Topic Highlight Open Access
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2014; 6(12): 830-835
Published online Dec 27, 2014. doi: 10.4254/wjh.v6.i12.830
Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out
Hong Sun, Department of Transplant Medicine, University Hospital Münster, 48149 Münster, Germany
Hong Sun, Man-Sheng Zhu, Wen-Rui Wu, Xiang-De Shi, Lei-Bo Xu, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China
Hong Sun, Man-Sheng Zhu, Wen-Rui Wu, Xiang-De Shi, Lei-Bo Xu, Department of Hepato-pancreato-biliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
Author contributions: Sun H and Zhu MS wrote the draft of the manuscript and contributed equally to this work; Wu WR and Shi XD collected the related references; Xu LB read through this paper and brought out several important opinions for revision.
Supported by The Special Research Foundation of the National Nature Science Foundation of China, No. 81302143; the Natural Science Foundation of Guangdong Province, China, No. S2013040015045
Correspondence to: Dr. Lei-Bo Xu, Department of Hepato-pancreato-biliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Xi Lu, Guangzhou 510120, Guangdong Province, China. mdxuleibo@hotmail.com
Telephone: +86-20-34071163 Fax: +86-20-34071091
Received: August 26, 2014
Revised: September 29, 2014
Accepted: October 28, 2014
Published online: December 27, 2014

Abstract

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.

Key Words: Hepatocellular carcinoma, Management, Molecularly targeted therapy, Anti-angiogenesis, Sorafenib

Core tip: Hepatocellular carcinoma (HCC) is a devastating disease with a high mortality rate. For a long period of time, no effective treatment options are available for patients with advanced HCC. During the last decade, molecularly targeted therapies have been introduced into the treatment of advanced HCC. However, the efficacy and safety of molecularly targeted therapies remain controversial. In addition, primary or acquired drug resistance limits the activity of molecularly targeted agents, but the underlying mechanisms have not been fully understood. This concise review aims to provide an overview of anti-angiogenesis therapy in the treatment of HCC.



INTRODUCTION

Primary liver cancer (PLC) is one of the most common malignancies and the second leading cause of cancer-related deaths around the world. Hepatocellular carcinoma (HCC), the most common type of PLC, accounts for approximate 90% of PLC cases in most countries. In addition, HCC is the 5th and 7th most common cancer in males and females, respectively. The worldwide incidence of HCC is increasing partially due to the rising number of infections caused by hepatitis B virus or hepatitis C virus[1-3]. Recently, while the diagnosis of HCC has been remarkably improved with the use of noninvasive imaging tests, a large number of patients were still diagnosed at the advanced stage due to the lack of symptoms during early stages and the rapid progression of cancer cells[4,5].

The management of HCC depends mainly on tumor stage and liver function reserve. Currently, curative treatments such as surgical resection, liver transplantation, and local ablation can significantly improve the survival of HCC patients at the early stage[2,6]. However for a long period of time, no effective treatment options are available for patients with advanced HCC or who progressed into an advanced stage after other treatments failed. In recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have been widely studied in cancer managements. Given that HCC is a highly vascularized tumor, anti-angiogenic treatments might be highly efficient for the treatment of HCC by inhibiting the formation of blood vessels in cancer tissues through small molecules[7-9].

RESISTANCE TO ANTI-ANGIOGENIC DRUGS OF HCC CELLS

As an oral multikinase inhibitor, sorafenib has both anti-proliferative and anti-angiogenic effects on tumors through blocking Raf and vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase signaling. Sorafenib is the first molecular target drug approved for the treatment of advanced HCC. A phase 3, randomized, double-blind, placebo-controlled, multicenter study was performed in 2008 in 21 Western countries to evaluate the effects of sorafenib on the treatment of HCC. This study showed that sorafenib prolonged the median survival and the time to radiologic progression by approximately 3 mo in advanced HCC patients[10,11]. Cheng et al[12] also reported that sorafenib was effective for advanced HCC and was well tolerated in HCC patients from the Asia-Pacific region. In addition, high safety and well-tolerance of sorafenib have been reported in a large phase 4 study including over 1500 patients with unresectable HCC[13,14]. Therefore, sorafenib has been established as the standard first-line monotherapy for patients with advanced HCC[9,15-17]. However, the efficacies of current anti-angiogenesis therapies are still far from satisfactory (Table 1). Currently, the median survival time of HCC patients who received sorafenib treatment is not longer than 1 year even after many years of research[18].

