The impact of hypoxia in hepatocellular carcinoma metastasis

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 secondar y 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)

References

[1] ChengAL, KangYK, ChenZ, TsaoCJ, QinS, KimJS, LuoR, FengJ, YeS, YangTS, XuJ, SunY, LiangH, LiuJ, WangJ, TakWY, PanH, BurockK, ZouJ, VoliotisD, GuanZ. 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 Oncol2009; 10(1): 25–34

[2] LlovetJM, RicciS, MazzaferroV, HilgardP, GaneE, BlancJF, de OliveiraAC, SantoroA, RaoulJL, FornerA, SchwartzM, PortaC, ZeuzemS, BolondiL, GretenTF, GallePR, SeitzJF, BorbathI, HäussingerD, GiannarisT, ShanM, MoscoviciM, VoliotisD, BruixJ; SHARP Investigators Study Group.Sorafenib in advanced hepatocellular carcinoma. N Engl J Med2008; 359(4): 378–390

[3] VaupelP, HöckelM, MayerA. Detection and characterization of tumor hypoxia using pO₂ histography. Antioxid Redox Signal2007; 9(8): 1221–1235

[4] LobodaA, JozkowiczA, DulakJ. HIF-1 and HIF-2 transcription factors—similar but not identical. Mol Cells2010; 29(5): 435–442

[5] HuangGW, YangLY, LuWQ. Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: Impact on neovascularization and survival. World J Gastroenterol2005; 11(11): 1705–1708

[6] ZhangL, HuangG, LiX, ZhangY, JiangY, ShenJ, LiuJ, WangQ, ZhuJ, FengX, DongJ, QianC. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor- 1α in hepatocellular carcinoma. BMC Cancer2013; 13(1): 108

[7] XiangZL, ZengZC, FanJ, TangZY, ZengHY, GaoDM. 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 Res2011; 17(16): 5463–5472

[8] MichaelsonJS, ChenLL, SilversteinMJ, CheongsiatmoyJA, MihmMC Jr, SoberAJ, TanabeKK, SmithBL, YoungerJ. Why cancer at the primary site and in the lymph nodes contributes to the risk of cancer death. Cancer2009; 115(21): 5084–5094

[9] XiaohongS, HuikaiL, FengW, TiZ, YunlongC, QiangL. Clinical significance of lymph node metastasis in patients undergoing partial hepatectomy for hepatocellular carcinoma. World J Surg2010; 34(5): 1028–1033

[10] TanakaH, YamamotoM, HashimotoN, MiyakoshiM, TamakawaS, YoshieM, TokusashiY, YokoyamaK, YaginumaY, OgawaK. Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res2006; 66(23): 11263–11270

[11] BangouraG, LiuZS, QianQ, JiangCQ, YangGF, JingS. Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol2007; 13(23): 3176–3182

[12] BangouraG, YangLY, HuangGW, WangW. Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World J Gastroenterol2004; 10(4): 525–530

[13] van MalensteinH, GevaertO, LibbrechtL, DaemenA, AllemeerschJ, NevensF, Van CutsemE, CassimanD, De MoorB, VerslypeC, van PeltJ. A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. Clin Cancer Res2010; 16(16): 4278–4288

[14] LiH, GeC, ZhaoF, YanM, HuC, JiaD, TianH, ZhuM, ChenT, JiangG, XieH, CuiY, GuJ, TuH, HeX, YaoM, LiuY, LiJ. 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. Hepatology2011; 54(3): 910–919

[15] van der SlotAJ, ZuurmondAM, BardoelAF, WijmengaC, PruijsHE, SillenceDO, BrinckmannJ, AbrahamDJ, BlackCM, VerzijlN, DeGrootJ, HanemaaijerR, TeKoppeleJM, HuizingaTW, BankRA. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem2003; 278(42): 40967–40972

[16] CoxTR, BirdD, BakerAM, BarkerHE, HoMW, LangG, ErlerJT. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res2013; 73(6): 1721–1732

[17] CondeelisJ, PollardJW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell2006; 124(2): 263–266

[18] NodaT, YamamotoH, TakemasaI, YamadaD, UemuraM, WadaH, KobayashiS, MarubashiS, EguchiH, TanemuraM, UmeshitaK, DokiY, MoriM, NaganoH. PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection. Liver Int2012; 32(1): 110–118

[19] SternlichtMD, WerbZ. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol2001; 17(1): 463–516

[20] DeryuginaEI, QuigleyJP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev2006; 25(1): 9–34

[21] KrishnamacharyB, Berg-DixonS, KellyB, AganiF, FeldserD, FerreiraG, IyerN, LaRuschJ, PakB, TaghaviP, SemenzaGL. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res2003; 63(5): 1138–1143

[22] YangS, KimJ, RyuJH, OhH, ChunCH, KimBJ, MinBH, ChunJS. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med2010; 16(6): 687–693

[23] FangJH, ZhouHC, ZengC, YangJ, LiuY, HuangX, ZhangJP, GuanXY, ZhuangSM. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology2011; 54(5): 1729–1740

[24] AriiS, MiseM, HaradaT, FurutaniM, IshigamiS, NiwanoM, MizumotoM, FukumotoM, ImamuraM. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology1996; 24(2): 316–322

[25] GiannelliG, BergaminiC, MarinosciF, FransveaE, QuarantaM, LupoL, SchiraldiO, AntonaciS. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer2002; 97(4): 425–431

