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Frontiers of Medicine

, Volume 8, Issue 1, pp 33–41 | Cite as

The impact of hypoxia in hepatocellular carcinoma metastasis

  • Carmen Chak-Lui Wong
  • Alan Ka-Lun Kai
  • Irene Oi-Lin Ng
Review

Abstract

Hypoxia is a common phenomenon in hepatocellular carcinoma (HCC). Hypoxia stabilizes transcription factor, hypoxia-inducible factor (HIF), to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondary growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.

Keywords

hypoxia hepatocellular carcinoma (HCC) metastasis hypoxia-inducible factor (HIF) 

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References

  1. 1.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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. Lancet Oncol 2009; 10(1): 25–34PubMedCrossRefGoogle Scholar
  2. 2.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390PubMedCrossRefGoogle Scholar
  3. 3.
    Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007; 9(8): 1221–1235PubMedCrossRefGoogle Scholar
  4. 4.
    Loboda A, Jozkowicz A, Dulak J. HIF-1 and HIF-2 transcription factors-similar but not identical. Mol Cells 2010; 29(5): 435–442PubMedCrossRefGoogle Scholar
  5. 5.
    Huang GW, Yang LY, Lu WQ. Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: Impact on neovascularization and survival. World J Gastroenterol 2005; 11(11): 1705–1708PubMedGoogle Scholar
  6. 6.
    Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, Liu J, Wang Q, Zhu J, Feng X, Dong J, Qian C. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxiainducible factor — 1α in hepatocellular carcinoma. BMC Cancer 2013; 13(1): 108PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, Gao DM. Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1alpha, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res 2011; 17(16): 5463–5472PubMedCrossRefGoogle Scholar
  8. 8.
    Michaelson JS, Chen LL, Silverstein MJ, Cheongsiatmoy JA, Mihm MC Jr, Sober AJ, Tanabe KK, Smith BL, Younger J. Why cancer at the primary site and in the lymph nodes contributes to the risk of cancer death. Cancer 2009; 115(21): 5084–5094PubMedCrossRefGoogle Scholar
  9. 9.
    Xiaohong S, Huikai L, Feng W, Ti Z, Yunlong C, Qiang L. Clinical significance of lymph node metastasis in patients undergoing partial hepatectomy for hepatocellular carcinoma. World J Surg 2010; 34(5): 1028–1033PubMedCrossRefGoogle Scholar
  10. 10.
    Tanaka H, Yamamoto M, Hashimoto N, Miyakoshi M, Tamakawa S, Yoshie M, Tokusashi Y, Yokoyama K, Yaginuma Y, Ogawa K. Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res 2006; 66(23): 11263–11270PubMedCrossRefGoogle Scholar
  11. 11.
    Bangoura G, Liu ZS, Qian Q, Jiang CQ, Yang GF, Jing S. Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 2007; 13(23): 3176–3182PubMedGoogle Scholar
  12. 12.
    Bangoura G, Yang LY, Huang GW, Wang W. Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World J Gastroenterol 2004; 10(4): 525–530PubMedGoogle Scholar
  13. 13.
    van Malenstein H, Gevaert O, Libbrecht L, Daemen A, Allemeersch J, Nevens F, Van Cutsem E, Cassiman D, De Moor B, Verslype C, van Pelt J. A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. Clin Cancer Res 2010; 16(16): 4278–4288PubMedCrossRefGoogle Scholar
  14. 14.
    Li H, Ge C, Zhao F, Yan M, Hu C, Jia D, Tian H, Zhu M, Chen T, Jiang G, Xie H, Cui Y, Gu J, Tu H, He X, Yao M, Liu Y, Li J. Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma. Hepatology 2011; 54(3): 910–919PubMedCrossRefGoogle Scholar
  15. 15.
    van der Slot AJ, Zuurmond AM, Bardoel AF, Wijmenga C, Pruijs HE, Sillence DO, Brinckmann J, Abraham DJ, Black CM, Verzijl N, DeGroot J, Hanemaaijer R, TeKoppele JM, Huizinga TW, Bank RA. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem 2003; 278(42): 40967–40972PubMedCrossRefGoogle Scholar
  16. 16.
    Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G, Erler JT. LOX-mediated collagen crosslinking is responsible for fibrosisenhanced metastasis. Cancer Res 2013; 73(6): 1721–1732PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006; 124(2): 263–266PubMedCrossRefGoogle Scholar
  18. 18.
    Noda T, Yamamoto H, Takemasa I, Yamada D, Uemura M, Wada H, Kobayashi S, Marubashi S, Eguchi H, Tanemura M, Umeshita K, Doki Y, Mori M, Nagano H. PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection. Liver Int 2012; 32(1): 110–118PubMedCrossRefGoogle Scholar
  19. 19.
    Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17(1): 463–516PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 2006; 25(1): 9–34PubMedCrossRefGoogle Scholar
  21. 21.
    Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 2003; 63(5): 1138–1143PubMedGoogle Scholar
  22. 22.
    Yang S, Kim J, Ryu JH, Oh H, Chun CH, Kim BJ, Min BH, Chun JS. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 2010; 16(6): 687–693PubMedCrossRefGoogle Scholar
  23. 23.
    Fang JH, Zhou HC, Zeng C, Yang J, Liu Y, Huang X, Zhang JP, Guan XY, Zhuang SM. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology 2011; 54(5): 1729–1740PubMedCrossRefGoogle Scholar
  24. 24.
