Table of Contents
ISRN Pathology
Volume 2011 (2011), Article ID 273924, 10 pages
http://dx.doi.org/10.5402/2011/273924
Review Article

Chronic Hypoxia Emerging as One of the Driving Forces behind Gene Expression and Prognosis of Hepatocellular Carcinoma

Liver Research Facility and Lab of Hepatology, University Hospital Gasthuisberg-Leuven, Herestraat 49, bus 703, 3000 Leuven, Belgium

Received 24 March 2011; Accepted 12 April 2011

Academic Editors: A. B. Galosi, C. K. Panda, A. Wincewicz, and T. Yazawa

Copyright © 2011 Jos F. van Pelt et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. M. Parkin, F. Bray, J. Ferlay, and P. Pisani, “Global cancer statistics, 2002,” Ca: A Cancer Journal for Clinicians, vol. 55, no. 2, pp. 74–108, 2005. View at Google Scholar · View at Scopus
  2. H. B. El-Serag and A. C. Mason, “Rising incidence of hepatocellular carcinoma in the United States,” The New England Journal of Medicine, vol. 340, no. 10, pp. 745–750, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. C. Guyot, S. Lepreux, C. Combe et al., “Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved,” The International Journal of Biochemistry and Cell Biology, vol. 38, no. 2, pp. 135–151, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. A. Sangiovanni, E. Del Ninno, P. Fasani et al., “Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance,” Gastroenterology, vol. 126, no. 4, pp. 1005–1014, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. J. M. Llovet, A. Burroughs, and J. Bruix, “Hepatocellular carcinoma,” The Lancet, vol. 362, no. 9399, pp. 1907–1917, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. T. Severi, H. Van Malenstein, C. Verslype, and J. F. Van Pelt, “Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets,” Acta Pharmacologica Sinica, vol. 31, no. 11, pp. 1409–1420, 2010. View at Publisher · View at Google Scholar · View at PubMed
  7. S. M. Hussain, P. E. Zondervan, J. N. M. Ijzermans, S. W. Schalm, R. A. de Man, and G. P. Krestin, “Benign versus malignant hepatic nodules: MR imaging findings with pathologic correlation,” Radiographics, vol. 22, no. 5, pp. 1023–1036, 2002. View at Google Scholar · View at Scopus
  8. J. Bruix and M. Sherman, “Management of hepatocellular carcinoma,” Hepatology, vol. 42, no. 5, pp. 1208–1236, 2005. View at Publisher · View at Google Scholar · View at PubMed
  9. J. M. Llovet, A. M. Di Bisceglie, J. Bruix et al., “Design and endpoints of clinical trials in hepatocellular carcinoma,” Journal of the National Cancer Institute, vol. 100, no. 10, pp. 698–711, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. L. Libbrecht, D. Bielen, C. Verslype et al., “Focal lesions in cirrhotic explant livers: pathological evaluation and accuracy of pretransplantation imaging examinations,” Liver Transplantation, vol. 8, no. 9, pp. 749–761, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. C. Verslype, E. Van Cutsem, M. Dicato et al., “The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008,” Annals of Oncology, vol. 20, supplement 7, pp. vii1–vii6, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. J. M. Llovet, S. Ricci, V. Mazzaferro et al., “Sorafenib in advanced hepatocellular carcinoma,” The New England Journal of Medicine, vol. 359, no. 4, pp. 378–390, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. A. L. Cheng, Y. K. Kang, Z. Chen et al., “Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial,” The Lancet Oncology, vol. 10, no. 1, pp. 25–34, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. I. P. Witz, “The tumor microenvironment: the making of a paradigm,” Cancer Microenvironment, vol. 2, no. 1, pp. S9–S17, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. A. Mantovani, P. Allavena, A. Sica, and F. Balkwill, “Cancer-related inflammation,” Nature, vol. 454, no. 7203, pp. 436–444, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. R. Kalluri and M. Zeisberg, “Fibroblasts in cancer,” Nature Reviews Cancer, vol. 6, no. 5, pp. 392–401, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. A. Mazzocca, E. Fransvea, F. Dituri, L. Lupo, S. Antonaci, and G. Giannelli, “Down-regulation