Skip to main content
SpringerLink
Log in

The impact of hypoxia in hepatocellular carcinoma metastasis

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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): 25–34

    Article  CAS  PubMed  Google Scholar 

  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): 378–390

    Article  CAS  PubMed  Google Scholar 

  3. Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007; 9(8): 1221–1235

    Article  CAS  PubMed  Google Scholar 

  4. Loboda A, Jozkowicz A, Dulak J. HIF-1 and HIF-2 transcription factors-similar but not identical. Mol Cells 2010; 29(5): 435–442

    Article  CAS  PubMed  Google Scholar 

  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): 1705–1708

    CAS  PubMed  Google Scholar 

  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): 108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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): 5463–5472

    Article  CAS  PubMed  Google Scholar 

  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): 5084–5094

    Article  PubMed  Google Scholar 

  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): 1028–1033

    Article  PubMed  Google Scholar 

  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): 11263–11270

    Article  CAS  PubMed  Google Scholar 

  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): 3176–3182

    CAS  PubMed  Google Scholar 

  12. Bangoura G, Yang LY, Huang GW, Wang W. Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World J Gastroenterol 2004; 10(4): 525–530

    CAS  PubMed  Google Scholar 

  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): 4278–4288

    Article  PubMed  Google Scholar 

  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): 910–919

    Article  CAS  PubMed  Google Scholar 

  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): 40967–40972

    Article  PubMed  Google Scholar 

  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): 1721–1732

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006; 124(2): 263–266

    Article  CAS  PubMed  Google Scholar 

  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): 110–118

    Article  CAS  PubMed  Google Scholar 

  19. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17(1): 463–516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 2006; 25(1): 9–34

    Article  CAS  PubMed  Google Scholar 

  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): 1138–1143

    CAS  PubMed  Google Scholar 

  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): 687–693

    Article  CAS  PubMed  Google Scholar 

  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): 1729–1740

    Article  CAS  PubMed  Google Scholar 

  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): 316–322

    Article  CAS  PubMed  Google Scholar 

  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): 425–431

    Article  CAS  PubMed  Google Scholar 

  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): 66–77

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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): 1757–1770

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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): 820–827

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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): 87–96

    Article  Google Scholar 

  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): 1517–1524

    Article  CAS  PubMed  Google Scholar 

  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): 184–190

    Article  CAS  PubMed  Google Scholar 

  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): 416–423

    Article  CAS  PubMed  Google Scholar 

  33. Shevde LA, Das S, Clark DW, Samant RS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med 2010; 10(1): 71–81

    Article  CAS  PubMed  Google Scholar 

  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): 5662–5671

    Article  CAS  PubMed  Google Scholar 

  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): 6910–6919

    Article  CAS  PubMed  Google Scholar 

  36. Kadesch T (1993) Consequences of heteromeric interactions among helix-loop-helix proteins. Cell Growth Differ 1993; 4(1): 49–55

    CAS  PubMed  Google Scholar 

  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): 1834–1842

    Article  CAS  PubMed  Google Scholar 

  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): 6555–6563

    CAS  PubMed  Google Scholar 

  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): 638–643

    CAS  PubMed  Google Scholar 

  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): 96–99

    Article  CAS  PubMed  Google Scholar 

  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): 181–192

    Article  CAS  PubMed  Google Scholar 

  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): 692–705

    Article  CAS  PubMed  Google Scholar 

  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): 396–404

    Article  Google Scholar 

  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): 62–68

    Article  CAS  PubMed  Google Scholar 

  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): 1734–1739

    Article  PubMed  Google Scholar 

  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): 1164–1171

    Article  CAS  PubMed  Google Scholar 

  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): 332–339

    Article  CAS  PubMed  Google Scholar 

  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): 314–324

    Article  CAS  PubMed  Google Scholar 

  49. Brahimi-Horn MC, Chiche J, Pouysségur J. Hypoxia and cancer. J Mol Med (Berl) 2007; 85(12): 1301–1307

    Article  Google Scholar 

  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): 839–851

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The State Key Laboratory for Liver Research and Department of Pathology, The University of Hong Kong, Hong Kong, China

    Carmen Chak-Lui Wong, Alan Ka-Lun Kai & Irene Oi-Lin Ng

Authors
  1. Carmen Chak-Lui Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Ka-Lun Kai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irene Oi-Lin Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Irene Oi-Lin Ng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, C.CL., Kai, A.KL. & Ng, I.OL. The impact of hypoxia in hepatocellular carcinoma metastasis. Front. Med. 8, 33–41 (2014). https://doi.org/10.1007/s11684-013-0301-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-013-0301-3

Keywords

Search

Navigation