Table 1 Clinical studies on anti-angiogenesis therapy of hepatocellular carcinoma included in this review.
Ref.YearPhaseInvestigational drugOutcome
Llovet et al[10]2008Phase 3SorafenibIncreased survival
Cheng et al[12]2009Phase 3SorafenibIncreased survival
Lencioni et al[13]2012Phase 4SorafenibHigh safety
Lencioni et al[14]2014Phase 4SorafenibHigh safety
Johnson et al[40]2013Phase 3BrivanibLess well-tolerated
Cheng et al[41]2013Phase 3SunitinibSignificantly inferior than sorafenib
Zhu et al[42]2012Phase 3Sorafenib plus erlotinibNo survival benefit
Llovet et al[43]2013Phase 3Brivanib after sorafenib failedNo survival benefit
Zhu et al[44]2014Phase 3Everolimus after sorafenib failedNo survival benefit

Resistance to molecularly targeted agents including sorafenib is a major reason causing the failure of anti-cancer therapies (Table 2)[17,19,20]. Primary resistance is observed in some HCC patients who are initially not susceptible to sorafenib therapy due to intrinsic indifference. After long-term exposure, tumor cells may gradually become resistant and/or less susceptible to sorafenib, leading to acquired resistance[17]. Both primary and acquired resistance to sorafenib has been commonly reported in HCC patients[21]. Ezzoukhry et al[22] found that HCC cells exhibited different susceptibilities to sorafenib. For example, some HCC cell lines such as Hep3B and SNU-449 were inherently resistant to sorafenib. The authors also showed that activation of the epidermal growth factor receptor (EGFR) was a possible determinant of inherent resistance of HCC cells to sorafenib. In an in vitro study, Zhang et al[23] showed that phosphorylated extracellular signal-regulated kinase was a potential predictor of sorafenib sensitivity in HCC. Similarly, Blivet-Van Eggelpoël et al[21] demonstrated that EGFR and human epidermal growth factor receptor-3 reduced the susceptibility of HCC cells to sorafenib.

Table 2 Studies on the mechanisms of anti-angiogenesis therapy resistance in hepatocellular carcinoma.
Ref.YearInvestigational drugPathways/genes involvedEffects
Blivet-Van Eggelpoël et al[21]2012SorafenibEGFR and HER-3Restrict cell response
Ezzoukhry et al[22]2012SorafenibEGFRPotential determinant of primary resistance
Zhang et al[23]2009SorafenibpERKPotential biomarker for sensitivity prediction
Chen et al[24]2011SorafenibPI3K/AktMediates acquired resistance
Xia et al[25]2013SorafenibTGF-β-and PI3K/AktMediates acquired resistance
Chen et al[26]2011SorafenibEMT and hedgehog signalingDrug resistance
Xin et al[27]2013SorafenibCSCsDrug resistance
Chow et al[28]2013SorafenibEMTAcquired resistance
Fernando et al[29]2014SorafenibTGF-β pathwayPrediction of low susceptibility
Huang et al[30]2013SorafenibEMTDrug resistance
Shi et al[31]2011SorafenibAutophagyDrug resistance
Shimizu et al[32]2012SorafenibAutophagyImpair antitumor effects
Zhai et al[33]2014SorafenibAutophagyAcquired resistance
Liu et al[34]2013SorafenibAutophagyFacilitates resistance
Liang et al[36]2013SorafenibHypoxiaDrug resistance
Mao et al[38]2014SorafenibmicroRNA-193bEnhances cell response
Ebos et al[46]2009SunitinibVEGFR/PDGFRAccelerate metastasis and decrease overall survival
Pàez-Ribes et al[47]2009SunitinibVEGFR/PDGFRIncrease local invasion and distant metastasis
Xiong et al[50]2009SorafenibTECsDrug resistance
Li et al[53]2011BevacizumabDll4-notch signalingDrug resistance

The exact molecular mechanisms underlying the acquired resistance to sorafenib are largely unknown[17]. In 2011, Chen et al[24] reported that activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway mediates acquired resistance to sorafenib in HCC cells. Xia et al[25] also showed that activation of the transforming growth factor beta-and PI3K/Akt-signaling pathways led to acquired resistance to sorafenib in HCC cells. Recently, a number of studies provided evidence showing that many mechanisms such as cancer stem cells[26-29], epithelial-mesenchymal transition[25,26,28-30], autophagy[31-34], and microenvironment (hypoxic, inflammation, and cytokines)[35-38] were involved in the acquired resistance to anti-angiogenesis therapies of HCC[17,39]. In addition, Zhai et al[17] suggested in a review article that sorafenib could simultaneously or sequentially activate the addiction switches and compensatory pathways when its targets were silenced, leading to acquired resistance. Taken together, the exact mechanisms of sorafenib resistance have not been fully elucidated. Therefore, further studies should be conducted to clarify the biological mechanisms, which may further improve the therapeutic effects of sorafenib.

The discovery and development of sorafenib have paved the way to the development of new anti-angiogenesis drugs for advanced HCC or for whom sorafenib failed. More recently, many clinical trials are conducted all over the world, but the problem still exists. Due to good results from preclinical and early-phase studies, some other molecularly targeted drugs have been applied as the second-line treatment for advanced HCC when sorafenib treatment fails. In a number of large-scale randomized phase 3 trials, unfortunately, none of them have shown survival benefits in the first-line (brivanib, sunitinib, erlotinib, and linifanib[40-42]) or second-line (brivanib[43], everolimus[44]) setting after sorafenib progression[18,45].

Furthermore, it was proposed that anti-angiogenic therapies may cause tumor progression and metastasis. Ebos et al[46] reported that sunitinib (a VEGF receptors/PDGF receptors kinase inhibitor) promoted tumor growth and metastasis after a short-term application. Similarly, Pàez-Ribes et al[47] demonstrated that application of angiogenic inhibitors targeting the VEGF signaling pathway elicit malignant progression of tumors to increased local invasion, lymphatic and distant metastasis. Recently, Chow et al[28] reported that advanced HCC patients with acquired resistance to sorafenib might have enhanced tumor growth properties or metastatic potentials. Therefore, understanding the molecular mechanisms underlying anti-angiogenesis therapy resistance may allow us to identify key molecular targets for efficient anti-angiogenesis therapy.

NEW MECHANISMS OF RESISTANCE TO ANTI-ANGIOGENIC DRUGS

During the last five years, increasing evidence suggested that tumor-derived endothelial cells (TECs), which exhibit distinct histologic appearance compared to normal endothelial cells (NECs), may contribute to the resistance of anti-angiogenic therapies[48,49]. In 2009, Xiong et al[50] reported that TECs in human HCC tissues had higher angiogenic capacity and sorafenib resistance than NECs. Some researchers have concluded that TECs can acquire molecular cytogenetic abnormalities in tumor microenvironment; however, the molecular mechanisms underlying the resistance of TECs to anti-angiogenic therapies remain largely unknown. Attempts to resolve this dilemma have resulted in the discovery of transdifferentiation of tumor cells to vascular endothelial cells. In 2010, Wang et al[51] and Ricci-Vitiani et al[52] provided strong evidence showing that a number of TECs that contribute to blood vessels in glioblastoma were transdifferentiated from tumor stem-like cells. Wang et al[51] also showed that blocking the VEGF/VEGFR2 signaling pathway inhibited the maturation of tumor endothelial progenitors into endothelia but not the differentiation of tumor stem-like cells into endothelial progenitors, while the initial differentiation of tumor stem-like cells to endothelial progenitor cells was regulated by Notch1. Consistently, Li et al[53] reported that Delta-like ligand 4 (Dll4; a novel Notch ligand)-Notch signaling mediated the resistance to VEGF inhibitor bevacizumab and Dll4-expressing tumors were resistant to a VEGFR targeting multikinase inhibitor in vivo. Furthermore, it has also been shown that Dll4-mediated Notch signaling played a central role in active vascularization[54] and blockade of Dll4 resulted in tumor growth inhibition even for tumors resistant to anti-VEGF treatments[55].

CONCLUSION

In summary, sorafenib is still the only approved drug for the therapy of advanced HCC. However, the long-term survival benefit from sorafenib treatment is relatively limited. Some other anti-angiogenesis drugs have been evaluated preclinically and clinically for the treatment of HCC, but their effects were not satisfactory. Therefore, identification of novel anti-angiogenic drugs and improvement of the currently available anti-angiogenesis therapies are highlighted for the treatment of HCC.

Footnotes

P- Reviewer: Chua MS, Tamori A S- Editor: Ji FF L- Editor: A E- Editor: Liu SQ

References
1.  Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-2917.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11128]  [Cited by in F6Publishing: 11613]  [Article Influence: 893.3]  [Reference Citation Analysis (4)]
2.  de Lope CR, Tremosini S, Forner A, Reig M, Bruix J. Management of HCC. J Hepatol. 2012;56 Suppl 1:S75-S87.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 409]  [Cited by in F6Publishing: 451]  [Article Influence: 37.6]  [Reference Citation Analysis (0)]
3.  Llovet JM. Focal gains of VEGFA: candidate predictors of sorafenib response in hepatocellular carcinoma. Cancer Cell. 2014;25:560-562.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047-2063.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 475]  [Cited by in F6Publishing: 500]  [Article Influence: 31.3]  [Reference Citation Analysis (0)]
5.  van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, Machat G, Grubinger M, Huber H, Mikulits W. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol. 2009;5:1169-1179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 236]  [Cited by in F6Publishing: 256]  [Article Influence: 18.3]  [Reference Citation Analysis (0)]
6.  Earl TM, Chapman WC. Hepatocellular carcinoma: resection versus transplantation. Semin Liver Dis. 2013;33:282-292.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 37]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
7.  Rahbari NN, Mehrabi A, Mollberg NM, Müller SA, Koch M, Büchler MW, Weitz J. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 2011;253:453-469.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 310]  [Cited by in F6Publishing: 354]  [Article Influence: 27.2]  [Reference Citation Analysis (0)]
8.  Zhu AX, Duda DG, Sahani DV, Jain RK. HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol. 2011;8:292-301.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 335]  [Cited by in F6Publishing: 393]  [Article Influence: 30.2]  [Reference Citation Analysis (0)]
9.  Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140:1410-1426.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 331]  [Cited by in F6Publishing: 363]  [Article Influence: 27.9]  [Reference Citation Analysis (0)]
10.  Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9016]  [Cited by in F6Publishing: 9474]  [Article Influence: 592.1]  [Reference Citation Analysis (1)]
11.  Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245-1255.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3249]  [Cited by in F6Publishing: 3472]  [Article Influence: 289.3]  [Reference Citation Analysis (3)]
12.  Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS. 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.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3854]  [Cited by in F6Publishing: 4327]  [Article Influence: 270.4]  [Reference Citation Analysis (0)]
13.  Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, Ladrón de Guevara L, Papandreou C. First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study. Int J Clin Pract. 2012;66:675-683.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 94]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
14.  Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, de Guevara LL, Papandreou C. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68:609-617.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 181]  [Cited by in F6Publishing: 182]  [Article Influence: 18.2]  [Reference Citation Analysis (0)]
15.  Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5972]  [Cited by in F6Publishing: 6326]  [Article Influence: 486.6]  [Reference Citation Analysis (1)]
16.  Zhang X, Yang XR, Huang XW, Wang WM, Shi RY, Xu Y, Wang Z, Qiu SJ, Fan J, Zhou J. Sorafenib in treatment of patients with advanced hepatocellular carcinoma: a systematic review. Hepatobiliary Pancreat Dis Int. 2012;11:458-466.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol. 2013;5:345-352.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 134]  [Cited by in F6Publishing: 140]  [Article Influence: 12.7]  [Reference Citation Analysis (1)]
18.  Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20:2072-2079.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 272]  [Cited by in F6Publishing: 301]  [Article Influence: 30.1]  [Reference Citation Analysis (0)]
19.  O’Connor R, Clynes M, Dowling P, O’Donovan N, O’Driscoll L. Drug resistance in cancer - searching for mechanisms, markers and therapeutic agents. Expert Opin Drug Metab Toxicol. 2007;3:805-817.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 43]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
20.  Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592-603.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2122]  [Cited by in F6Publishing: 2181]  [Article Influence: 136.3]  [Reference Citation Analysis (0)]
21.  Blivet-Van Eggelpoël MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, Housset C, Rosmorduc O, Desbois-Mouthon C. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012;57:108-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 118]  [Cited by in F6Publishing: 125]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
22.  Ezzoukhry Z, Louandre C, Trécherel E, Godin C, Chauffert B, Dupont S, Diouf M, Barbare JC, Mazière JC, Galmiche A. EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib. Int J Cancer. 2012;131:2961-2969.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 109]  [Cited by in F6Publishing: 119]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
23.  Zhang Z, Zhou X, Shen H, Wang D, Wang Y. Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study. BMC Med. 2009;7:41.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 108]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
24.  Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, Cheng AL. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 2011;337:155-161.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 217]  [Cited by in F6Publishing: 235]  [Article Influence: 18.1]  [Reference Citation Analysis (1)]
25.  Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013;58:629-641.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 295]  [Cited by in F6Publishing: 315]  [Article Influence: 28.6]  [Reference Citation Analysis (0)]
26.  Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA, Wu J. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 2011;55:838-845.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 157]  [Cited by in F6Publishing: 153]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
27.  Xin HW, Ambe CM, Hari DM, Wiegand GW, Miller TC, Chen JQ, Anderson AJ, Ray S, Mullinax JE, Koizumi T. Label-retaining liver cancer cells are relatively resistant to sorafenib. Gut. 2013;62:1777-1786.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 79]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
28.  Chow AK, Ng L, Lam CS, Wong SK, Wan TM, Cheng NS, Yau TC, Poon RT, Pang RW. The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance. PLoS One. 2013;8:e78675.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 89]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
29.  Fernando J, Malfettone A, Cepeda EB, Vilarrasa-Blasi R, Bertran E, Raimondi G, Fabra A, Alvarez-Barrientos A, Fernández-Salguero P, Fernández-Rodríguez CM. A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells. Int J Cancer. 2014;Epub ahead of print.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 87]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
30.  Huang XY, Ke AW, Shi GM, Zhang X, Zhang C, Shi YH, Wang XY, Ding ZB, Xiao YS, Yan J. αB-crystallin complexes with 14-3-3ζ to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma. Hepatology. 2013;57:2235-2247.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 117]  [Cited by in F6Publishing: 127]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
31.  Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, Wang XY, Dai Z, Peng YF, Gu CY. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011;7:1159-1172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 229]  [Cited by in F6Publishing: 259]  [Article Influence: 19.9]  [Reference Citation Analysis (0)]
32.  Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T. Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer. 2012;131:548-557.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 197]  [Cited by in F6Publishing: 187]  [Article Influence: 15.6]  [Reference Citation Analysis (0)]
33.  Zhai B, Hu F, Jiang X, Xu J, Zhao D, Liu B, Pan S, Dong X, Tan G, Wei Z. Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther. 2014;13:1589-1598.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 173]  [Cited by in F6Publishing: 197]  [Article Influence: 19.7]  [Reference Citation Analysis (0)]
34.  Liu B, Cao Y, Jiang H, Mao A. Autophagy facilitates the sorafenib resistance of hepatocellular carcinoma cells. West Indian Med J. 2013;62:698-700.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 7]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
35.  Ribatti D, Crivellato E, Vacca A. Inflammation and antiangiogenesis in cancer. Curr Med Chem. 2012;19:955-960.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, Liu H, Tian L, Fang X, Meng X. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology. 2013;57:1847-1857.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 182]  [Cited by in F6Publishing: 203]  [Article Influence: 18.5]  [Reference Citation Analysis (0)]
37.  Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144:512-527.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 486]  [Cited by in F6Publishing: 552]  [Article Influence: 50.2]  [Reference Citation Analysis (0)]
38.  Mao K, Zhang J, He C, Xu K, Liu J, Sun J, Wu G, Tan C, Zeng Y, Wang J. Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib. Cancer Lett. 2014;352:245-252.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 46]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
39.  Makarova AS, Lazarevich NL. Deregulation of signaling pathways involved in sorafenib resistance of hepatocellular carcinoma. Klin Lab Diagn. 2013;66-68, 34-37.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517-3524.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 557]  [Cited by in F6Publishing: 564]  [Article Influence: 51.3]  [Reference Citation Analysis (0)]
41.  Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067-4075.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 523]  [Cited by in F6Publishing: 563]  [Article Influence: 51.2]  [Reference Citation Analysis (0)]
42.  Zhu AX, Rosmorduc O, Evans J, Ross P, Santoro A, Carrilho FJ, Leberre MA, Jensen M, Meinhardt G, Kang YK. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with hepatocellular carcinoma (HCC). ESMO Congress. 2012;Abstr 917.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509-3516.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 434]  [Cited by in F6Publishing: 463]  [Article Influence: 42.1]  [Reference Citation Analysis (0)]
44.  Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57-67.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 436]  [Cited by in F6Publishing: 456]  [Article Influence: 45.6]  [Reference Citation Analysis (0)]
45.  Patel A, Sun W. Molecular targeted therapy in hepatocellular carcinoma: from biology to clinical practice and future. Curr Treat Options Oncol. 2014;15:380-394.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 20]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
46.  Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232-239.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1371]  [Cited by in F6Publishing: 1382]  [Article Influence: 92.1]  [Reference Citation Analysis (0)]
47.  Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220-231.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1813]  [Cited by in F6Publishing: 1855]  [Article Influence: 123.7]  [Reference Citation Analysis (0)]
48.  Hida K, Hida Y, Shindoh M. Understanding tumor endothelial cell abnormalities to develop ideal anti-angiogenic therapies. Cancer Sci. 2008;99:459-466.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 90]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
49.  Bussolati B, Deregibus MC, Camussi G. Characterization of molecular and functional alterations of tumor endothelial cells to design anti-angiogenic strategies. Curr Vasc Pharmacol. 2010;8:220-232.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Xiong YQ, Sun HC, Zhang W, Zhu XD, Zhuang PY, Zhang JB, Wang L, Wu WZ, Qin LX, Tang ZY. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res. 2009;15:4838-4846.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 153]  [Cited by in F6Publishing: 166]  [Article Influence: 11.1]  [Reference Citation Analysis (0)]
51.  Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829-833.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 882]  [Cited by in F6Publishing: 867]  [Article Influence: 61.9]  [Reference Citation Analysis (0)]
52.  Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 2010;468:824-828.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 962]  [Cited by in F6Publishing: 966]  [Article Influence: 69.0]  [Reference Citation Analysis (0)]
53.  Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, Bridges E, Shi W, Snell C, Bowden ET. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011;71:6073-6083.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 169]  [Cited by in F6Publishing: 183]  [Article Influence: 14.1]  [Reference Citation Analysis (0)]
54.  Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444:1083-1087.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 743]  [Cited by in F6Publishing: 738]  [Article Influence: 43.4]  [Reference Citation Analysis (0)]
55.  Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444:1032-1037.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 768]  [Cited by in F6Publishing: 792]  [Article Influence: 46.6]  [Reference Citation Analysis (0)]