of connective tissue growth factor by inhibition of transforming growth factor β blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma,” Hepatology, vol. 51, no. 2, pp. 523–534, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. F. Van Zijl, M. Mair, A. Csiszar et al., “Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge,” Oncogene, vol. 28, no. 45, pp. 4022–4033, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. K. Sasaki, S. Natsugoe, S. Ishigami et al., “Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma,” Journal of Experimental & Clinical Cancer Research, vol. 28, no. 1, p. 158, 2009. View at Publisher · View at Google Scholar · View at PubMed
  20. M. Iwatsuki, K. Mimori, T. Fukagawa et al., “The clinical significance of vimentin-expressing gastric cancer cells in bone marrow,” Annals of Surgical Oncology, vol. 17, no. 9, pp. 2526–2533, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. T. Jäger, M. Becker, A. Eisenhardt et al., “The prognostic value of cadherin switch in bladder cancer,” Oncology Reports, vol. 23, no. 4, pp. 1125–1132, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Soltermann, V. Tischler, S. Arbogast et al., “Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non-small cell lung cancer,” Clinical Cancer Research, vol. 14, no. 22, pp. 7430–7437, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. J. M. M. Cates, R. H. Byrd, L. E. Fohn, A. D. Tatsas, M. K. Washington, and C. C. Black, “Epithelial-mesenchymal transition markers in pancreatic ductal adenocarcinoma,” Pancreas, vol. 38, no. 1, pp. e1–e6, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. M. H. Yang, C. L. Chen, G. Y. Chau et al., “Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma,” Hepatology, vol. 50, no. 5, pp. 1464–1474, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. R. F. Niu, L. Zhang, G. M. Xi et al., “Up-regulation of twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma,” Journal of Experimental & Clinical Cancer Research, vol. 26, no. 3, pp. 385–394, 2007. View at Google Scholar · View at Scopus
  26. L. Chen, T. H. M. Chan, Y. F. Yuan et al., “CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1178–1191, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. F. van Zijl, G. Zulehner, M. Petz et al., “Epithelial-mesenchymal transition in hepatocellular carcinoma,” Future Oncology, vol. 5, no. 8, pp. 1169–1179, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. T. K. Lee, R. T. P. Poon, A. P. Yuen et al., “Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition,” Clinical Cancer Research, vol. 12, no. 18, pp. 5369–5376, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. C. Cicchini, I. Laudadio, F. Citarella et al., “TGFβ-induced EMT requires focal adhesion kinase (FAK) signaling,” Experimental Cell Research, vol. 314, no. 1, pp. 143–152, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. N. Matsuo, H. Shiraha, T. Fujikawa et al., “Twist expression promotes migration and invasion in hepatocellular carcinoma,” BMC Cancer, vol. 9, article 240, 2009. View at Publisher · View at Google Scholar · View at PubMed
  31. M. I. Kokkinos, R. Wafai, M. K. Wong, D. F. Newgreen, E. W. Thompson, and M. Waltham, “Vimentin and epithelial-mesenchymal transition in human breast cancer—observations in vitro and in vivo,” Cells Tissues Organs, vol. 185, no. 1–3, pp. 191–203, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. M. Zeisberg and E. G. Neilson, “Biomarkers for epithelial-mesenchymal transitions,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1429–1437, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. C. D. Venkov, A. J. Link, J. L. Jennings et al., “A proximal activator of transcription in epithelial-mesenchymal transition,” Journal of Clinical Investigation, vol. 117, no. 2, pp. 482–491, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. J. Gotzmann, A. N. M. Fischer, M. Zojer et al., “A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes,” Oncogene, vol. 25, no. 22, pp. 3170–3185, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. C. Y. Lin, C. J. Lin, K. H. Chen, J. C. Wu, S. H. Huang, and S. M. Wang, “Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction,” FEBS Letters, vol. 580, no. 13, pp. 3042–3050, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. W. Ding, H. You, H. Dang et al., “Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion,” Hepatology, vol. 52, no. 3, pp. 945–953, 2010. View at Publisher · View at Google Scholar · View at PubMed