    Arii S, Mise M, Harada T, Furutani M, Ishigami S, Niwano M, Mizumoto M, Fukumoto M, Imamura M. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 1996; 24(2): 316–322PubMedCrossRefGoogle Scholar
  25. 25.
    Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, Schiraldi O, Antonaci S. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 2002; 97(4): 425–431PubMedCrossRefGoogle Scholar
  26. 26.
    Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133(1): 66–77PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr, Raman V, Zhen L, Mitzner WA, Sukumar S, Semenza GL. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 2012; 31(14): 1757–1770PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438(7069): 820–827PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    von Marschall Z, Cramer T, Höcker M, Finkenzeller G, Wiedenmann B, Rosewicz S. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 2001; 48(1): 87–96CrossRefGoogle Scholar
  30. 30.
    Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, Yanase K, Namisaki T, Kitade M, Yamazaki M, Tsujinoue H, Masaki T, Fukui H. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology 2004; 39(6): 1517–1524PubMedCrossRefGoogle Scholar
  31. 31.
    Coppola D, Szabo M, Boulware D, Muraca P, Alsarraj M, Chambers AF, Yeatman TJ. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res 2004; 10(1 Pt 1): 184–190PubMedCrossRefGoogle Scholar
  32. 32.
    Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9(4): 416–423PubMedCrossRefGoogle Scholar
  33. 33.
    Shevde LA, Das S, Clark DW, Samant RS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med 2010; 10(1): 71–81PubMedCrossRefGoogle Scholar
  34. 34.
    Liu LP, Ho RL, Chen GG, Lai PB. Sorafenib inhibits hypoxia-inducible factor-1alpha synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res 2012; 18(20): 5662–5671PubMedCrossRefGoogle Scholar
  35. 35.
    Lee TK, Poon RT, Yuen AP, Ling MT, Wang XH, Wong YC, Guan XY, Man K, Tang ZY, Fan ST. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res 2006; 12(23): 6910–6919PubMedCrossRefGoogle Scholar
  36. 36.
    Kadesch T (1993) Consequences of heteromeric interactions among helix-loop-helix proteins. Cell Growth Differ 1993; 4(1): 49–55PubMedGoogle Scholar
  37. 37.
    Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, Ren N, Qin LX. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology 2008; 48(6): 1834–1842PubMedCrossRefGoogle Scholar
  38. 38.
    Zhu Y, Denhardt DT, Cao H, Sutphin PD, Koong AC, Giaccia AJ, Le QT. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene 2005; 24(43): 6555–6563PubMedGoogle Scholar
  39. 39.
    Fu XY, Wang HY, Tan L, Liu SQ, Cao HF, Wu MC. Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. World J Gastroenterol 2002; 8(4): 638–643PubMedGoogle Scholar
  40. 40.
    Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 2000; 6(1): 96–99PubMedCrossRefGoogle Scholar
  41. 41.
    Fu J, Chen Y, Cao J, Luo T, Qian YW, Yang W, Ren YB, Su B, Cao GW, Yang Y, Yan YQ, Shen F, Wu MC, Feng GS, Wang HY. p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways. Hepatology 2011; 53(1): 181–192PubMedCrossRefGoogle Scholar
  42. 42.
    Liu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, Guo L, Zhang B, Lin Z, Liu J, Ren ZG, Ye QH, Xie Y. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology 2013; 58(2): 692–705PubMedCrossRefGoogle Scholar
  43. 43.
    Artinyan A, Nelson R, Soriano P, Chung V, Retseck J, Reynolds J, Marx H, Kim J, Wagman L Treatment response to transcatheter arterial embolization and chemoembolization in primary and metastatic tumors of the liver. HPB (Oxford) 2008; 10(6): 396–404CrossRefGoogle Scholar
  44. 44.
    Toyama T, Nitta N, Ohta S, Tanaka T, Nagatani Y, Takahashi M, Murata K, Shiomi H, Naka S, Kurumi Y, Tani T, Tabata Y. Clinical trial of cisplatin-conjugated gelatin microspheres for patients with hepatocellular carcinoma. Jpn J Radiol 2012; 30(1): 62–68PubMedCrossRefGoogle Scholar
  45. 45.
    Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359(9319): 1734–1739PubMedCrossRefGoogle Scholar
  46. 46.
    Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35(5): 1164–1171PubMedCrossRefGoogle Scholar
  47. 47.
    Woo HY, Jang JW, Choi JY, Bae SH, You CR, Rha SE, Lee YJ, Yoon SK, Lee CD. Tumor doubling time after initial response to transarterial chemoembolization in patients with hepatocellular carcinoma. Scand J Gastroenterol 2010; 45(3): 332–339PubMedCrossRefGoogle Scholar
  48. 48.
    Sun X, Jiang H, Jiang X, Tan H, Meng Q, Sun B, Xu R, Krissansen GW. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther 2009; 20(4): 314–324PubMedCrossRefGoogle Scholar
  49. 49.
    Brahimi-Horn MC, Chiche J, Pouysségur J. Hypoxia and cancer. J Mol Med (Berl) 2007; 85(12): 1301–1307CrossRefGoogle Scholar
  50. 50.
    Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragonés J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009; 136(5): 839–851PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Carmen Chak-Lui Wong
    • 1
  • Alan Ka-Lun Kai
    • 1
  • Irene Oi-Lin Ng
    • 1
  1. 1.The State Key Laboratory for Liver Research and Department of PathologyThe University of Hong KongHong KongChina

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