. Hepatology 39, 617–627 (2004).
Dabeva, M.D. & Shafritz, D.A. Hepatic stem cells and liver repopulation. Semin. Liver Dis. 23, 349–362 (2003).
Thorgeirsson, S.S. & Grisham, J.W. Overview of recent experimental studies on liver stem cells. Semin. Liver Dis. 23, 303–312 (2003).
Lee, J.S. et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 40, 667–676 (2004).
Chambers, A.F. & Matrisian, L.M. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst. 89, 1260–1270 (1997).
Andreasen, P.A., Egelund, R. & Petersen, H.H. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell. Mol. Life Sci. 57, 25–40 (2000).
Chang, C. & Werb, Z. The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol. 11, S37–S43 (2001).
Jothy, S. CD44 and its partners in metastasis. Clin. Exp. Metastasis 20, 195–201 (2003).
Yu, Y. et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat. Med. 10, 175–181 (2004).
Khanna, C. et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186 (2004).
Curto, M. & McClatchey, A.I. Ezrin.a metastatic detERMinant? Cancer Cell 5, 113–114 (2004).
Martin, T.A., Harrison, G., Mansel, R.E. & Jiang, W.G. The role of the CD44/ezrin complex in cancer metastasis. Crit. Rev. Oncol. Hematol. 46, 165–186 (2003).
Kondo, K. et al. Risk factors for early death after liver resection in patients with solitary hepatocellular carcinoma. J. Hepatobiliary Pancreat. Surg. 12, 399–404 (2005).
Gouillat, C., Manganas, D., Saguier, G., Duque-Campos, R. & Berard, P. Resection of hepatocellular carcinoma in cirrhotic patients: longterm results of a prospective study. J. Am. Coll. Surg. 189, 282–290 (1999).
Lee, J.S. & Thorgeirsson, S.S. Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets. Gastroenterology 127, S51–S55 (2004).
Kitano, H. Cancer robustness: tumour tactics. Nature 426, 125 (2003).
Postic, C. & Magnuson, M.A. DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis 26, 149–150 (2000).
Pinkert, C.A., Ornitz, D.M., Brinster, R.L. & Palmiter, R.D. An albumin enhancer located 10 kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice. Genes Dev. 1, 268–276 (1987).
Huh, C.G. et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl. Acad. Sci. USA 101, 4477–4482 (2004).
Ferrando, A.A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).
Sarraf, C. et al. Cell behavior in the acetylaminofluorene-treated regenerating rat liver. Light and electron microscopic observations. Am. J. Pathol. 145, 1114–1126 (1994).
Eferl, R. et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112, 181–192 (2003).
Hilberg, F., Aguzzi, A., Howells, N. & Wagner, E.F. c-jun is essential for normal mouse development and hepatogenesis. Nature 365, 179–181 (1993).
Logan, C.Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).
Lee, J.S. & Thorgeirsson, S.S. Genetic profiling of human hepatocellular carcinoma. Semin. Liver Dis. 25, 125–132 (2005).
Robrechts, C. et al. Primary liver tumour of intermediate (hepatocyte-bile duct cell) phenotype: a progenitor cell tumour? Liver 18, 288–293 (1998).
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. 33, 76–84 (2000).
Wu, P.C. et al. Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am. J. Pathol. 149, 1167–1175 (1996).
Uenishi, T. et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci. 94, 851–857 (2003).
Durnez, A. et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. Hepatology (in the press).
Acknowledgements
This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. L. Libbrecht is a “postdoctoraal onderzoeker” of the “F.W.O.-Vlaanderen.” I.-S. Chu is supported by a grant from the Ministry of Science and Technology (21C Frontier Functional Human Genome Project), Korea.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Gene networks from PathwayAssist. (PDF 332 kb)
Supplementary Fig. 2
Expression of hepatic oval cell marker genes in human HCC. (PDF 25 kb)
Supplementary Fig. 3
Comparison of proliferation and apoptosis indices among subtypes of HCC. (PDF 21 kb)
Supplementary Table 1
Top 10 list of gene networks from Ingenuity Pathway Analysis. (PDF 35 kb)
Supplementary Table 2
Clinical and pathological features of HCC patients. (PDF 8 kb)
Supplementary Table 3
Univariate and multivariate Cox proportional hazard regression analyses of HCC. (PDF 8 kb)
Rights and permissions
About this article
Cite this article
Lee, JS., Heo, J., Libbrecht, L. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12, 410–416 (2006). https://doi.org/10.1038/nm1377
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1377
This article is cited by
-
ZBTB7B is a permissive regulator of hepatocellular carcinoma initiation by repressing c-Jun expression and function
Cell Death & Disease (2024)
-
Friend or foe? The elusive role of hepatic stellate cells in liver cancer
Nature Reviews Gastroenterology & Hepatology (2023)
-
Proliferative hepatocellular carcinomas in cirrhosis: patient outcomes of LI-RADS category 4/5 and category M
European Radiology (2023)
-
Potential role of human umbilical cord stem cells-derived exosomes as novel molecular inhibitors of hepatocellular carcinoma growth
Apoptosis (2023)
-
The added value of 18F-FDG PET/MRI multimodal imaging in hepatocellular carcinoma for identifying cytokeratin 19 status
Abdominal Radiology (2023)