  37. S. Z. Yang, L. D. Zhang, YI. Zhang et al., “HBx protein induces EMT through c-Src activation in SMMC-7721 hepatoma cell line,” Biochemical & Biophysical Research Communications, vol. 382, no. 3, pp. 555–560, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. S. Battaglia, N. Benzoubir, S. Nobilet et al., “Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition,” PloS One, vol. 4, no. 2, Article ID e4355, 2009. View at Publisher · View at Google Scholar · View at PubMed
  39. J. Kim, S. J. Hong, J. Y. Park et al., “Epithelial—mesenchymal transition gene signature to predict clinical outcome of hepatocellular carcinoma,” Cancer Science, vol. 101, no. 6, pp. 1521–1528, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. F. Dayan, N. M. Mazure, M. C. Brahimi-Horn, and J. Pouysségur, “A dialogue between the hypoxia-inducible factor and the tumor microenvironment,” Cancer Microenvironment, vol. 1, no. 1, pp. 53–68, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. K. Murata, H. Suzuki, H. Okano, T. Oyamada, Y. Yasuda, and A. Sakamoto, “Hypoxia-induced des-γ-carboxy prothrombin production in hepatocellular carcinoma,” International Journal of Oncology, vol. 36, no. 1, pp. 161–170, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. B. L. Copple, “Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-β-dependent mechanisms,” Liver International, vol. 30, no. 5, pp. 669–682, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. W. Yan, Y. Fu, D. Tian et al., “PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells,” Biochemical & Biophysical Research Communications, vol. 382, no. 3, pp. 631–636, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. V. H. Haase, “Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease,” Kidney International, vol. 76, no. 5, pp. 492–499, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. S. Sun, X. Ning, Y. Zhang et al., “Hypoxia-inducible factor-1α induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition,” Kidney International, vol. 75, no. 12, pp. 1278–1287, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. S. Cannito, E. Novo, A. Compagnone et al., “Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells,” Carcinogenesis, vol. 29, no. 12, pp. 2267–2278, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. A. Villanueva, P. Newell, D. Y. Chiang, S. L. Friedman, and J. M. Llovet, “Genomics and signaling pathways in hepatocellular carcinoma,” Seminars in Liver Disease, vol. 27, no. 1, pp. 55–76, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. S. Boyault, D. S. Rickman, A. de Reyniès et al., “Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets,” Hepatology, vol. 45, no. 1, pp. 42–52, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. D. Y. Chiang, A. Villanueva, Y. Hoshida et al., “Focal gains of VEGFA and molecular classification of hepatocellular carcinoma,” Cancer Research, vol. 68, no. 16, pp. 6779–6788, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. J. S. Lee, J. Heo, L. Libbrecht et al., “A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells,” Nature Medicine, vol. 12, no. 4, pp. 410–416, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. J. S. Lee, IN. S. Chu, J. Heo et al., “Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling,” Hepatology, vol. 40, no. 3, pp. 667–676, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. Y. Hoshida, A. Villanueva, M. Kobayashi et al., “Gene expression in fixed tissues and outcome in hepatocellular carcinoma,” The New England Journal of Medicine, vol. 359, no. 19, pp. 1995–2004, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. A. Budhu, M. Forgues, Q. H. Ye et al., “Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment,” Cancer Cell, vol. 10, no. 2, pp. 99–111, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. F. Simon, M. Bockhorn, C. Praha et al., “Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue-influence of a modulated host stroma on the prognosis of HCC,” Langenbeck's Archives of Surgery, vol. 395, no. 4, pp. 395–405, 2010. View at Publisher · View at Google Scholar · View at PubMed
