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Erschienen in: Cancer Cell International 1/2018

Open Access 01.12.2018 | Review

Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight

verfasst von: K. Lohitesh, Rajdeep Chowdhury, Sudeshna Mukherjee

Erschienen in: Cancer Cell International | Ausgabe 1/2018

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, accounting for almost 90% of total liver cancer burden. Surgical resection followed by adjuvant and systemic chemotherapy are the most meticulously followed treatment procedures but the complex etiology and high metastatic potential of the disease renders surgical treatment futile in majority of the cases. Another hindrance to the scenario is the acquired resistance to drugs resulting in relapse of the disease. Hence, to provide insights into development of novel therapeutic targets and diagnostic biomarkers, this review focuses on the various molecular mechanisms underlying chemoresistance in HCC. We have provided a comprehensive summary of the various strategies adopted by HCC cells, extending from apoptosis evasion, autophagy activation, drug expulsion to epigenetic transformation as modes of therapy resistance. The role of stem cells in imparting chemoresistance is also discussed. Furthermore, the review also focuses on how this knowledge might be exploited for the development of an effective, prospective therapy against HCC.
Hinweise
K. Lohitesh and Rajdeep Chowdhury contributed equally to this work

Introduction

Hepatocellular carcinoma is currently considered as a rapidly evolving disease. According to the Globocan report, an estimated 782,451 new liver cancer cases and 745,517 cancer deaths have occurred worldwide in 2012. Also, as per the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) the relative 5-year survival rate of HCC between 2002 and 2008 has been as low as 15%. The main causative factors contributing to the disease have been chronic alcohol abuse, infection with hepatitis B or hepatitis C virus and food contaminations [1]. As a consequence of such varied etiologies, HCC is a heterogeneous malignancy with complex carcinogenesis. Also despite advances in development of early detection methodologies, the ineffective and expensive procedures available for treatment of HCC pose a challenge for the disease management. In fact, 80% of HCC patients are currently diagnosed at an advanced stage of the disease with a median survival of 6–8 months only. Surgical resection followed by chemotherapy is the most established curative treatment for HCC. However, operating on the liver can be both complicated and unachievable due to size and distribution of the tumor in the liver, blood vessels and other vital organs. Also, complete surgical removal is mostly not possible for more than two-third of HCC patients where the disease have already metastasized and the patients are at an advanced stage [24]. Current treatment procedures mainly include cryosurgery, radiofrequency ablation and embolization but they are mostly palliative approaches without much success rate [5]. Moreover, post-surgery recurrence of the tumor has been a major issue for more than 90% of HCC patients. This has forced to shift the treatment regime towards systemic chemotherapy. Drugs that are used in HCC as monotherapy are listed in Table 1. But currently the use of single agents in therapy is practically non-existent because of their low response. For example, in a large study of doxorubicin, no responses were noted among 109 patients; also among 475 patients who received doxorubicin in various studies, only 16% response rate was documented, with a median survival of 3–4 months only [6]. This led to the evolution of combined regimen drugs. A combination of capecitabine + oxaliplatin + cetuximab showed modest activity only [7]. Among cisplatin-based regimens, the best response rate was obtained with the treatment of PIAF (cisplatin + adriamycin + 5-FU + INF) [8]. More recently, GEMOX (gemcitabine + oxaliplatin) has also been evaluated in a phase-II study, with promising results [9]. Other chemotherapeutic drugs like, sorafenib are also often used to attenuate HCC tumor [10, 11]. But, acquisition of chemoresistance continues to be a major constraint in chemotherapy-based treatment of the disease. An alternative strategy adopted was the administration of chemo-drugs like cisplatin, mitomycin C and doxorubicin through hepatic artery infusion [12]. However, surgical catheter insertion into the hepatic artery and inoperable conditions of the tumor owing to HCC’s high metastatic potential became a limiting factor. Thus despite recent advancements in chemotherapy, HCC still remain a fatal disease. Hence, focus should be reoriented more on unraveling the molecular mechanisms behind chemoresistance with an objective to develop novel therapeutic targets and diagnostic biomarkers.
Table 1
List of drugs and their targets used against HCC
S. No.
Name of the drug
Target molecule
Mechanism
Limitation
Year and references
1
Tamoxifen
Antagonist of estrogen receptor
To inhibit P-glycoprotein-mediated drug resistance
Minimum effect
2000 [88]
2
5-Fluoracil
Thymidylate synthase
Incorporated its metabolites into RNA and DNA
Requires co-treatment with leucovorin and methotrexate, to increase the anticancer activity of 5-Fu
2003 [89]
3
Thalidomide
VEGF, inhibits TNF-α synthesis, inhibition of Ikβ kinase activity
Anti-angiogenic activity and immune-modulatory
Fatigue, somnolence, constipation
2003, 2004 [90, 91]
4
Octreotide
Analogue of somatostatin receptors
Anti-tumor effect.
Somatostatin receptor type 2 (SSTR2) was found in some but not all patients with HCC
2004, 2006 [92, 93]
5
Sorafenib
Raf, VEGFR2, VEGFR3, PDGFRs
Inhibits tumor angiogenesis by blocking the activation of the tyrosine kinase receptors
Hypertension, diarrhea, proteinuria, skin-related toxicities, an increased risk for thromboembolism and bleeding events
2006, 2008 [10, 11]
6
Sunitinib
PDGFRs, KIT, RET, and FLT3
Inhibits tumor angiogenesis by blocking the activation of the tyrosine kinase receptors
Modest clinical efficacy
2009 [94]
7
Bevacizumab
VEGF
Blocks VEGF binding to its receptor
Low rate of response, gastrointestinal bleeding, including variceal bleeding
2009 [95]
8
Erlotinib, gefitinib and cetuximab
EGFR
Tyrosine kinase inhibitor, acts on the epidermal growth factor receptor (EGFR)
Minimum effect
2009 [96]
9
Doxorubicin
DNA topoisomerase II inhibitors
Induce histone eviction
The use of single agents in therapy is practically non-existent currently because of its erratic and low response
2013 [97]
10
Cisplatin
DNA
Cross link with purine causes DNA damage and ultimately induces apoptosis
Allergic reactions, gastrointestinal disorders, decrease immunity to infections, kidney problems, hemorrhage
2014 [98]
11
Oxaliplatin
DNA
Binds to guanine and cytosine leading to cross-linking of DNA
Increase autophagy level results in a tumor resistance
Reduction of DYRK2 promotes cell proliferation, and resistance to Oxaliplatin
2016 [99]

