Skip to main content

Advertisement

SpringerLink
Log in

Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy

  • Review
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BMP-7:

Bone morphogenetic protein 7

CAF:

Cancer-associated fibroblast

CCL22:

Chemokine C–C motif chemokine 22

CSC:

Cancer stem cell

CTC:

Circulating tumor cell

CXCR4:

Chemokine receptor 4

DEG:

Differentially expressed gene

DNMT1:

DNA methyltransferase 1

ECM:

Extracellular matrix

EDIL3:

EGF like repeats and discoidin I like domains protein 3

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

EpCAM:

Epithelial cell adhesion molecule

EZH2:

Enhancer of zeste homolog 2

FAK:

Focal adhesion kinase

FAM83D:

Family with sequence similarity 83, member D

HAIC:

Hepatic arterial infusion chemotherapy

HBx:

Hepatitis B virus X protein

HCC:

Hepatocellular carcinoma

HIF-1α:

Hypoxia-inducible factor 1α

HMGB1:

High mobility group box 1

HPSE:

Heparinise

HUVEC:

Human umbilical vein endothelial cell

ICAM-1:

Intercellular adhesion molecule-1

ICR:

ICAM-1–Related Noncoding RNA

IDO:

Indoleamine 2,3-dioxygenase

IL-6:

Interleukin 6

ITGA5:

Integrin subunit alpha 5

KITLG:

KIT proto-oncogene ligand

LOXL2:

Lysyl oxidase-like 2

MAPK:

Mitogen-activated protein kinases

MDSC:

Marrow-derived immature myeloid cell

MMP:

Matrix metalloproteinase

MT1X:

Metallothionein 1X

NET:

Neutrophils extracellular trap

PCBP1:

Poly C binding protein 1

PVTT:

Portal vein tumor thrombosis

P4HA2:

Prolyl-4-hydroxylase alpha subunit 2

RMP:

RNA polymerase II subunit 5-mediating protein

SBRT:

Stereotactic body radiotherapy

SDC-1:

Syndecan-1

SDF-1:

Stromal cell-derived factor-1

SLA:

Sialyl Lewis A

SPP1:

Secreted phosphoprotein 1

TACE:

Transarterial chemoembolization

TAM:

Tumor-associated macrophage

TARE:

Transarterial radioembolization

TEN:

Tumor entrained neutrophil

TGF-β:

Transforming growth factor-beta

TLR4:

Toll-like receptor 4

TNF:

Tumor necrosis factor

Treg:

Regulatory T cell

VEGF-A:

Vascular endothelial growth factor A

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660

    Article  Google Scholar 

  2. McGlynn KA, Petrick JL, El-Serag HB (2021) Epidemiology of hepatocellular carcinoma. Hepatology 73(Suppl 1):4–13. https://doi.org/10.1002/hep.31288

    Article  CAS  Google Scholar 

  3. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M et al (2016) Hepatocellular carcinoma. Nat Rev Dis Primers 2:16018. https://doi.org/10.1038/nrdp.2016.18

    Article  Google Scholar 

  4. Lau WY, Sangro B, Chen PJ, Cheng SQ, Chow P, Lee RC et al (2013) Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology 84(5):311–318. https://doi.org/10.1159/000348325

    Article  CAS  Google Scholar 

  5. Wang JC, Xia AL, Xu Y, Lu XJ (2019) Comprehensive treatments for hepatocellular carcinoma with portal vein tumor thrombosis. J Cell Physiol 234(2):1062–1070. https://doi.org/10.1002/jcp.27324

    Article  CAS  Google Scholar 

  6. Lin DX, Zhang QY, Li X, Ye QW, Lin F, Li LL (2011) An aggressive approach leads to improved survival in hepatocellular carcinoma patients with portal vein tumor thrombus. J Cancer Res Clin Oncol 137(1):139–149. https://doi.org/10.1007/s00432-010-0868-x

    Article  CAS  Google Scholar 

  7. Sun JX, Shi J, Li N, Guo WX, Wu MC, Lau WY et al (2016) Portal vein tumor thrombus is a bottleneck in the treatment of hepatocellular carcinoma. Cancer Biol Med 13(4):452–458. https://doi.org/10.20892/j.issn.2095-3941.2016.0059

    Article  Google Scholar 

  8. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC et al (2003) Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 9(4):416–423. https://doi.org/10.1038/nm843

    Article  CAS  Google Scholar 

  9. Zhang J, Pan YF, Ding ZW, Yang GZ, Tan YX, Yang C et al (2015) RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription. Oncogene 34(12):1575–1583. https://doi.org/10.1038/onc.2014.84

    Article  CAS  Google Scholar 

  10. Li N, Guo W, Shi J, Xue J, Hu H, Xie D et al (2010) Expression of the chemokine receptor CXCR4 in human hepatocellular carcinoma and its role in portal vein tumor thrombus. J Exp Clin Cancer Res 29(1):156. https://doi.org/10.1186/1756-9966-29-156

    Article  CAS  Google Scholar 

  11. Xue TC, Chen RX, Han D, Chen J, Xue Q, Gao DM et al (2012) Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential. Exp Ther Med 3(1):117–123. https://doi.org/10.3892/etm.2011.358

    Article  CAS  Google Scholar 

  12. Liu S, Guo W, Shi J, Li N, Yu X, Xue J et al (2012) MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol 56(2):389–396. https://doi.org/10.1016/j.jhep.2011.08.008

    Article  CAS  Google Scholar 

  13. Zhuang L, Xu L, Wang P, Meng Z (2015) Serum miR-128-2 serves as a prognostic marker for patients with hepatocellular carcinoma. PLoS ONE 10(2):e0117274. https://doi.org/10.1371/journal.pone.0117274

    Article  CAS  Google Scholar 

  14. Ji J, Rong Y, Luo CL, Li S, Jiang X, Weng H et al (2018) Up-regulation of hsa-miR-210 promotes venous metastasis and predicts poor prognosis in hepatocellular carcinoma. Front Oncol 8:569. https://doi.org/10.3389/fonc.2018.00569

    Article  Google Scholar 

  15. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S et al (2012) TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 22(3):291–303. https://doi.org/10.1016/j.ccr.2012.07.023

    Article  CAS  Google Scholar 

  16. Wang W, Lin H, Zhou L, Zhu Q, Gao S, Xie H et al (2014) MicroRNA-30a-3p inhibits tumor proliferation, invasiveness and metastasis and is downregulated in hepatocellular carcinoma. Eur J Surg Oncol 40(11):1586–1594. https://doi.org/10.1016/j.ejso.2013.11.008

    Article  CAS  Google Scholar 

  17. Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM (2014) MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting met/snail signaling. Oncogene 33(31):4069–4076. https://doi.org/10.1038/onc.2013.369

    Article  CAS  Google Scholar 

  18. Wu G, Zheng K, Xia S, Wang Y, Meng X, Qin X et al (2016) MicroRNA-655-3p functions as a tumor suppressor by regulating ADAM10 and beta-catenin pathway in hepatocellular carcinoma. J Exp Clin Cancer Res 35(1):89. https://doi.org/10.1186/s13046-016-0368-1

    Article  CAS  Google Scholar 

  19. Wang J, Wu S, Huang T (2018) Expression and role of VEGFA and miR-381 in portal vein tumor thrombi in patients with hepatocellular carcinoma. Exp Ther Med 15(6):5450–5456. https://doi.org/10.3892/etm.2018.6129

    Article  CAS  Google Scholar 

  20. Yuan W, Li F (2020) Roles of microRNA-186 and vascular endothelial growth factor in hepatocellular carcinoma complicated with portal vein tumor thrombus. Exp Ther Med 20(4):3860–3867. https://doi.org/10.3892/etm.2020.9092

    Article  CAS  Google Scholar 

  21. Zhang T, Cao C, Wu D, Liu L (2016) SNHG3 correlates with malignant status and poor prognosis in hepatocellular carcinoma. Tumour Biol 37(2):2379–2385. https://doi.org/10.1007/s13277-015-4052-4

    Article  CAS  Google Scholar 

  22. Guo W, Liu S, Cheng Y, Lu L, Shi J, Xu G et al (2016) ICAM-1-related noncoding RNA in cancer stem cells maintains ICAM-1 expression in hepatocellular carcinoma. Clin Cancer Res 22(8):2041–2050. https://doi.org/10.1158/1078-0432.Ccr-14-3106