  55. J. F. Dufour and P. Johnson, “Liver cancer: from molecular pathogenesis to new therapies. Summary of the EASL single topic conference,” Journal of Hepatology, vol. 52, no. 2, pp. 296–304, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. E. H. Gort, A. J. Groot, E. van der Wall, P. J. van Diest, and M. A. Vooijs, “Hypoxic regulation of metastasis via hypoxia-inducible factors,” Current Molecular Medicine, vol. 8, no. 1, pp. 60–67, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. G. L. Semenza, “Targeting HIF-1 for cancer therapy,” Nature Reviews Cancer, vol. 3, no. 10, pp. 721–732, 2003. View at Google Scholar · View at Scopus
  58. J. M. Brown and W. R. Wilson, “Exploiting tumour hypoxia in cancer treatment,” Nature Reviews Cancer, vol. 4, no. 6, pp. 437–447, 2004. View at Google Scholar · View at Scopus
  59. J. M. Brown and A. J. Giaccia, “The unique physiology of solid tumors: opportunities (and problems) for cancer therapy,” Cancer Research, vol. 58, no. 7, pp. 1408–1416, 1998. View at Google Scholar · View at Scopus
  60. K. R. Kim, H. E. Moon, and K. W. Kim, “Hypoxia-induced angiogenesis in human hepatocellular carcinoma,” Journal of Molecular Medicine, vol. 80, no. 11, pp. 703–714, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. J. Folkman, P. Hahnfeldt, and L. Hlatky, “Cancer: looking outside the genome,” Nature Reviews Molecular Cell Biology, vol. 1, no. 1, pp. 76–79, 2000. View at Google Scholar · View at Scopus
  62. M. C. Brahimi-Horn, J. Chiche, and J. Pouysségur, “Hypoxia and cancer,” Journal of Molecular Medicine, vol. 85, no. 12, pp. 1301–1307, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. T. Fink, P. Ebbesen, and V. Zachar, “Quantitative gene expression profiles of human liver-derived cell lines exposed to moderate hypoxia,” Cellular Physiology and Biochemistry, vol. 11, no. 2, pp. 105–114, 2001. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Vengellur, J. M. Phillips, J. B. Hogenesch, and J. J. LaPres, “Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells,” Physiological Genomics, vol. 22, pp. 308–318, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. L. A. Sonna, M. L. Cullivan, H. K. Sheldon, R. E. Pratt, and C. M. Lilly, “Effect of hypoxia on gene expression by human hepatocytes (HepG2),” Physiological Genomics, vol. 12, pp. 195–207, 2003. View at Google Scholar · View at Scopus
  66. X. Zhao, J. Li, J. Zhuo, and L. Cai, “Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma,” Biochemical & Biophysical Research Communications, vol. 403, no. 3-4, pp. 417–421, 2010. View at Publisher · View at Google Scholar · View at PubMed
  67. H. Zhu, X. P. Chen, S. F. Luo, J. Guan, W. G. Zhang, and B. X. Zhang, “Involvement of hypoxia-inducible factor-1-α in multidrug resistance induced by hypoxia in HepG2 cells,” Journal of Experimental & Clinical Cancer Research, vol. 24, no. 4, pp. 565–574, 2005. View at Google Scholar · View at Scopus
  68. A. Sermeus, J. P. Cosse, M. Crespin et al., “Hypoxia induces protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor activity,” Molecular Cancer, vol. 7, article 27, 2008. View at Publisher · View at Google Scholar · View at PubMed
  69. J.-P. Cosse, G. Rommelaere, N. Ninane, T. Arnould, and C. Michiels, “BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway,” Biochemical Pharmacology, vol. 80, no. 8, pp. 1160–1169, 2010. View at Publisher · View at Google Scholar · View at PubMed
  70. E. U. Jung, J. H. Yoon, Y. J. Lee et al., “Hypoxia and retinoic acid-inducible NDRG1 expression is responsible for doxorubicin and retinoic acid resistance in hepatocellular carcinoma cells,” Cancer Letters, vol. 298, no. 1, pp. 9–15, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. E. Tak, S. Lee, J. Lee et al., “Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells,” Journal of Hepatology, vol. 54, no. 2, pp. 328–339, 2011. View at Publisher · View at Google Scholar · View at PubMed