[26] PaduaD, ZhangXH, WangQ, NadalC, GeraldWL, GomisRR, MassaguéJ. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell2008; 133(1): 66–77

[27] ZhangH, WongCC, WeiH, GilkesDM, KorangathP, ChaturvediP, SchitoL, ChenJ, KrishnamacharyB, WinnardPT Jr, RamanV, ZhenL, MitznerWA, SukumarS, SemenzaGL. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene2012; 31(14): 1757–1770

[28] KaplanRN, RibaRD, ZacharoulisS, BramleyAH, VincentL, CostaC, MacDonaldDD, JinDK, ShidoK, KernsSA, ZhuZ, HicklinD, WuY, PortJL, AltorkiN, PortER, RuggeroD, ShmelkovSV, JensenKK, RafiiS, LydenD. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature2005; 438(7069): 820–827

[29] von MarschallZ, CramerT, HöckerM, FinkenzellerG, WiedenmannB, RosewiczS. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut2001; 48(1): 87–96

[30] YoshijiH, KuriyamaS, YoshiiJ, IkenakaY, NoguchiR, HicklinDJ, WuY, YanaseK, NamisakiT, KitadeM, YamazakiM, TsujinoueH, MasakiT, FukuiH. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology2004; 39(6): 1517–1524

[31] CoppolaD, SzaboM, BoulwareD, MuracaP, AlsarrajM, ChambersAF, YeatmanTJ. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res2004; 10(1 Pt 1): 184–190

[32] YeQH, QinLX, ForguesM, HeP, KimJW, PengAC, SimonR, LiY, RoblesAI, ChenY, MaZC, WuZQ, YeSL, LiuYK, TangZY, WangXW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med2003; 9(4): 416–423

[33] ShevdeLA, DasS, ClarkDW, SamantRS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med2010; 10(1): 71–81

[34] LiuLP, HoRL, ChenGG, LaiPB. Sorafenib inhibits hypoxia-inducible factor-1alpha synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res2012; 18(20): 5662–5671

[35] LeeTK, PoonRT, YuenAP, LingMT, WangXH, WongYC, GuanXY, ManK, TangZY, FanST. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res2006; 12(23): 6910–6919

[36] KadeschT (1993) Consequences of heteromeric interactions among helix-loop-helix proteins. Cell Growth Differ1993; 4(1): 49–55

[37] SunBS, DongQZ, YeQH, SunHJ, JiaHL, ZhuXQ, LiuDY, ChenJ, XueQ, ZhouHJ, RenN, QinLX. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology2008; 48(6): 1834–1842

[38] ZhuY, DenhardtDT, CaoH, SutphinPD, KoongAC, GiacciaAJ, LeQT. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene2005; 24(43): 6555–6563

[39] FuXY, WangHY, TanL, LiuSQ, CaoHF, WuMC. Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. World J Gastroenterol2002; 8(4): 638–643

[40] HigashitsujiH, ItohK, NagaoT, DawsonS, NonoguchiK, KidoT, MayerRJ, AriiS, FujitaJ. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med2000; 6(1): 96–99

[41] FuJ, ChenY, CaoJ, LuoT, QianYW, YangW, RenYB, SuB, CaoGW, YangY, YanYQ, ShenF, WuMC, FengGS, WangHY. p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways. Hepatology2011; 53(1): 181–192

[42] LiuY, ZhangJB, QinY, WangW, WeiL, TengY, GuoL, ZhangB, LinZ, LiuJ, RenZG, YeQH, XieY. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology2013; 58(2): 692–705

[43] ArtinyanA, NelsonR, SorianoP, ChungV, RetseckJ, ReynoldsJ, MarxH, KimJ, 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

[44] ToyamaT, NittaN, OhtaS, TanakaT, NagataniY, TakahashiM, MurataK, ShiomiH, NakaS, KurumiY, TaniT, TabataY. Clinical trial of cisplatin-conjugated gelatin microspheres for patients with hepatocellular carcinoma. Jpn J Radiol2012; 30(1): 62–68

[45] LlovetJM, RealMI, MontañaX, PlanasR, CollS, AponteJ, AyusoC, SalaM, MuchartJ, SolàR, RodésJ, BruixJ; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet2002; 359(9319): 1734–1739

[46] LoCM, NganH, TsoWK, LiuCL, LamCM, PoonRT, FanST, WongJ. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology2002; 35(5): 1164–1171

[47] WooHY, JangJW, ChoiJY, BaeSH, YouCR, RhaSE, LeeYJ, YoonSK, LeeCD. Tumor doubling time after initial response to transarterial chemoembolization in patients with hepatocellular carcinoma. Scand J Gastroenterol2010; 45(3): 332–339

[48] SunX, JiangH, JiangX, TanH, MengQ, SunB, XuR, KrissansenGW. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther2009; 20(4): 314–324

[49] Brahimi-HornMC, ChicheJ, PouysségurJ. Hypoxia and cancer. J Mol Med (Berl)2007; 85(12): 1301–1307

[50] MazzoneM, DettoriD, Leite de OliveiraR, LogesS, SchmidtT, JonckxB, TianYM, LanahanAA, PollardP, Ruiz de AlmodovarC, De SmetF, VinckierS, AragonésJ, DebackereK, LuttunA, WynsS, JordanB, PisacaneA, GallezB, LampugnaniMG, DejanaE, SimonsM, RatcliffeP, MaxwellP, CarmelietP. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell2009; 136(5): 839–851

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