    Article  CAS  Google Scholar 

  23. Xiao C, Wang C, Cheng S, Lai C, Zhang P, Wang Z et al (2016) The significance of low levels of LINC RP1130-1 expression in human hepatocellular carcinoma. Biosci Trends 10(5):378–385. https://doi.org/10.5582/bst.2016.01123

    Article  CAS  Google Scholar 

  24. Li Y, Guo D, Zhao Y, Ren M, Lu G, Wang Y et al (2018) Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-26a-5p/GSK3beta signal pathway. Cell Death Dis 9(9):888. https://doi.org/10.1038/s41419-018-0882-5

    Article  CAS  Google Scholar 

  25. Li M, Wei L, Liu PY, Zhang XM, Liu F, Yang F et al (2021) Lnc-ATG9B-4 aggravates progress of hepatocellular carcinoma through cell proliferation and migration by upregulating CDK5. Exp Biol Med (Maywood) 246(2):177–186. https://doi.org/10.1177/1535370220963197

    Article  CAS  Google Scholar 

  26. Qiu Z, Wang G, Yang G, Wang G, Jiang W, Chen Z et al (2021) Transcriptome sequencing-based personalized analysis of hepatocellular carcinoma patients with portal vein tumor thrombus. J Gastrointest Oncol 12(2):795–805. https://doi.org/10.21037/jgo-21-162

    Article  Google Scholar 

  27. Chang L, Li C, Lan T, Wu L, Yuan Y, Liu Q et al (2016) Decreased expression of long non-coding RNA GAS5 indicates a poor prognosis and promotes cell proliferation and invasion in hepatocellular carcinoma by regulating vimentin. Mol Med Rep 13(2):1541–1550. https://doi.org/10.3892/mmr.2015.4716

    Article  CAS  Google Scholar 

  28. Lin X, Xiaoqin H, Jiayu C, Li F, Yue L, Ximing X (2019) Long non-coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen-activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma. Hepatol Res 49(8):902–918. https://doi.org/10.1111/hepr.13344

    Article  CAS  Google Scholar 

  29. Lin B, He H, Zhang Q, Zhang J, Xu L, Zhou L et al (2020) Long non-coding RNA00844 inhibits MAPK signaling to suppress the progression of hepatocellular carcinoma by targeting AZGP1. Ann Transl Med 8(21):1365. https://doi.org/10.21037/atm-20-3848

    Article  CAS  Google Scholar 

  30. Yang Y, Chen L, Gu J, Zhang H, Yuan J, Lian Q et al (2017) Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun 8:14421. https://doi.org/10.1038/ncomms14421

    Article  CAS  Google Scholar 

  31. Song LN, Qiao GL, Yu J, Yang CM, Chen Y, Deng ZF et al (2020) Hsa_circ_0003998 promotes epithelial to mesenchymal transition of hepatocellular carcinoma by sponging miR-143-3p and PCBP1. J Exp Clin Cancer Res 39(1):114. https://doi.org/10.1186/s13046-020-01576-0

    Article  CAS  Google Scholar 

  32. Fan H, Chen L, Zhang F, Quan Y, Su X, Qiu X et al (2012) MTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma. Oncogene 31(18):2298–2308. https://doi.org/10.1038/onc.2011.411

    Article  CAS  Google Scholar 

  33. Huang XY, Huang ZL, Xu B, Chen Z, Re TJ, Zheng Q et al (2016) Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma. J Exp Clin Cancer Res 35(1):85. https://doi.org/10.1186/s13046-016-0361-8

    Article  CAS  Google Scholar 

  34. Xia L, Huang W, Tian D, Zhu H, Zhang Y, Hu H et al (2012) Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. J Hepatol 57(3):600–612. https://doi.org/10.1016/j.jhep.2012.04.020

    Article  CAS  Google Scholar 

  35. Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2(2):76–83. https://doi.org/10.1038/35000025

    Article  CAS  Google Scholar 

  36. Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A et al (2008) Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47(3):897–907. https://doi.org/10.1002/hep.22160

    Article  CAS  Google Scholar 

  37. Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J (2010) miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis 31(5):766–776. https://doi.org/10.1093/carcin/bgp250

    Article  CAS  Google Scholar 

  38. Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP et al (2012) The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 61(2):278–289. https://doi.org/10.1136/gut.2011.239145

    Article  CAS  Google Scholar 

  39. Jiang H, Cao HJ, Ma N, Bao WD, Wang JJ, Chen TW et al (2020) Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis. Proc Natl Acad Sci USA 117(9):4770–4780. https://doi.org/10.1073/pnas.1914937117

    Article  CAS  Google Scholar 

  40. Lee E, Wang J, Yumoto K, Jung Y, Cackowski FC, Decker AM et al (2016) DNMT1 regulates epithelial-mesenchymal transition and cancer stem cells, which promotes prostate cancer metastasis. Neoplasia 18(9):553–566. https://doi.org/10.1016/j.neo.2016.07.007

    Article  CAS  Google Scholar 

  41. Liao W, Liu W, Liu X, Yuan Q, Ou Y, Qi Y et al (2015) Upregulation of FAM83D affects the proliferation and invasion of hepatocellular carcinoma. Oncotarget 6(27):24132–24147. https://doi.org/10.18632/oncotarget.4432

    Article  Google Scholar 

  42. Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO et al (2012) Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology 56(2):622–631. https://doi.org/10.1002/hep.25679

    Article  CAS  Google Scholar 

  43. Yamashita T, Wang XW (2013) Cancer stem cells in the development of liver cancer. J Clin Invest 123(5):1911–1918. https://doi.org/10.1172/JCI66024

    Article  CAS  Google Scholar 

  44. Liu YC, Yeh CT, Lin KH (2020) Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells. https://doi.org/10.3390/cells9061331

    Article  Google Scholar 

  45. Hu B, Xu Y, Li YC, Huang JF, Cheng JW, Guo W et al (2020) CD13 promotes hepatocellular carcinogenesis and sorafenib resistance by activating HDAC5-LSD1-NF-kappaB oncogenic signaling. Clin Transl Med 10(8):e233. https://doi.org/10.1002/ctm2.233

    Article  CAS  Google Scholar 

  46. Inagaki Y, Tang W, Zhang L, Du G, Xu W, Kokudo N (2010) Novel aminopeptidase N (APN/CD13) inhibitor 24F can suppress invasion of hepatocellular carcinoma cells as well as angiogenesis. Biosci Trends 4(2):56–60

    CAS  Google Scholar 

  47. Sun L, Zhang L, Chen J, Li C, Sun H, Wang J et al (2020) Activation of tyrosine metabolism in CD13+ cancer stem cells drives relapse in hepatocellular carcinoma. Cancer Res Treat 52(2):604–621. https://doi.org/10.4143/crt.2019.444

    Article  CAS  Google Scholar 

  48. Yamashita M, Wada H, Eguchi H, Ogawa H, Yamada D, Noda T et al (2016) A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma. Int J Oncol 49(1):89–98. https://doi.org/10.3892/ijo.2016.3496

    Article  CAS  Google Scholar 

  49. Zhao Y, Wu H, Xing X, Ma Y, Ji S, Xu X et al (2020) CD13 Induces autophagy to promote hepatocellular carcinoma cell chemoresistance through the P38/Hsp27/CREB/ATG7 pathway. J Pharmacol Exp Ther 374(3):512–520. https://doi.org/10.1124/jpet.120.265637

    Article  CAS  Google Scholar 

  50. Toshiyama R, Konno M, Eguchi H, Takemoto H, Noda T, Asai A et al (2019) Poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells. Oncogene 38(2):244–260. https://doi.org/10.1038/s41388-018-0406-x

    Article  CAS  Google Scholar 

  51. Wu J, Zhu P, Lu T, Du Y, Wang Y, He L et al (2019) The long non-coding RNA LncHDAC2 drives the self-renewal of liver cancer stem cells via activation of hedgehog signaling. J Hepatol 70(5):918–929. https://doi.org/10.1016/j.jhep.2018.12.015

    Article  CAS  Google Scholar 

  52. Sun ZP, Zhang J, Shi LH, Zhang XR, Duan Y, Xu WF et al (2015) Aminopeptidase N inhibitor 4cc synergizes antitumor effects of 5-fluorouracil on human liver cancer cells through ROS-dependent CD13 inhibition. Biomed Pharmacother 76:65–72. https://doi.org/10.1016/j.biopha.2015.10.023

    Article  CAS  Google Scholar 

  53. Zhai M, Yang Z, Zhang C, Li J, Jia J, Zhou L et al (2020) APN-mediated phosphorylation of BCKDK promotes hepatocellular carcinoma metastasis and proliferation via the ERK signaling pathway. Cell Death Dis 11(5):396. https://doi.org/10.1038/s41419-020-2610-1

    Article  CAS  Google Scholar 

  54. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO (2011) CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 9(1):50–63. https://doi.org/10.1016/j.stem.2011.06.005

    Article  CAS  Google Scholar 

  55. Han Y, Sun F, Zhang X, Wang T, Jiang J, Cai J et al (2019) CD24 targeting bi-specific antibody that simultaneously stimulates NKG2D enhances the efficacy of cancer immunotherapy. J Cancer Res Clin Oncol 145(5):1179–1190. https://doi.org/10.1007/s00432-019-02865-8

    Article  CAS  Google Scholar 

  56. Lu S, Yao Y, Xu G, Zhou C, Zhang Y, Sun J et al (2018) CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis 9(6):646. https://doi.org/10.1038/s41419-018-0681-z

    Article  CAS  Google Scholar 

  57. He H, Tu X, Zhang J, Acheampong DO, Ding L, Ma Z et al (2015) A novel antibody targeting CD24 and hepatocellular carcinoma in vivo by near-infrared fluorescence imaging. Immunobiology 220(12):1328–1336. https://doi.org/10.1016/j.imbio.2015.07.010

    Article  CAS  Google Scholar 

  58. Wang R, Li Y, Tsung A, Huang H, Du Q, Yang M et al (2018) iNOS promotes CD24(+)CD133(+) liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci USA 115(43):E10127–E10136. https://doi.org/10.1073/pnas.1722100115

    Article  CAS  Google Scholar 

  59. Han Z, Zhu S, Han X, Wang Z, Wu S, Zheng R (2015) Baicalein inhibits hepatocellular carcinoma cells through suppressing the expression of CD24. Int Immunopharmacol 29(2):416–422. https://doi.org/10.1016/j.intimp.2015.10.021

    Article  CAS  Google Scholar 

  60. Wan X, Cheng C, Shao Q, Lin Z, Lu S, Chen Y (2016) CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment. Tumour Biol 37(5):6073–6084. https://doi.org/10.1007/s13277-015-4442-7

    Article  CAS  Google Scholar 

  61. Ma Z, He H, Sun F, Xu Y, Huang X, Ma Y et al (2017) Selective targeted delivery of doxorubicin via conjugating to anti-CD24 antibody results in enhanced antitumor potency for hepatocellular carcinoma both in vitro and in vivo. J Cancer Res Clin Oncol 143(10):1929–1940. https://doi.org/10.1007/s00432-017-2436-0

    Article  CAS  Google Scholar 

  62. Yang Y, Hou J, Lin Z, Zhuo H, Chen D, Zhang X et al (2014) Attenuated listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells. Cell Mol Immunol 11(2):184–196. https://doi.org/10.1038/cmi.2013.64

    Article  CAS  Google Scholar 

  63. Sun F, Wang T, Jiang J, Wang Y, Ma Z, Li Z et al (2017) Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design. Oncotarget 8(31):51238–51252. https://doi.org/10.18632/oncotarget.17228

    Article  Google Scholar 

  64. Asai R, Tsuchiya H, Amisaki M, Makimoto K, Takenaga A, Sakabe T et al (2019) CD44 standard isoform is involved in maintenance of cancer stem cells of a hepatocellular carcinoma cell line. Cancer Med 8(2):773–782. https://doi.org/10.1002/cam4.1968

    Article  CAS  Google Scholar 

  65. Wang L, Su W, Liu Z, Zhou M, Chen S, Chen Y et al (2012) CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma. Biomaterials 33(20):5107–5114. https://doi.org/10.1016/j.biomaterials.2012.03.067

    Article  CAS  Google Scholar 

  66. Lee D, Na J, Ryu J, Kim HJ, Nam SH, Kang M et al (2015) Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells. Hepatology 61(6):1978–1997. https://doi.org/10.1002/hep.27721

    Article  CAS  Google Scholar 

  67. Dhar D, Antonucci L, Nakagawa H, Kim JY, Glitzner E, Caruso S et al (2018) Liver cancer initiation requires p53 inhibition by CD44-enhanced growth factor signaling. Cancer Cell 33(6):1061–77 e6. https://doi.org/10.1016/j.ccell.2018.05.003

    Article  CAS  Google Scholar 

  68. Fan Z, Xia H, Xu H, Ma J, Zhou S, Hou W et al (2018) Standard CD44 modulates YAP1 through a positive feedback loop in hepatocellular carcinoma. Biomed Pharmacother 103:147–156. https://doi.org/10.1016/j.biopha.2018.03.042

    Article  CAS  Google Scholar 

  69. Park NR, Cha JH, Jang JW, Bae SH, Jang B, Kim JH et al (2016) Synergistic effects of CD44 and TGF-beta1 through AKT/GSK-3beta/beta-catenin signaling during epithelial-mesenchymal transition in liver cancer cells. Biochem Biophys Res Commun 477(4):568–574. https://doi.org/10.1016/j.bbrc.2016.06.077

    Article  CAS  Google Scholar 

  70. Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H et al (2012) CD44s regulates the TGF-beta-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res 72(13):3414–3423. https://doi.org/10.1158/0008-5472.CAN-12-0299

    Article  CAS  Google Scholar 

  71. Okabe H, Ishimoto T, Mima K, Nakagawa S, Hayashi H, Kuroki H et al (2014) CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma. Br J Cancer 110(4):958–966. https://doi.org/10.1038/bjc.2013.759

    Article  CAS  Google Scholar 

  72. Lee D, Lee JW (2015) Self-renewal and circulating capacities of metastatic hepatocarcinoma cells required for collaboration between TM4SF5 and CD44. BMB Rep 48(3):127–128. https://doi.org/10.5483/bmbrep.2015.48.3.047

    Article  CAS  Google Scholar 

  73. Lee TK, Cheung VC, Lu P, Lau EY, Ma S, Tang KH et al (2014) Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60(1):179–191. https://doi.org/10.1002/hep.27070

    Article  CAS  Google Scholar 

  74. Rodriguez MM, Fiore E, Bayo J, Atorrasagasti C, Garcia M, Onorato A et al (2018) 4Mu decreases CD47 expression on hepatic cancer stem cells and primes a potent antitumor T cell response induced by interleukin-12. Mol Ther 26(12):2738–2750. https://doi.org/10.1016/j.ymthe.2018.09.012

    Article  CAS  Google Scholar 

  75. Du K, Li Y, Liu J, Chen W, Wei Z, Luo Y et al (2021) A bispecific antibody targeting GPC3 and CD47 induced enhanced antitumor efficacy against dual antigen-expressing HCC. Mol Ther 29(4):1572–1584. https://doi.org/10.1016/j.ymthe.2021.01.006

    Article  CAS  Google Scholar 

  76. Xiao Z, Chung H, Banan B, Manning PT, Ott KC, Lin S et al (2015) Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett 360(2):302–309. https://doi.org/10.1016/j.canlet.2015.02.036

    Article  CAS  Google Scholar 

  77. Lo J, Lau EY, So FT, Lu P, Chan VS, Cheung VC et al (2016) Anti-CD47 antibody suppresses tumour growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma. Liver Int 36(5):737–745. https://doi.org/10.1111/liv.12963

    Article  CAS  Google Scholar 

  78. Zhang X, Wu L, Xu Y, Yu H, Chen Y, Zhao H et al (2020) Microbiota-derived SSL6 enhances the sensitivity of hepatocellular carcinoma to sorafenib by down-regulating glycolysis. Cancer Lett 481:32–44. https://doi.org/10.1016/j.canlet.2020.03.027

    Article  CAS  Google Scholar 

  79. Luo J, Wang P, Wang R, Wang J, Liu M, Xiong S et al (2016) The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma. Oncotarget 7(8):9525–9537. https://doi.org/10.18632/oncotarget.6672

    Article  Google Scholar 

  80. Yang R, An LY, Miao QF, Li FM, Han Y, Wang HX et al (2016) Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes. Oncotarget 7(24):35894–35916. https://doi.org/10.18632/oncotarget.9116

    Article  Google Scholar 

  81. Zhang K, Che S, Su Z, Zheng S, Zhang H, Yang S et al (2018) CD90 promotes cell migration, viability and sphereforming ability of hepatocellular carcinoma cells. Int J Mol Med 41(2):946–954. https://doi.org/10.3892/ijmm.2017.3314

    Article  CAS  Google Scholar 

  82. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P et al (2008) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13(2):153–166. https://doi.org/10.1016/j.ccr.2008.01.013

    Article  CAS  Google Scholar 

  83. Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y et al (2018) CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology 7(7):e1440169. https://doi.org/10.1080/2162402X.2018.1440169

    Article  Google Scholar 

  84. Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY (2008) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27(12):1749–1758. https://doi.org/10.1038/sj.onc.1210811

    Article  CAS  Google Scholar 

  85. Zhou G, Da Won BS, Nguyen R, Huo X, Han S, Zhang Z et al (2021) An aptamer-based drug delivery agent (CD133-apt-Dox) selectively and effectively kills liver cancer stem-like cells. Cancer Lett 501:124–132. https://doi.org/10.1016/j.canlet.2020.12.022

    Article  CAS  Google Scholar 

  86. Jang JW, Song Y, Kim SH, Kim JS, Kim KM, Choi EK et al (2017) CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma. Cancer Lett 389:1–10. https://doi.org/10.1016/j.canlet.2016.12.023

    Article  CAS  Google Scholar 

  87. Kohga K, Tatsumi T, Takehara T, Tsunematsu H, Shimizu S, Yamamoto M et al (2010) Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol 52(6):872–879. https://doi.org/10.1016/j.jhep.2009.12.030

    Article  CAS  Google Scholar 

  88. Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM et al (2012) CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology 55(3):807–820. https://doi.org/10.1002/hep.24739

    Article  CAS  Google Scholar 

  89. Piao LS, Hur W, Kim TK, Hong SW, Kim SW, Choi JE et al (2012) CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett 315(2):129–137. https://doi.org/10.1016/j.canlet.2011.10.012

    Article  CAS  Google Scholar 

  90. Hagiwara S, Kudo M, Nagai T, Inoue T, Ueshima K, Nishida N et al (2012) Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer 106(12):1997–2003. https://doi.org/10.1038/bjc.2012.145

    Article  CAS  Google Scholar 

  91. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY et al (2009) EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136(3):1012–1024. https://doi.org/10.1053/j.gastro.2008.12.004

    Article  CAS  Google Scholar 

  92. Zhang P, Shi B, Gao H, Jiang H, Kong J, Yan J et al (2014) An EpCAM/CD3 bispecific antibody efficiently eliminates hepatocellular carcinoma cells with limited galectin-1 expression. Cancer Immunol Immunother 63(2):121–132. https://doi.org/10.1007/s00262-013-1497-4

    Article  CAS  Google Scholar 

  93. Park DJ, Sung PS, Kim JH, Lee GW, Jang JW, Jung ES et al (2020) EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer. https://doi.org/10.1136/jitc-2019-000301

    Article  Google Scholar 

  94. Ogawa K, Tanaka S, Matsumura S, Murakata A, Ban D, Ochiai T et al (2014) EpCAM-targeted therapy for human hepatocellular carcinoma. Ann Surg Oncol 21(4):1314–1322. https://doi.org/10.1245/s10434-013-3430-7

    Article  Google Scholar 

  95. Khosla R, Rastogi A, Ramakrishna G, Pamecha V, Mukhopadhyay A, Vasudevan M et al (2017) EpCAM+ liver cancer stem-like cells exhibiting autocrine Wnt signaling potentially originate in cirrhotic patients. Stem Cells Transl Med 6(3):807–818. https://doi.org/10.1002/sctm.16-0248

    Article  CAS  Google Scholar 

  96. Choi YJ, Park SJ, Park YS, Park HS, Yang KM, Heo K (2018) EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells. PLoS ONE 13(1):e0190638. https://doi.org/10.1371/journal.pone.0190638

    Article  CAS  Google Scholar 

  97. Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX et al (2008) Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68(11):4287–4295. https://doi.org/10.1158/0008-5472.CAN-07-6691

    Article  CAS  Google Scholar 

  98. Yang W, Wang C, Lin Y, Liu Q, Yu LX, Tang L et al (2012) OV6(+) tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma. J Hepatol 57(3):613–620. https://doi.org/10.1016/j.jhep.2012.04.024

    Article  CAS  Google Scholar 

  99. Qi LN, Ma L, Wu FX, Chen YY, Xing WT, Jiang ZJ et al (2021) S100P as a novel biomarker of microvascular invasion and portal vein tumor thrombus in hepatocellular carcinoma. Hepatol Int 15(1):114–126. https://doi.org/10.1007/s12072-020-10130-1

    Article  Google Scholar 

  100. Zhao RC, Zhou J, Chen KF, Gong J, Liu J, He JY et al (2016) The prognostic value of combination of CD90 and OCT4 for hepatocellular carcinoma after curative resection. Neoplasma 63(2):288–298. https://doi.org/10.4149/neo_2016_036

    Article  CAS  Google Scholar 

  101. Hinshaw DC, Shevde LA (2019) The tumor microenvironment innately modulates cancer progression. Cancer Res 79(18):4557–4566. https://doi.org/10.1158/0008-5472.CAN-18-3962

    Article  CAS  Google Scholar 

  102. Lu C, Rong D, Zhang B, Zheng W, Wang X, Chen Z et al (2019) Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol Cancer 18(1):130. https://doi.org/10.1186/s12943-019-1047-6

    Article  CAS  Google Scholar 

  103. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA et al (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10(2):99–111. https://doi.org/10.1016/j.ccr.2006.06.016

    Article  CAS  Google Scholar 

  104. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S et al (2012) TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 22(3):291–303. https://doi.org/10.1016/j.ccr.2012.07.023

    Article  CAS  Google Scholar 

  105. Chen J, Shi X, Luo T, Zhao Y, Ye J, Bai T et al (2020) The correlations between hepatitis B virus infection and hepatocellular carcinoma with portal vein tumor thrombus or extrahepatic metastasis. Eur J Gastroenterol Hepatol 32(3):373–377. https://doi.org/10.1097/meg.0000000000001514

    Article  CAS  Google Scholar 

  106. Yan W, Liu X, Ma H, Zhang H, Song X, Gao L et al (2015) Tim-3 fosters HCC development by enhancing TGF-beta-mediated alternative activation of macrophages. Gut 64(10):1593–1604. https://doi.org/10.1136/gutjnl-2014-307671

    Article  CAS  Google Scholar 

  107. Ning J, Ye Y, Bu D, Zhao G, Song T, Liu P et al (2021) Imbalance of TGF-beta1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness. Mol Ther 29(6):2067–2087. https://doi.org/10.1016/j.ymthe.2021.02.016

    Article  CAS  Google Scholar 

  108. Jiang J, Wang GZ, Wang Y, Huang HZ, Li WT, Qu XD (2018) Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res 367(1):81–88. https://doi.org/10.1016/j.yexcr.2018.03.025

    Article  CAS  Google Scholar 

  109. Tang Y, Liu S, Li N, Guo W, Shi J, Yu H et al (2016) 14–3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α. Oncotarget 7(13):15854–15867. https://doi.org/10.18632/oncotarget.7493

    Article  Google Scholar 

  110. Rofstad EK, Gaustad JV, Egeland TA, Mathiesen B, Galappathi K (2010) Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer 127(7):1535–1546. https://doi.org/10.1002/ijc.25176

    Article  CAS  Google Scholar 

  111. Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF et al (2016) Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res 76(4):818–830. https://doi.org/10.1158/0008-5472.Can-15-0977

    Article  CAS  Google Scholar 

  112. Hu B, Tang WG, Fan J, Xu Y, Sun HX (2018) Differentially expressed miRNAs in hepatocellular carcinoma cells under hypoxic conditions are associated with transcription and phosphorylation. Oncol Lett 15(1):467–474. https://doi.org/10.3892/ol.2017.7349

    Article  CAS  Google Scholar 

  113. Wong CM, Wong CC, Lee JM, Fan DN, Au SL, Ng IO (2012) Sequential alterations of microRNA expression in hepatocellular carcinoma development and venous metastasis. Hepatology 55(5):1453–1461. https://doi.org/10.1002/hep.25512

    Article  CAS  Google Scholar 

  114. Wei X, Li N, Li S, Shi J, Guo W, Zheng Y et al (2017) Hepatitis B virus infection and active replication promote the formation of vascular invasion in hepatocellular carcinoma. BMC Cancer 17(1):304. https://doi.org/10.1186/s12885-017-3293-6

    Article  CAS  Google Scholar 

  115. Li Z, Lei Z, Xia Y, Li J, Wang K, Zhang H et al (2018) Association of preoperative antiviral treatment with incidences of microvascular invasion and early tumor recurrence in hepatitis B virus-related hepatocellular carcinoma. JAMA Surg 153(10):e182721. https://doi.org/10.1001/jamasurg.2018.2721

    Article  Google Scholar 

  116. Zhang C, Gao Y, Du C, Markowitz GJ, Fu J, Zhang Z et al (2021) Hepatitis B-induced IL8 promotes hepatocellular carcinoma venous metastasis and intrahepatic treg accumulation. Cancer Res 81(9):2386–2398. https://doi.org/10.1158/0008-5472.CAN-20-3453

    Article  CAS  Google Scholar 

  117. Chung TW, Kim SJ, Choi HJ, Song KH, Jin UH, Yu DY et al (2014) Hepatitis B virus X protein specially regulates the sialyl lewis a synthesis among glycosylation events for metastasis. Mol Cancer 13:222. https://doi.org/10.1186/1476-4598-13-222

    Article  CAS  Google Scholar 

  118. Paoli P, Giannoni E, Chiarugi P (2013) Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta 1833(12):3481–3498. https://doi.org/10.1016/j.bbamcr.2013.06.026

    Article  CAS  Google Scholar 

  119. Feng MX, Ma MZ, Fu Y, Li J, Wang T, Xue F et al (2014) Elevated autocrine EDIL3 protects hepatocellular carcinoma from anoikis through RGD-mediated integrin activation. Mol Cancer 13:226. https://doi.org/10.1186/1476-4598-13-226

    Article  CAS  Google Scholar 

  120. Song J, Liu Y, Liu F, Zhang L, Li G, Yuan C et al (2021) The 14–3-3σ protein promotes HCC anoikis resistance by inhibiting EGFR degradation and thereby activating the EGFR-dependent ERK1/2 signaling pathway. Theranostics 11(3):996–1015. https://doi.org/10.7150/thno.51646

    Article  CAS  Google Scholar 

  121. Tang Y, Liu S, Li N, Guo W, Shi J, Yu H et al (2016) 14–3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1alpha. Oncotarget 7(13):15854–15867. https://doi.org/10.18632/oncotarget.7493

    Article  Google Scholar 

  122. Tang Y, Wang R, Zhang Y, Lin S, Qiao N, Sun Z et al (2018) Co-upregulation of 14–3-3ζ and P-Akt is associated with oncogenesis and recurrence of hepatocellular carcinoma. Cell Physiol Biochem 45(3):1097–1107. https://doi.org/10.1159/000487351

    Article  CAS  Google Scholar 

  123. Tang Y, Lv P, Sun Z, Han L, Zhou W (2016) 14–3-3β promotes migration and invasion of human hepatocellular carcinoma cells by modulating expression of MMP2 and MMP9 through PI3K/Akt/NF-κB pathway. PLoS ONE 11(1):e0146070. https://doi.org/10.1371/journal.pone.0146070

    Article  CAS  Google Scholar 

  124. Zhang H, Ye J, Weng X, Liu F, He L, Zhou D et al (2015) Comparative transcriptome analysis reveals that the extracellular matrix receptor interaction contributes to the venous metastases of hepatocellular carcinoma. Cancer Genet 208(10):482–491. https://doi.org/10.1016/j.cancergen.2015.06.002

    Article  CAS  Google Scholar 

  125. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67. https://doi.org/10.1016/j.cell.2010.03.015

    Article  CAS  Google Scholar 

  126. Wang J, Zhu CP, Hu PF, Qian H, Ning BF, Zhang Q et al (2014) FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition. Carcinogenesis 35(11):2576–2583. https://doi.org/10.1093/carcin/bgu180

    Article  CAS  Google Scholar 

  127. Hou YK, Wang Y, Cong WM, Wu MC (2007) Expression of tumor metastasis-suppressor gene KiSS-1 and matrix metalloproteinase-9 in portal vein tumor thrombus of hepatocellular carcinoma. Ai Zheng 26(6):591–595

    CAS  Google Scholar 

  128. Najafi M, Farhood B, Mortezaee K (2019) Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem 120(3):2782–2790. https://doi.org/10.1002/jcb.27681

    Article  CAS  Google Scholar 

  129. Xing X, Wang Y, Zhang X, Gao X, Li M, Wu S et al (2020) Matrix stiffness-mediated effects on macrophages polarization and their LOXL2 expression. FEBS J. https://doi.org/10.1111/febs.15566

    Article  Google Scholar 

  130. Wu S, Zheng Q, Xing X, Dong Y, Wang Y, You Y et al (2018) Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation. J Exp Clin Cancer Res 37(1):99. https://doi.org/10.1186/s13046-018-0761-z

    Article  CAS  Google Scholar 

  131. Giannelli G, Koudelkova P, Dituri F, Mikulits W (2016) Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 65(4):798–808. https://doi.org/10.1016/j.jhep.2016.05.007

    Article  CAS  Google Scholar 

  132. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273. https://doi.org/10.1038/nrc2620

    Article  CAS  Google Scholar 

  133. Wen W, Ding J, Sun W, Fu J, Chen Y, Wu K et al (2012) Cyclin G1-mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression. Hepatology 55(6):1787–1798. https://doi.org/10.1002/hep.25596

    Article  CAS  Google Scholar 

  134. Sugino T, Yamaguchi T, Hoshi N, Kusakabe T, Ogura G, Goodison S et al (2008) Sinusoidal tumor angiogenesis is a key component in hepatocellular carcinoma metastasis. Clin Exp Metastasis 25(7):835–841. https://doi.org/10.1007/s10585-008-9199-6

    Article  Google Scholar 

  135. Clouthier DE, Hosoda K, Richardson JA, Williams SC, Yanagisawa H, Kuwaki T et al (1998) Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125(5):813–824

    Article  CAS  Google Scholar 

  136. Kantarci H, Gerberding A, Riley BB (2016) Spemann organizer gene Goosecoid promotes delamination of neuroblasts from the otic vesicle. Proc Natl Acad Sci USA 113(44):E6840–E6848. https://doi.org/10.1073/pnas.1609146113

    Article  CAS  Google Scholar 

  137. Luu O, Nagel M, Wacker S, Lemaire P, Winklbauer R (2008) Control of gastrula cell motility by the Goosecoid/Mix.1/Siamois network: basic patterns and paradoxical effects. Dev Dyn 237(5):1307–1320. https://doi.org/10.1002/dvdy.21522

    Article  Google Scholar 

  138. Reymond N, d’Agua BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13(12):858–870. https://doi.org/10.1038/nrc3628

    Article  CAS  Google Scholar 

  139. Li H, Ge C, Zhao F, Yan M, Hu C, Jia D et al (2011) Hypoxia-inducible factor 1α-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin beta1 signaling in human hepatocellular carcinoma. Hepatology 54(3):910–919. https://doi.org/10.1002/hep.24479

    Article  CAS  Google Scholar 

  140. Abe M, Hiura K, Ozaki S, Kido S, Matsumoto T (2009) Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production. J Bone Miner Metab 27(1):16–23. https://doi.org/10.1007/s00774-008-0012-z

    Article  CAS  Google Scholar 

  141. Garmy-Susini B, Jin H, Zhu Y, Sung RJ, Hwang R, Varner J (2005) Integrin alpha4beta1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Invest 115(6):1542–1551. https://doi.org/10.1172/JCI23445

    Article  CAS  Google Scholar 

  142. Kucuk C, Wang J, Xiang Y, You H (2020) Epigenetic aberrations in natural killer/T-cell lymphoma: diagnostic, prognostic and therapeutic implications. Ther Adv Med Oncol. https://doi.org/10.1177/1758835919900856

    Article  Google Scholar 

  143. Fang JH, Zhang ZJ, Shang LR, Luo YW, Lin YF, Yuan Y et al (2018) Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology 68(4):1459–1475. https://doi.org/10.1002/hep.29920

    Article  CAS  Google Scholar 

  144. Kong J, Yao C, Dong S, Wu S, Xu Y, Li K et al (2021) ICAM-1 Activates platelets and promotes endothelial permeability through VE-Cadherin after insufficient radiofrequency ablation. Adv Sci (Weinh) 8(4):2002228. https://doi.org/10.1002/advs.202002228

    Article  CAS  Google Scholar 

  145. Strilic B, Yang L, Albarran-Juarez J, Wachsmuth L, Han K, Muller UC et al (2016) Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536(7615):215–218. https://doi.org/10.1038/nature19076

    Article  CAS  Google Scholar 

  146. Chen X, Jiang W, Yue C, Zhang W, Tong C, Dai D et al (2017) Heparanase contributes to trans-endothelial migration of hepatocellular carcinoma cells. J Cancer 8(16):3309–3317. https://doi.org/10.7150/jca.20159

    Article  CAS  Google Scholar 

  147. Chen X, Cheng B, Dai D, Wu Y, Feng Z, Tong C et al (2021) Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma. Cell Death Discov 7(1):33. https://doi.org/10.1038/s41420-021-00411-5

    Article  CAS  Google Scholar 

  148. Verhoeven J, Baelen J, Agrawal M, Agostinis P (2021) Endothelial cell autophagy in homeostasis and cancer. FEBS Lett 595(11):1497–1511. https://doi.org/10.1002/1873-3468.14087

    Article  CAS  Google Scholar 

  149. Lopes-Coelho F, Martins F, Hipolito A, Mendes C, Sequeira CO, Pires RF et al (2021) The activation of endothelial cells relies on a ferroptosis-like mechanism: novel perspectives in management of angiogenesis and cancer therapy. Front Oncol 11:656229. https://doi.org/10.3389/fonc.2021.656229

    Article  Google Scholar 

  150. Hou Y, Zou Q, Ge R, Shen F, Wang Y (2012) The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers. Cell Res 22(1):259–272. https://doi.org/10.1038/cr.2011.139

    Article  CAS  Google Scholar 

  151. Strilic B, Offermanns S (2017) Intravascular survival and extravasation of tumor cells. Cancer Cell 32(3):282–293. https://doi.org/10.1016/j.ccell.2017.07.001

    Article  CAS  Google Scholar 

  152. Stegner D, Dutting S, Nieswandt B (2014) Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res 133(Suppl 2):S149–S157. https://doi.org/10.1016/S0049-3848(14)50025-4

    Article  CAS  Google Scholar 

  153. Labelle M, Begum S, Hynes RO (2014) Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci USA 111(30):E3053–E3061. https://doi.org/10.1073/pnas.1411082111

    Article  CAS  Google Scholar 

  154. Gil-Bernabe AM, Lucotti S, Muschel RJ (2013) Coagulation and metastasis: what does the experimental literature tell us? Br J Haematol 162(4):433–441. https://doi.org/10.1111/bjh.12381

    Article  CAS  Google Scholar 

  155. Hou JM, Krebs M, Ward T, Sloane R, Priest L, Hughes A et al (2011) Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol 178(3):989–996. https://doi.org/10.1016/j.ajpath.2010.12.003

    Article  Google Scholar 

  156. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA et al (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5):1110–1122. https://doi.org/10.1016/j.cell.2014.07.013

    Article  CAS  Google Scholar 

  157. Ahn JC, Teng PC, Chen PJ, Posadas E, Tseng HR, Lu SC et al (2021) Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology 73(1):422–436. https://doi.org/10.1002/hep.31165

    Article  Google Scholar 

  158. Mincheva-Nilsson L, Baranov V (2014) Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin Cancer Biol 28:24–30. https://doi.org/10.1016/j.semcancer.2014.02.010

    Article  CAS  Google Scholar 

  159. Morvan MG, Lanier LL (2016) NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16(1):7–19. https://doi.org/10.1038/nrc.2015.5

    Article  CAS  Google Scholar 

  160. Xue TC, Ge NL, Xu X, Le F, Zhang BH, Wang YH (2016) High platelet counts increase metastatic risk in huge hepatocellular carcinoma undergoing transarterial chemoembolization. Hepatol Res 46(10):1028–1036. https://doi.org/10.1111/hepr.12651

    Article  CAS  Google Scholar 

  161. Chen H, Zhou XH, Li JR, Zheng TH, Yao FB, Gao B et al (2021) Neutrophils: driving inflammation during the development of hepatocellular carcinoma. Cancer Lett 522:22–31. https://doi.org/10.1016/j.canlet.2021.09.011

    Article  CAS  Google Scholar 

  162. Winograd P, Hou S, Court CM, Lee YT, Chen PJ, Zhu Y et al (2020) Hepatocellular carcinoma-circulating tumor cells expressing PD-L1 are prognostic and potentially associated with response to checkpoint inhibitors. Hepatol Commun 4(10):1527–1540. https://doi.org/10.1002/hep4.1577

    Article  CAS  Google Scholar 

  163. Sakuraoka Y, Kubota K, Tanaka G, Shimizu T, Tago K, Park KH et al (2020) Features of hepatocellular carcinoma with micro hepatic vein invasion and their correlation with hepatitis B and C virus. Anticancer Res 40(7):3983–3990. https://doi.org/10.21873/anticanres.14391

    Article  CAS  Google Scholar 

  164. Wen JM, Huang JF, Hu L, Wang WS, Zhang M, Sham JS et al (2002) Establishment and characterization of human metastatic hepatocellular carcinoma cell line. Cancer Genet Cytogenet 135(1):91–95. https://doi.org/10.1016/s0165-4608(01)00636-7

    Article  CAS  Google Scholar 

  165. Qin LX, Tang ZY, Sham JS, Ma ZC, Ye SL, Zhou XD et al (1999) The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res 59(22):5662–5665

    CAS  Google Scholar 

  166. Zimonjic DB, Keck CL, Thorgeirsson SS, Popescu NC (1999) Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology 29(4):1208–1214. https://doi.org/10.1002/hep.510290410

    Article  CAS  Google Scholar 

  167. Hu L, Wen JM, Sham JS, Wang W, Xie D, Tjia WM et al (2004) Establishment of cell lines from a primary hepatocellular carcinoma and its metastatis. Cancer Genet Cytogenet 148(1):80–84. https://doi.org/10.1016/s0165-4608(03)00206-1

    Article  CAS  Google Scholar 

  168. Wang T, Hu HS, Feng YX, Shi J, Li N, Guo WX et al (2010) Characterisation of a novel cell line (CSQT-2) with high metastatic activity derived from portal vein tumour thrombus of hepatocellular carcinoma. Br J Cancer 102(11):1618–1626. https://doi.org/10.1038/sj.bjc.6605689

    Article  CAS  Google Scholar 

  169. Lin YL, Li Y (2020) Study on the hepatocellular carcinoma model with metastasis. Genes Dis 7(3):336–350. https://doi.org/10.1016/j.gendis.2019.12.008

    Article  Google Scholar 

  170. Sawada S, Murakami K, Yamaura T, Mitani N, Tsukada K, Saiki I (2002) Therapeutic and analysis model of intrahepatic metastasis reflects clinical behavior of hepatocellular carcinoma. Jpn J Cancer Res 93(2):190–197. https://doi.org/10.1111/j.1349-7006.2002.tb01258.x

    Article  CAS  Google Scholar 

  171. Chai ZT, Chen ZH, Zhang XP, Feng JK, Liu ZH, Cheng SQ (2021) A stable and reliable animal model for hepatocellular carcinoma with portal vein tumor thrombus. Hepatobiliary Pancreat Dis Int. https://doi.org/10.1016/j.hbpd.2021.03.003

    Article  Google Scholar 

  172. Zhang W, Luo J, Liu Q, Ma J, Qu X, Yang M et al (2016) Brachytherapy with Iodine-125 seeds strand for treatment of main portal vein tumor thrombi: an experimental study in a rabbit model. Am J Cancer Res 6(3):587–599

    CAS  Google Scholar 

  173. Qi YY, Zou LG, Liang P, Zhang D (2007) Establishing models of portal vein occlusion and evaluating value of multi-slice CT in hepatic VX2 tumor in rabbits. World J Gastroenterol 13(24):3333–3341. https://doi.org/10.3748/wjg.v13.i24.3333

    Article  Google Scholar 

  174. Ikai I, Yamamoto Y, Yamamoto N, Terajima H, Hatano E, Shimahara Y et al (2003) Results of hepatic resection for hepatocellular carcinoma invading major portal and/or hepatic veins. Surg Oncol Clin N Am 12(1):65–75. https://doi.org/10.1016/s1055-3207(02)00082-0

    Article  Google Scholar 

  175. Shi J, Lai EC, Li N, Guo WX, Xue J, Lau WY et al (2011) A new classification for hepatocellular carcinoma with portal vein tumor thrombus. J Hepatobiliary Pancreat Sci 18(1):74–80. https://doi.org/10.1007/s00534-010-0314-0

    Article  Google Scholar 

  176. Lu J, Zhang XP, Zhong BY, Lau WY, Madoff DC, Davidson JC et al (2019) Management of patients with hepatocellular carcinoma and portal vein tumour thrombosis: comparing east and west. Lancet Gastroenterol Hepatol 4(9):721–730. https://doi.org/10.1016/S2468-1253(19)30178-5

    Article  Google Scholar 

  177. Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S et al (2021) Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 Update. Liver Cancer 10(3):181–223. https://doi.org/10.1159/000514174

    Article  CAS  Google Scholar 

  178. Vogel A, Martinelli E (2021) ESMO guidelines committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO clinical practice guidelines. Ann Oncol 32(6):801–805. https://doi.org/10.1016/j.annonc.2021.02.014

    Article  CAS  Google Scholar 

  179. Cheng S, Chen M, Cai J, Sun J, Guo R, Bi X et al (2020) Chinese expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus (2018 Edition). Liver Cancer 9(1):28–40. https://doi.org/10.1159/000503685

    Article  Google Scholar 

  180. Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T et al (2018) Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 29(Suppl 4):iv238–iv255. https://doi.org/10.1093/annonc/mdy308

    Article  CAS  Google Scholar 

  181. European Association for the Study of the Liver (2018) EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 69(1):182–236. https://doi.org/10.1016/j.jhep.2018.03.019

    Article  Google Scholar 

  182. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR et al (2018) AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67(1):358–380. https://doi.org/10.1002/hep.29086

    Article  Google Scholar 

  183. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM et al (2018) Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases. Hepatology 68(2):723–750. https://doi.org/10.1002/hep.29913

    Article  Google Scholar 

  184. Kokudo T, Hasegawa K, Matsuyama Y, Takayama T, Izumi N, Kadoya M et al (2016) Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 65(5):938–943. https://doi.org/10.1016/j.jhep.2016.05.044

    Article  Google Scholar 

  185. Liang L, Chen TH, Li C, Xing H, Han J, Wang MD et al (2018) A systematic review comparing outcomes of surgical resection and non-surgical treatments for patients with hepatocellular carcinoma and portal vein tumor thrombus. HPB (Oxford) 20(12):1119–1129. https://doi.org/10.1016/j.hpb.2018.06.1804

    Article  Google Scholar 

  186. Kokudo N, Kokudo T, Hasegawa K (2021) Role of liver resection for hepatocellular carcinoma with vascular invasion: emerging evidence from Western Countries. Liver Cancer. https://doi.org/10.1159/000517418

    Article  Google Scholar 

  187. Zhang YF, Le Y, Wei W, Zou RH, Wang JH, OuYang HY et al (2016) Optimal surgical strategy for hepatocellular carcinoma with portal vein tumor thrombus: a propensity score analysis. Oncotarget 7(25):38845–38856. https://doi.org/10.18632/oncotarget.8642

    Article  Google Scholar 

  188. Ma KW, Chan ACY, Chok KSH, She WH, Cheung TT, Dai WC et al (2021) Liver transplantation: would it be the best and last chance of cure for hepatocellular carcinoma with major venous invasion? Hepatobiliary Surg Nutr 10(3):308–314. https://doi.org/10.21037/hbsn.2020.03.09

    Article  CAS  Google Scholar 

  189. Lv JY, Zhang NN, Du YW, Wu Y, Song TQ, Zhang YM et al (2021) Comparison of liver transplantation and liver resection for hepatocellular carcinoma patients with portal vein tumor thrombus type I and type II. Yonsei Med J 62(1):29–40. https://doi.org/10.3349/ymj.2021.62.1.29

    Article  CAS  Google Scholar 

  190. Choi HJ, Kim DG, Na GH, Hong TH, Bae SH, You YK et al (2017) The clinical outcomes of patients with portal vein tumor thrombi after living donor liver transplantation. Liver Transpl 23(8):1023–1031. https://doi.org/10.1002/lt.24782

    Article  Google Scholar 

  191. Peng BG, He Q, Li JP, Zhou F (2009) Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Surg 198(3):313–318. https://doi.org/10.1016/j.amjsurg.2008.09.026

    Article  Google Scholar 

  192. Hatano E, Uemoto S, Yamaue H, Yamamoto M, Japanese Society of Hepato-Biliary-Pancreatic S (2018) Significance of hepatic resection and adjuvant hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein tumor thrombus in the first branch of portal vein and the main portal trunk: a project study for hepatic surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 25(9):395–402. https://doi.org/10.1002/jhbp.574

    Article  Google Scholar 

  193. Wei X, Jiang Y, Zhang X, Feng S, Zhou B, Ye X et al (2019) Neoadjuvant three-dimensional conformal radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus: A Randomized, Open-Label Multicenter Controlled Study. J Clin Oncol 37(24):2141–2151. https://doi.org/10.1200/JCO.18.02184

    Article  CAS  Google Scholar 

  194. Feng YX, Wang T, Deng YZ, Yang P, Li JJ, Guan DX et al (2011) Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model. Hepatology 53(2):483–492. https://doi.org/10.1002/hep.24075

    Article  CAS  Google Scholar 

  195. Tang ZY, Zhou BH, Wang W, Du G, Liu ZY, Li J et al (2015) Curative analysis of several therapeutic methods for primary hepatocellular carcinoma with portal vein tumor thrombus. Hepatogastroenterology 62(139):703–709

    Google Scholar 

  196. Sun HC, Zhu XD, Zhou J, Gao Q, Shi YH, Ding ZB et al (2020) Adjuvant apatinib treatment after resection of hepatocellular carcinoma with portal vein tumor thrombosis: a phase II trial. Ann Transl Med 8(20):1301. https://doi.org/10.21037/atm-20-6181

    Article  CAS  Google Scholar 

  197. Sun J, Shi J, Huang B, Cheng F, Guo W, Lau WY et al (2017) The degree of hepatic arterial blood supply of portal vein tumor thrombus in patients with hepatocellular carcinoma and its impact on overall survival after transarterial chemoembolization. Oncotarget 8(45):79816–79824. https://doi.org/10.18632/oncotarget.19767

    Article  Google Scholar 

  198. Xue TC, Xie XY, Zhang L, Yin X, Zhang BH, Ren ZG (2013) Transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a meta-analysis. BMC Gastroenterol 13:60. https://doi.org/10.1186/1471-230X-13-60

    Article  Google Scholar 

  199. He MK, Le Y, Li QJ, Yu ZS, Li SH, Wei W et al (2017) Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer 36(1):83. https://doi.org/10.1186/s40880-017-0251-2

    Article  Google Scholar 

  200. Choi JH, Chung WJ, Bae SH, Song DS, Song MJ, Kim YS et al (2018) Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol 82(3):469–478. https://doi.org/10.1007/s00280-018-3638-0

    Article  CAS  Google Scholar 

  201. Liu M, Shi J, Mou T, Wang Y, Wu Z, Shen A (2020) Systematic review of hepatic arterial infusion chemotherapy versus sorafenib in patients with hepatocellular carcinoma with portal vein tumor thrombosis. J Gastroenterol Hepatol 35(8):1277–1287. https://doi.org/10.1111/jgh.15010

    Article  CAS  Google Scholar 

  202. Yu JI, Park HC (2016) Radiotherapy as valid modality for hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol 22(30):6851–6863. https://doi.org/10.3748/wjg.v22.i30.6851

    Article  Google Scholar 

  203. Huang YJ, Hsu HC, Wang CY, Wang CJ, Chen HC, Huang EY et al (2009) The treatment responses in cases of radiation therapy to portal vein thrombosis in advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 73(4):1155–1163. https://doi.org/10.1016/j.ijrobp.2008.06.1486

    Article  Google Scholar 

  204. Yoon SM, Ryoo BY, Lee SJ, Kim JH, Shin JH, An JH et al (2018) Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial. JAMA Oncol 4(5):661–669. https://doi.org/10.1001/jamaoncol.2017.5847