  72. S. W. Jusman, A. Halim, S. I. Wanandi, and M. Sadikin, “Expression of hypoxia-inducible factor-1alpha (HIF-1alpha) related to oxidative stress in liver of rat-induced by systemic chronic normobaric hypoxia,” Acta medica Indonesiana, vol. 42, no. 1, pp. 17–23, 2010. View at Google Scholar
  73. J. E. Klaunig, L. M. Kamendulis, and B. A. Hocevar, “Oxidative stress and oxidative damage in carcinogenesis,” Toxicologic Pathology, vol. 38, no. 1, pp. 96–109, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. S. Detre, G. S. Jotti, and M. Dowsett, “A ‘quickscore’ method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas,” Journal of Clinical Pathology, vol. 48, no. 9, pp. 876–878, 1995. View at Google Scholar · View at Scopus
  75. E. Wurmbach, Y. B. Chen, G. Khitrov et al., “Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma,” Hepatology, vol. 45, no. 4, pp. 938–947, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. J. J. Goeman, S. van de Geer, F. de Kort, and H. C. van Houwellingen, “A global test for groups fo genes: testing association with a clinical outcome,” Bioinformatics, vol. 20, no. 1, pp. 93–99, 2004. View at Publisher · View at Google Scholar
  77. A. Cucchetti, F. Piscaglia, E. Caturelli et al., “Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population,” Annals of Surgical Oncology, vol. 16, no. 2, pp. 413–422, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. H. Imamura, Y. Matsuyama, E. Tanaka et al., “Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy,” Journal of Hepatology, vol. 38, no. 2, pp. 200–207, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. H. van Malenstein, O. Gevaert, L. Libbrecht et al., “A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma,” Clinical Cancer Research, vol. 16, no. 16, pp. 4278–4288, 2010. View at Publisher · View at Google Scholar · View at PubMed
  80. L. Liu, X. D. Zhu, W. Q. Wang et al., “Activation of β-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis,” Clinical Cancer Research, vol. 16, no. 10, pp. 2740–2750, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  81. J. M. Llovet and J. Bruix, “Molecular targeted therapies in hepatocellular carcinoma,” Hepatology, vol. 48, no. 4, pp. 1312–1327, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. C.-X. Dai, Q. Gao, S.-J. Qiu et al., “Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery,” BMC Cancer, vol. 9, article 418, 2009. View at Publisher · View at Google Scholar · View at PubMed
  83. T. M. Kalliomäki, G. McCallum, P. G. Wells, and R. P. Hill, “Progression and metastasis in a transgenic mouse breast cancer model: effects of exposure to in vivo hypoxia,” Cancer Letters, vol. 282, no. 1, pp. 98–108, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. E. Louie, S. Nik, J.-S. Chen et al., “Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation,” Breast Cancer Research, vol. 12, no. 6, article R94, 2010. View at Publisher · View at Google Scholar · View at PubMed
  85. L. Terraneo, P. Bianciardi, A. Caretti, R. Ronchi, and M. Samaja, “Chronic systemic hypoxia promotes LNCaP prostate cancer growth in vivo,” Prostate, vol. 70, no. 11, pp. 1243–1254, 2010. View at Publisher · View at Google Scholar · View at PubMed
  86. J. A. Watson, C. J. Watson, A. M. McCrohan et al., “Generation of an epigenetic signature by chronic hypoxia in prostate cells,” Human Molecular Genetics, vol. 18, no. 19, pp. 3594–3604, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. A. Ginouvès, K. Ilc, N. Macías, J. Pouysségur, and E. Berra, “PHDs overactivation during chronic hypoxia “desensitizes” HIFα and protects cells from necrosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 12, pp. 4745–4750, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. R. G. Bristow and R. P. Hill, “Hypoxia and metabolism: hypoxia, DNA repair and genetic instability,” Nature Reviews Cancer, vol. 8, no. 3, pp. 180–192, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus