Journal Home > Volume 20 , Issue 1

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.


menu
Abstract
Full text
Outline
About this article

Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies

Show Author's information Changyu Yao1,*Shilun Wu1,*Jian Kong1Yiwen Sun2Yannan Bai3Ruhang Zhu1Zhuxin Li1Wenbing Sun1 ( )Lemin Zheng4,5 ( )
Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China
Department of Pathology, Peking University People’s Hospital, Peking University, Beijing 100044, China
Department of Hepatobiliary Pancreatic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China
The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Sciences Center, Peking University, Beijing 100083, China
Beijing Tiantan Hospital, China National Clinical Research Center of Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100050, China

*These authors contributed equally to this work.

Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.

Keywords: Angiogenesis, tumor microenvironment, hepatocellular carcinoma, anti-angiogenic therapy, pro-angiogenic factors

References(139)

1

Wang C, Cao Y, Yang C, Bernards R, Qin W. Exploring liver cancer biology through functional genetic screens. Nat Rev Gastroenterol Hepatol. 2021; 18: 690-704.

2

Jamshidi-Parsian A, Griffin RJ, Kore RA, Todorova VK, Makhoul I. Tumor-endothelial cell interaction in an experimental model of human hepatocellular carcinoma. Exp Cell Res. 2018; 372: 16-24.

3

Yan T, Yu L, Zhang N, Peng C, Su G, Jing Y, et al. The advanced development of molecular targeted therapy for hepatocellular carcinoma. Cancer Biol Med. 2022; 19: 802-17.

4

Ribatti D, Annese T, Ruggieri S, Tamma R, Crivellato E. Limitations of anti-angiogenic treatment of tumors. Transl Oncol. 2019; 12: 981-6.

5

Cheng W, Cheng Z, Weng L, Xing D, Zhang M. Asparagus polysaccharide inhibits the hypoxia-induced migration, invasion and angiogenesis of hepatocellular carcinoma cells partly through regulating HIF1α/VEGF expression via MAPK and PI3K signaling pathway. J Cancer. 2021; 12: 3920-9.

6

Xiong XX, Qiu XY, Hu DX, Chen XQ. Advances in hypoxiamediated mechanisms in hepatocellular carcinoma. Mol Pharmacol. 2017; 92: 246-55.

7

Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020; 39: 126.

8

Shah AA, Kamal MA, Akhtar S. Tumor angiogenesis and VEGFR- 2: mechanism, pathways and current biological therapeutic interventions. Curr Drug Metab. 2021; 22: 50-9.

9

Muppala S. Growth factor-induced angiogenesis in hepatocellular carcinoma. Crit Rev Oncog. 2021; 26: 61-8.

10

Elaimy AL, Mercurio AM. Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology. Sci Signal. 2018; 11: 1165.

11

Pulkkinen HH, Kiema M, Lappalainen JP, Toropainen A, Beter M, Tirronen A, et al. BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF. Angiogenesis. 2021; 24: 129-44.

12

Aguilar-Cazares D, Chavez-Dominguez R, Carlos-Reyes A, Lopez-Camarillo C, Hernadez de la Cruz ON, Lopez-Gonzalez JS. Contribution of angiogenesis to inflammation and cancer. Front Oncol. 2019; 9: 1399.

13

Lacin S, Yalcin S. The prognostic value of circulating VEGF-A level in patients with hepatocellular cancer. Technol Cancer Res Treat. 2020; 19: 1533033820971677.

14

Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019; 176: 1248-64.

15

Chen H, Nio K, Tang H, Yamashita T, Okada H, Li Y, et al. BMP9-ID1 signaling activates HIF-1α and VEGFA expression to promote tumor angiogenesis in hepatocellular carcinoma. Int J Mol Sci. 2022; 23: 1475.

16

Zhu AX, Duda DG, Sahani DV, Jain RK. HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol. 2011; 8: 292-301.

17

Demoulin JB, Essaghir A. PDGF receptor signaling networks in normal and cancer cells. Cytokine Growth Factor Rev. 2014; 25: 273-83.

18

Chen B, Liu J, Wang X, Shen Q, Li C, Dai C. Co-expression of PDGF-B and VEGFR-3 strongly correlates with poor prognosis in hepatocellular carcinoma patients after hepatectomy. Clin Res Hepatol Gastroenterol. 2018; 42: 126-33.

19

Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018; 62: 75-88.

20

Zou X, Tang XY, Qu ZY, Sun ZW, Ji CF, Li YJ, et al. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: a review. Int J Biol Macromol. 2022; 202: 539-57.

21

Tsioumpekou M, Cunha SI, Ma H, Åhgren A, Cedervall J, Olsson AK, et al. Specific targeting of PDGFRβ in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression. Theranostics. 2020; 10: 1122-35.

22

Olsen RS, Dimberg J, Geffers R, Wågsäter D. Possible role and therapeutic target of PDGF-D signalling in colorectal cancer. Cancer Invest. 2019; 37: 99-112.

23

Li L, Ji Y, Chen YC, Zhen ZJ. MiR-325-3p mediate the CXCL17/ CXCR8 axis to regulate angiogenesis in hepatocellular carcinoma. Cytokine. 2021; 141: 155436.

24

Chen CY, Wu SM, Lin YH, Chi HC, Lin SL, Yeh CT, et al. Induction of nuclear protein-1 by thyroid hormone enhances plateletderived growth factor A mediated angiogenesis in liver cancer. Theranostics. 2019; 9: 2361-79.

25

Presta M, Chiodelli P, Giacomini A, Rusnati M, Ronca R. Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach. Pharmacol Ther. 2017; 179: 171-87.

26

Szybowska P, Kostas M, Wesche J, Wiedlocha A, Haugsten EM. Cancer mutations in FGFR2 prevent a negative feedback loop mediated by the ERK1/2 pathway. Cells. 2019; 8: 518.

27

Wang Y, Liu D, Zhang T, Xia L. FGF/FGFR signaling in hepatocellular carcinoma: from carcinogenesis to recent therapeutic intervention. Cancers (Basel). 2021; 13: 1360.

28

Lieu C, Heymach J, Overman M, Tran H, Kopetz S. Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis. Clin Cancer Res. 2011; 17: 6130-9.

29

Pallotta MT, Nickel W. FGF2 and IL-1β - explorers of unconventional secretory pathways at a glance. J Cell Sci. 2020; 133: 250449.

30

Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, et al. The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res. 2019; 25: 912-20.

31

Wang L, Park H, Chhim S, Ding Y, Jiang W, Queen C, et al. A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts. Mol Cancer Ther. 2012; 11: 864-72.

32

Margioula-Siarkou G, Margioula-Siarkou C, Petousis S, Margaritis K, Vavoulidis E, Gullo G, et al. The role of endoglin and its soluble form in pathogenesis of preeclampsia. Mol Cell Biochem. 2022; 477: 479-91.

33

Ungogo MA. Targeting Smad-mediated TGFβ pathway in coronary artery bypass graft. J Cardiovasc Pharmacol Ther. 2021; 26: 119-30.

34

Alsamman M, Sterzer V, Meurer SK, Sahin H, Schaeper U, Kuscuoglu D, et al. Endoglin in human liver disease and murine models of liver fibrosis - a protective factor against liver fibrosis. Liver Int. 2018; 38: 858-67.

35

Jeng KS, Sheen IS, Lin SS, Leu CM, Chang CF. The role of endoglin in hepatocellular carcinoma. Int J Mol Sci. 2021; 22: 3208.

36

Kasprzak A, Adamek A. Role of endoglin (CD105) in the progression of hepatocellular carcinoma and anti-angiogenic therapy. Int J Mol Sci. 2018; 19: 3887.

37

Li L, Zhong L, Tang C, Gan L, Mo T, Na J, et al. CD105: tumor diagnosis, prognostic marker and future tumor therapeutic target. Clin Transl Oncol. 2022; 24: 1447-58.

38

Schoonderwoerd MJA, Goumans MTH, Hawinkels LJAC. Endoglin: beyond the endothelium. Biomolecules. 2020; 10: 289.

39

Pomeraniec L, Hector-Greene M, Ehrlich M, Blobe GC, Henis YI. Regulation of TGF-β receptor hetero-oligomerization and signaling by endoglin. Mol Biol Cell. 2015; 26: 3117-27.

40

Hong JM, Hu YD, Chai XQ, Tang CL. Role of activin receptor-like kinase 1 in vascular development and cerebrovascular diseases. Neural Regen Res. 2020; 15: 1807-13.

41

Yang Y, Guan Q, Guo L, Han C. The prognostic correlation between CD105 expression level in tumor tissue and peripheral blood and sunitinib administration in advanced hepatocellular carcinoma. Cancer Biol Ther. 2018; 19: 1006-14.

42

Zhao W, Yang L, Chen X, Qian H, Zhang S, Chen Y, et al. Phenotypic and functional characterization of tumor-derived endothelial cells isolated from primary human hepatocellular carcinoma. Hepatol Res. 2018; 48: 1149-62.

43

Benetti A, Berenzi A, Gambarotti M, Garrafa E, Gelati M, Dessy E, et al. Transforming growth factor-beta1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium. Cancer Res. 2008; 68: 8626-34.

44

Li Y, Zhai Z, Liu D, Zhong X, Meng X, Yang Q, et al. CD105 promotes hepatocarcinoma cell invasion and metastasis through VEGF. Tumour Biol. 2015; 36: 737-45.

45

Yao Y, Pan Y, Chen J, Sun X, Qiu Y, Ding Y. Endoglin (CD105) expression in angiogenesis of primary hepatocellular carcinomas: analysis using tissue microarrays and comparisons with CD34 and VEGF. Ann Clin Lab Sci. 2007; 37: 39-48.

46

Xiong YQ, Sun HC, Zhang W, Zhu XD, Zhuang PY, Zhang JB, et al. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res. 2009; 15: 4838-46.

47

Duffy AG, Ma C, Ulahannan SV, Rahma OE, Makarova-Rusher O, Cao L, et al. Phase I and preliminary phase Ⅱ study of TRC105 in combination with sorafenib in hepatocellular carcinoma. Clin Cancer Res. 2017; 23: 4633-41.

48

Bupathi M, Kaseb A, Janku F. Angiopoietin 2 as a therapeutic target in hepatocellular carcinoma treatment: current perspectives. Onco Targets Ther. 2014; 7: 1927-32.

49

Vanderborght B, Lefere S, Vlierberghe HV, Devisscher L. The angiopoietin/Tie2 pathway in hepatocellular carcinoma. Cells. 2020; 9: 2382.

50

Akwii RG, Sajib MS, Zahra FT, Mikelis CM. Role of angiopoietin-2 in vascular physiology and pathophysiology. Cells. 2019; 8: 471.

51

Choi GH, Jang ES, Kim JW, Jeong SH. Prognostic role of plasma level of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor in hepatocellular carcinoma. World J Gastroenterol. 2021; 27: 4453-67.

52

Ao J, Chiba T, Kanzaki H, Kanayama K, Shibata S, Kurosugi A, et al. Serum angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma. J Cancer. 2021; 12: 2694-701.

53

Roškar L, Roškar I, Rižner TL, Smrkolj Š. Diagnostic and therapeutic values of angiogenic factors in endometrial cancer. Biomolecules. 2021; 12: 7.

54

Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut. 2005; 54: 1768-75.

55

Wang Q, Lash GE. Angiopoietin 2 in placentation and tumor biology: the yin and yang of vascular biology. Placenta. 2017; 56: 73-8.

56

Wang F, Dong X, Xiu P, Zhong J, Wei H, Xu Z, et al. T7 peptide inhibits angiogenesis via downregulation of angiopoietin-2 and autophagy. Oncol Rep. 2015; 33: 675-84.

57

Tanaka S, Wands JR, Arii S. Induction of angiopoietin-2 gene expression by COX-2: a novel role for COX-2 inhibitors during hepatocarcinogenesis. J Hepatol. 2006; 44: 233-5.

58

Terlikowska KM, Dobrzycka B, Terlikowski R, Sienkiewicz A, Kinalski M, Terlikowski SJ. Clinical value of selected markers of angiogenesis, inflammation, insulin resistance and obesity in type 1 endometrial cancer. BMC Cancer. 2020; 20: 921.

59

Modzelewska P, Chludzińska S, Lewko J, Reszeć J. The influence of leptin on the process of carcinogenesis. Contemp Oncol (Pozn). 2019; 23: 63-8.

60

Huang H, Zhang J, Ling F, Huang Y, Yang M, Zhang Y, et al. Leptin receptor (LEPR) promotes proliferation, migration, and invasion and inhibits apoptosis in hepatocellular carcinoma by regulating ANXA7. Cancer Cell Int. 2021; 21: 4.

61

Ho Y, Wang SH, Chen YR, Li ZL, Chin YT, Yang YSH, et al. Leptinderived peptides block leptin-induced proliferation by reducing expression of pro-inflammatory genes in hepatocellular carcinoma cells. Food Chem Toxicol. 2019; 133: 110808.

62

Ribatti D, Belloni AS, Nico B, Di Comite M, Crivellato E, Vacca A. Leptin-leptin receptor are involved in angiogenesis in human hepatocellular carcinoma. Peptides. 2008; 29: 1596-602.

63

Lin TC, Hsiao M. Leptin and cancer: updated functional roles in carcinogenesis, therapeutic niches, and developments. Int J Mol Sci. 2021; 22: 2870.

64

Zabeau L, Wauman J, Dam J, Van Lint S, Burg E, De Geest J, et al. A novel leptin receptor antagonist uncouples leptin’s metabolic and immune functions. Cell Mol Life Sci. 2019; 76: 1201-14.

65

Fiedor E, Gregoraszczuk EL. Superactive human leptin antagonist (SHLA), triple Lan1 and quadruple Lan2 leptin mutein as a promising treatment for human folliculoma. Cancer Chemother Pharmacol. 2017; 80: 815-27.

66

Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, et al. The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res. 2020; 39: 204.

67

Liu Y, Han ZP, Zhang SS, Jing YY, Bu XX, Wang CY, et al. Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. J Biol Chem. 2011; 286: 25007-15.

68

Mu HQ, He YH, Wang SB, Yang S, Wang YJ, Nan CJ, et al. MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis. Clin Transl Oncol. 2020; 22: 111-21.

69

Tsai CN, Yu SC, Lee CW, Pang JS, Wu CH, Lin SE, et al. SOX4 activates CXCL12 in hepatocellular carcinoma cells to modulate endothelial cell migration and angiogenesis in vivo. Oncogene. 2020; 39: 4695-710.

70

Li Y, Turpin CP, Wang S. Role of thrombospondin 1 in liver diseases. Hepatol Res. 2017; 47: 186-93.

71

Yang HD, Kim HS, Kim SY, Na MJ, Yang G, Eun JW, et al. HDAC6 suppresses let-7i-5p to elicit TSP1/CD47-mediated antitumorigenesis and phagocytosis of hepatocellular carcinoma. Hepatology. 2019; 70: 1262-79.

72

Poluzzi C, Iozzo RV, Schaefer L. Endostatin and endorepellin: a common route of action for similar angiostatic cancer avengers. Adv Drug Deliv Rev. 2016; 97: 156-73.

73

Ji Y, Fan H, Yang M, Bai C, Yang W, Wang Z. Synergistic effect of baculovirus-mediated endostatin and angiostatin combined with gemcitabine in hepatocellular carcinoma. Biol Pharm Bull. 2022; 45: 309-15.

74

Kapoor A, Chen CG, Iozzo RV. Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells. J Biol Chem. 2020; 295: 6344-56.

75

Wang K, Qiu X, Zhao Y, Wang H, Chen L. The Wnt/β- catenin signaling pathway in the tumor microenvironment of hepatocellular carcinoma. Cancer Biol Med. 2021; 19: 305-18.

76

Yang W, Li Z, Qin R, Wang X, An H, Wang Y, et al. YY1 promotes endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma by transcriptionally activating VEGFA. Front Oncol. 2019; 9: 1187.

77

Meng J, Liu Y, Han J, Tan Q, Chen S, Qiao K, et al. Hsp90β promoted endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma. Mol Cancer. 2017; 16: 72.

78

Wang W, Wu F, Fang F, Tao Y, Yang L. RhoC is essential for angiogenesis induced by hepatocellular carcinoma cells via regulation of endothelial cell organization. Cancer Sci. 2008; 99: 2012-8.

79

Dong ZR, Sun D, Yang YF, Zhou W, Wu R, Wang XW, et al. TMPRSS4 drives angiogenesis in hepatocellular carcinoma by promoting HB-EGF expression and proteolytic cleavage. Hepatology. 2020; 72: 923-39.

80

Sun XT, Yuan XW, Zhu HT, Deng ZM, Yu DC, Zhou X, et al. Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma. World J Gastroenterol. 2012; 18: 4925-33.

81

Ruan Q, Wang H, Burke LJ, Bridle KR, Li X, Zhao CX, et al. Therapeutic modulators of hepatic stellate cells for hepatocellular carcinoma. Int J Cancer. 2020; 147: 1519-27.

82

Lin JZ, Meng LL, Li YZ, Chen SX, Xu JL, Tang YJ, et al. Importance of activated hepatic stellate cells and angiopoietin-1 in the pathogenesis of hepatocellular carcinoma. Mol Med Rep. 2016; 14: 1721-5.

83

Lin N, Meng L, Lin J, Chen S, Zhang P, Chen Q, et al. Activated hepatic stellate cells promote angiogenesis in hepatocellular carcinoma by secreting angiopoietin-1. J Cell Biochem. 2020; 121: 1441-51.

84

Zhu B, Lin N, Zhang M, Zhu Y, Cheng H, Chen S, et al. Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma. J Transl Med. 2015; 13: 365.

85

Li ZQ, Wu WR, Zhao C, Zhao C, Zhang XL, Yang Z, et al. CCN1/ Cyr61 enhances the function of hepatic stellate cells in promoting the progression of hepatocellular carcinoma. Int J Mol Med. 2018; 41: 1518-28.

86

Mußbach F, Ungefroren H, Günther B, Katenkamp K, Henklein P, Westermann M, et al. Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells - evidence for a role in hepatocellular carcinoma growth in vivo. Mol Cancer. 2016; 15: 54.

87

Lu Y, Lin N, Chen Z, Xu R. Hypoxia-induced secretion of plateletderived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A. Mol Med Rep. 2015; 11: 691-7.

88

Li W, Miao S, Miao M, Li R, Cao X, Zhang K, et al. Hedgehog signaling activation in hepatic stellate cells promotes angiogenesis and vascular mimicry in hepatocellular carcinoma. Cancer Invest. 2016; 34: 424-30.

89

Li Z, Wang F, Li Y, Wang X, Lu Q, Wang D, et al. Combined anti-hepatocellular carcinoma therapy inhibit drug-resistance and metastasis via targeting “substance P-hepatic stellate cellshepatocellular carcinoma” axis. Biomaterials. 2021; 276: 121003.

90

Peng H, Zhu E, Zhang Y. Advances of cancer-associated fibroblasts in liver cancer. Biomark Res. 2022; 10: 59.

91

Khan GJ, Sun L, Khan S, Yuan S, Nongyue H. Versatility of cancer associated fibroblasts: commendable targets for anti-tumor therapy. Curr Drug Targets. 2018; 19: 1573-88.

92

Biffi G, Tuveson DA. Diversity and biology of cancer-associated fibroblasts. Physiol Rev. 2021; 101: 147-76.

93

Wang SS, Tang XT, Lin M, Yuan J, Peng YJ, Yin X, et al. Perivenous stellate cells are the main source of myofibroblasts and cancerassociated fibroblasts formed after chronic liver injuries. Hepatology. 2021; 74: 1578-94.

94

Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancerassociated fibroblasts. J Exp Clin Cancer Res. 2018; 37: 324.

95

Huang B, Huang M, Li Q. Cancer-associated fibroblasts promote angiogenesis of hepatocellular carcinoma by VEGF-mediated EZH2/VASH1 pathway. Technol Cancer Res Treat. 2019; 18: 1533033819879905.

96

Liu Z, Chen M, Zhao R, Huang Y, Liu F, Li B, et al. CAFinduced placental growth factor facilitates neoangiogenesis in hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai). 2020; 52: 18-25.

97

Chiavarina B, Ronca R, Otaka Y, Sutton RB, Rezzola S, Yokobori T, et al. Fibroblast-derived prolargin is a tumor suppressor in hepatocellular carcinoma. Oncogene. 2022; 41: 1410-20.

98

de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, et al. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2019; 70: 710-21.

99

Ye Y, Xu Y, Lai Y, He W, Li Y, Wang R, et al. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization. J Cell Biochem. 2018; 119: 2951-63.

100

Pu J, Li W, Wang A, Zhang Y, Qin Z, Xu Z, et al. Long non-coding RNA HOMER3-AS1 drives hepatocellular carcinoma progression via modulating the behaviors of both tumor cells and macrophages. Cell Death Dis. 2021; 12: 1103.

101

Hou ZH, Xu XW, Fu XY, Zhou LD, Liu SP, Tan DM. Long non-coding RNA MALAT1 promotes angiogenesis and immunosuppressive properties of HCC cells by sponging miR-140. Am J Physiol Cell Physiol. 2020; 318: 649-63.

102

Goswami KK, Bose A, Baral R. Macrophages in tumor: an inflammatory perspective. Clin Immunol. 2021; 232: 108875.

103

Yan C, Huo X, Wang S, Feng Y, Gong Z. Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish. J Hepatol. 2015; 63: 420-8.

104

Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology. 2016; 150: 1646-58.

105

Yan C, Yang Q, Gong Z. Tumor-associated neutrophils and macrophages promote gender disparity in hepatocellular carcinoma in zebrafish. Cancer Res. 2017; 77: 1395-407.

106

Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020; 20: 485-503.

107

Mossenta M, Busato D, Baboci L, Cintio FD, Toffoli G, Bo MD. New insight into therapies targeting angiogenesis in hepatocellular carcinoma. Cancers (Basel). 2019; 11: 1086.

108

Yang X, Zhao J, Duan S, Hou X, Li X, Hu Z, et al. Enhanced cytotoxic T lymphocytes recruitment targeting tumor vasculatures by endoglin aptamer and IP-10 plasmid presenting liposome-based nanocarriers. Theranostics. 2019; 9: 4066-83.

109

Duan S, Song M, He J, Zhou N, Zhou S, Zhao J, et al. Folate-modified chitosan nanoparticles coated interferon-inducible protein-10 gene enhance cytotoxic T lymphocytes’ responses to hepatocellular carcinoma. J Biomed Nanotechnol. 2016; 12: 700-9.

110

Yao H, Liu N, Lin MC, Zheng J. Positive feedback loop between cancer stem cells and angiogenesis in hepatocellular carcinoma. Cancer Lett. 2016; 379: 213-9.

111

Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma-from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022; 19: 26-44.

112

Zeng SS, Yamashita T, Kondo M, Nio K, Hayashi T, Hara Y, et al. The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma. J Hepatol. 2014; 60: 127-34.

113

Yang XR, Xu Y, Yu B, Zhou J, Qiu SJ, Shi GM, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut. 2010; 59: 953-62.

114

Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, et al. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/ CXCL1 signaling. Hepatology. 2012; 55: 807-20.

115

Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, et al. CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer. 2015; 14: 155.

116

Suda T, Yamashita T, Sunagozaka H, Okada H, Nio K, Sakai Y, et al. Dickkopf-1 promotes angiogenesis and is a biomarker for hepatic stem cell-like hepatocellular carcinoma. Int J Mol Sci. 2022; 23: 2801.

117

Cheng CC, Chao WT, Shih JH, Lai YS, Hsu YH, Liu YH. Sorafenib combined with dasatinib therapy inhibits cell viability, migration, and angiogenesis synergistically in hepatocellular carcinoma. Cancer Chemother Pharmacol. 2021; 88: 143-53.

118

Zheng N, Zhang S, Wu W, Zhang N, Wang J. Regulatory mechanisms and therapeutic targeting of vasculogenic mimicry in hepatocellular carcinoma. Pharmacol Res. 2021; 166: 105507.

119

Zhao X, Sun B, Liu T, Shao B, Sun R, Zhu D, et al. Long noncoding RNA n339260 promotes vasculogenic mimicry and cancer stem cell development in hepatocellular carcinoma. Cancer Sci. 2018; 109: 3197-208.

120

Ou H, Chen Z, Xiang L, Fang Y, Xu Y, Liu Q, et al. Frizzled 2-induced epithelial-mesenchymal transition correlates with vasculogenic mimicry, stemness, and Hippo signaling in hepatocellular carcinoma. Cancer Sci. 2019; 110: 1169-82.

121

Akce M, El-Rayes BF, Bekaii-Saab TS. Frontline therapy for advanced hepatocellular carcinoma: an update. Therap Adv Gastroenterol. 2022; 15: 17562848221086126.

122

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359: 378-90.

123

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009; 10: 25-34.

124

Zhao Y, Zhang YN, Wang KT, Chen L. Lenvatinib for hepatocellular carcinoma: from preclinical mechanisms to anti-cancer therapy. Biochim Biophys Acta Rev Cancer. 2020; 1874: 188391.

125

Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391: 1163-73.

126

Guan H, Wang C, Zhao Z, Han S. Cost-effectiveness of donafenib as first-line treatment of unresectable hepatocellular carcinoma in China. Adv Ther. 2022; 39: 3334-46.

127

Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase Ⅱ-Ⅲ trial. J Clin Oncol. 2021; 39: 3002-11.

128

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389: 56-66.

129

Huang A, Yang XR, Chung WY, Dennison AR, Zhou J. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther. 2020; 5: 146.

130

Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018; 379: 54-63.

131

Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20: 282-96.

132

Niu M, Yi M, Li N, Wu K, Wu K. Advances of targeted therapy for hepatocellular carcinoma. Front Oncol. 2021; 11: 719896.

133

Zhang XH, Cao MQ, Li XX, Zhang T. Apatinib as an alternative therapy for advanced hepatocellular carcinoma. World J Hepatol. 2020; 12: 766-74.

134

Qin S, Li Q, Gu S, Chen X, Lin L, Wang Z, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2021; 6: 559-68.

135

Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019; 18(1): 60.

136

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382: 1894-95.

137

Luo XY, Wu KM, He XX. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res. 2021; 40: 172.

138

He M, Hu J, Fang T, Tang W, Lv B, Yang B, et al. Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway. Cancer Biol Med. 2021; 19: 90-103.

139

Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020; 5: 87.

Publication history
Copyright
Rights and permissions

Publication history

Received: 27 July 2022
Accepted: 19 October 2022
Published: 12 January 2023
Issue date: January 2023

Copyright

©2023 Cancer Biology & Medicine.

Rights and permissions

Creative Commons Attribution-NonCommercial 4.0 International License

Return