    Article  Google Scholar 

  205. Zhang XB, Wang JH, Yan ZP, Qian S, Du SS, Zeng ZC (2009) Hepatocellular carcinoma with main portal vein tumor thrombus: treatment with 3-dimensional conformal radiotherapy after portal vein stenting and transarterial chemoembolization. Cancer 115(6):1245–1252. https://doi.org/10.1002/cncr.24139

    Article  Google Scholar 

  206. Cao Y, Shi S, Wang L, Yao J, Yao T (2014) Ultrasensitive fluorescence detection of heparin based on quantum dots and a functional ruthenium polypyridyl complex. Biosens Bioelectron 55:174–179. https://doi.org/10.1016/j.bios.2013.12.009

    Article  CAS  Google Scholar 

  207. Sun H, Zhang M, Liu R, Liu Y, Hou Y, Wu C (2018) Endovascular implantation of (125)I seed combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma. Future Oncol 14(12):1165–1176. https://doi.org/10.2217/fon-2017-0354

    Article  CAS  Google Scholar 

  208. Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J et al (2018) SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 36(19):1913–1921. https://doi.org/10.1200/JCO.2017.76.0892

    Article  CAS  Google Scholar 

  209. de la Torre MA, Buades-Mateu J, de la Rosa PA, Lue A, Bustamante FJ, Serrano MT et al (2016) A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib. Liver Int 36(8):1206–1212. https://doi.org/10.1111/liv.13098

    Article  CAS  Google Scholar 

  210. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390. https://doi.org/10.1056/NEJMoa0708857

    Article  CAS  Google Scholar 

  211. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS et al (2009) 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 10(1):25–34. https://doi.org/10.1016/S1470-2045(08)70285-7

    Article  CAS  Google Scholar 

  212. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F et al (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391(10126):1163–1173. https://doi.org/10.1016/S0140-6736(18)30207-1

    Article  CAS  Google Scholar 

  213. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY et al (2020) Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382(20):1894–1905. https://doi.org/10.1056/NEJMoa1915745

    Article  CAS  Google Scholar 

  214. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G et al (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389(10064):56–66. https://doi.org/10.1016/S0140-6736(16)32453-9

    Article  CAS  Google Scholar 

  215. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY et al (2018) Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379(1):54–63. https://doi.org/10.1056/NEJMoa1717002

    Article  CAS  Google Scholar 

  216. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM et al (2019) Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20(2):282–296. https://doi.org/10.1016/S1470-2045(18)30937-9

    Article  CAS  Google Scholar 

  217. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY et al (2020) Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a Randomized, Double-Blind Phase III Trial. J Clin Oncol 38(3):193–202. https://doi.org/10.1200/JCO.19.01307

    Article  CAS  Google Scholar 

  218. Breder VV, Vogel A, Merle P, Finn RS, Galle PR, Zhu AX et al (2021) IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study. J Clin Oncol 39(15_suppl):4073. https://doi.org/10.1200/JCO.2021.39.15_suppl.4073

    Article  Google Scholar 

  219. Huang C, Zhu XD, Shen YH, Wu D, Ji Y, Ge NL et al (2021) Organ specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis. Biomark Res 9(1):19. https://doi.org/10.1186/s40364-021-00274-z

    Article  Google Scholar 

  220. He M, Li Q, Zou R, Shen J, Fang W, Tan G et al (2019) Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol 5(7):953–960. https://doi.org/10.1001/jamaoncol.2019.0250

    Article  Google Scholar 

  221. Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N et al (2018) Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol Hepatol 3(6):424–432. https://doi.org/10.1016/S2468-1253(18)30078-5

    Article  Google Scholar 

  222. Chen ZW, Lin ZY, Chen YP, Chen J, Chen J (2018) Clinical efficacy of endovascular radiofrequency ablation in the treatment of portal vein tumor thrombus of primary hepatocellular carcinoma. J Cancer Res Ther 14(1):145–149. https://doi.org/10.4103/jcrt.JCRT_784_17

    Article  Google Scholar 

  223. Yu JI, Park HC, Oh D, Noh JM, Jung SH, Kim HY et al (2016) Combination treatment of trans-arterial chemo-embolisation, radiotherapy and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumour thrombosis: interim analysis of prospective phase II trial. Int J Hyperth 32(3):331–338. https://doi.org/10.3109/02656736.2016.1144895

    Article  CAS  Google Scholar 

  224. Yu JI, Park HC, Jung SH, Choi C, Shin SW, Cho SK et al (2017) Combination treatment with transarterial chemoembolization, radiotherapy, and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumor thrombosis: final results of a prospective phase II trial. Oncotarget 8(32):52651–52664. https://doi.org/10.18632/oncotarget.17072

    Article  Google Scholar 

  225. Wang D, Zhu Y, Tang J, Lian Q, Luo G, Wen W et al (2019) Integrative molecular analysis of metastatic hepatocellular carcinoma. BMC Med Genom 12(1):164. https://doi.org/10.1186/s12920-019-0586-4

    Article  CAS  Google Scholar 

  226. Li XY, Shen Y, Zhang L, Guo X, Wu J (2022) Understanding initiation and progression of hepatocellular carcinoma through single cell sequencing. Biochim Biophys Acta Rev Cancer 1877(3):188720. https://doi.org/10.1016/j.bbcan.2022.188720

    Article  CAS  Google Scholar 

  227. Carr BI, Guerra V, Donghia R (2020) Portal vein thrombosis and markers of inflammation in hepatocellular carcinoma. J Gastrointest Cancer 51(4):1141–1147. https://doi.org/10.1007/s12029-020-00489-7

    Article  CAS  Google Scholar 

  228. Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ et al (2022) Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 19(3):151–172. https://doi.org/10.1038/s41571-021-00573-2

    Article  CAS  Google Scholar 

  229. Raybould AL, Sanoff H (2020) Combination antiangiogenic and immunotherapy for advanced hepatocellular carcinoma: evidence to date. J Hepatocell Carcinoma 7:133–142. https://doi.org/10.2147/JHC.S224938

    Article  CAS  Google Scholar 

  230. Lee TK, Guan XY, Ma S (2021) Cancer stem cells in hepatocellular carcinoma—from origin to clinical implications. Nat Rev Gastroenterol Hepatol. https://doi.org/10.1038/s41575-021-00508-3

    Article  Google Scholar 

  231. Dituri F, Mancarella S, Cigliano A, Chieti A, Giannelli G (2019) TGF-beta as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives. Semin Liver Dis 39(1):53–69. https://doi.org/10.1055/s-0038-1676121

    Article  CAS  Google Scholar 

  232. Gilkes DM, Semenza GL, Wirtz D (2014) Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer 14(6):430–439. https://doi.org/10.1038/nrc3726

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

This review was sponsored by grants from National Clinical Research Center for Interventional Medicine (Grant No. 2021–008), Clinical Research Fund of Zhongshan Hospital, Fudan University (Grant No. 2020ZSLC60) and Science and Technology Planning Projects of Xiamen Science and Technology (Grant No. 3502Z20194031).

Author information

Authors and Affiliations

  1. Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China

    Xing-Hao Zhou, Jing-Ru Li, Tang-Hui Zheng, Hong Chen, Chen Cai, Sheng-Long Ye & Tong-Chun Xue

  2. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China

    Xing-Hao Zhou, Jing-Ru Li, Chen Cai, Sheng-Long Ye & Tong-Chun Xue

  3. Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China

    Xing-Hao Zhou, Jing-Ru Li, Chen Cai, Sheng-Long Ye & Tong-Chun Xue

  4. National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China

    Xing-Hao Zhou, Jing-Ru Li, Chen Cai, Sheng-Long Ye & Tong-Chun Xue

  5. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Medical College, Shanghai, 200032, China

    Bo Gao

  6. Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China

    Tang-Hui Zheng & Hong Chen

Authors
  1. Xing-Hao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-Ru Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tang-Hui Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sheng-Long Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bo Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tong-Chun Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XHZ: investigation, formal analysis, writing-original draft, visualization. JRL: investigation, formal analysis. THZ: investigation. HC: investigation. CC: investigation. SY: writing-review. BG: writing-review and editing. TCX: conceptualization, investigation, formal analysis, writing-review and editing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Bo Gao or Tong-Chun Xue.

Ethics declarations

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, XH., Li, JR., Zheng, TH. et al. Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy. Clin Exp Metastasis 40, 5–32 (2023). https://doi.org/10.1007/s10585-022-10188-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-022-10188-1

Keywords

Search

Navigation