Various mechanism of chemoresistance in HCC cells

Reduced drug uptake, efflux of drugs and drug metabolism

A poor response to pharmacological regimens in the treatment of liver cancer can be due to complex mechanisms like, reduced drug uptake, enhanced drug efflux, intracellular drug metabolism leading to reduced concentrations of active agents, changes in the molecular targets of the drugs and enhanced repair of drug-induced modifications. In some cases, the conjoint enhanced expression of drug efflux pumps like, both MDR1 and MRP2 seems to be a contributing factor towards resistance [13]. Thus in patients with non-surgical HCC the response to chemotherapy has been found to be inversely proportional to the expression of multi-drug transport system. In this context, different transporters with their mode of action are listed in Table 2. Hence, recent therapeutic strategies must involve drug pump antagonist against the resistant cells. Alternate mechanisms employed by the tumor cells to inactivate anti-cancer drugs are over-expression of detoxifying enzymes like phase-I (cytochrome P450) and phase-II enzymes in conjugation with glucuronic acid or with glutathione. Cytochrome P450 enzymes and glutathione S-transferases, along with other enzymes like epoxide hydrolase, phase II xenobiotic metabolizing enzymes are reported to increase cells’ resistance to alkylating agents or drugs like, cisplatin in HCC [14, 15]. Enhanced drug in-activation by uridine glucuronosyltransferase-1A has also been found to be associated with drug resistance in HCC [14, 16]. Thus, a vivid understanding of the intra-cellular biology of chemoresistance is desirable to develop new therapies, which would help to override the resistance acquired by the conventional cytotoxic drugs.
Table 2
List of drug transport systems and their status in HCC
S. No.
Transporter
Mode of action
Up-regulated or down-regulated
References
1
MDR1 (ABCB1 or P-glycoprotein), MRP1 (ABCC1), MRP2 (ABCC2), MRP3(ABCC3) and ABCG2
Extrudes unrelated anti-tumoral agents like anthracyclines, taxanes, vinca alkaloids etc. from the cell
Up regulated
[18, 100]
2
OATP1B1 and OATP1B3
Transports anti-tumor drugs inside the cells
Down regulated
[101, 102]
3
SLC28 and SLC29
Uptake of nucleoside derived anticancer drugs
Down regulated
[103]
4
Organic cationic transporter-1 (OCT1)
Uptake of tyrosine kinase inhibitors
Down regulated; hyper-methylation of the SLC22A1 promoter
[104]

DNA repair pathway aberrations and chemoresistance in HCC

HCC develops in a milieu of underlying chronic inflammation, which promotes DNA damage and chromosomal aberration. It has been observed that HCC deploys DNA repair mechanisms, like stalled DNA replication fork by homologous recombination (HR), base mismatches by mismatch repair (MMR), double-strand break (DSB), non homologous end joining (NHEJ) to become chemoresistant. They can upregulate various enzymes involved in DNA repair mechanisms for acquisition of chemoresistance [17]. However, it is not necessary that the repair pathways are always upregulated in chemoresistant models. Defect in MMR pathway genes can also induce resistance to certain therapeutic agents. In HCC cells, over-expression of MDR-1 is associated with patients having defective MMR genes contributing to drug resistance [18]. A better understanding of the role of DDR pathways in HCC may help us to develop novel strategies for treatment or prevention of HCC. Various DNA repair enzymes, which are involved in chemoresistance, are listed in Table 3; these can be exploited in a judicious way to develop novel therapeutic strategies.
Table 3
List of DNA repair enzymes de-regulated in HCC
S .No.
DNA repair enzyme
Therapy given
Repair mechanism involved
Reference
1
ERCC-1
Platinum based anti-cancer agents
Nucleotide excision repair (NER)
[105]
2
Flap endonucleases (FENs)
Cisplatin
Nucleotide excision repair (NER) and Base excision repair (BER)
[106]
3
Chk2
Paclitaxel
DNA damage checkpoint
[107]
4
ATM signaling
Sorafenib
DNA damage checkpoint
[108]
5
Apurinic/apyrimidinic endonuclease (APE1)
Irradiation
Base excision repair (BER)
[109]

Impairment of the apoptotic machinery and associated chemoresistance in HCC

Apoptosis is a highly conserved phenomenon contributing to tissue homeostasis by targeted elimination of single cells without disrupting the functionality of the respective tissue. Cancer strikes by developing resistance against cell death signaling pathways, like apoptosis upon failure of immune surveillance. A similar aspect underlies the poor responsiveness of HCC towards chemotherapy. Upon exposure to cytotoxic agents, HCC cells down regulate death receptor CD95 and upregulate CD95-ligand (FasL) [1922]. The defect in down-stream Fas-associated death domain (FADD) signaling also potentially contributes to the chemoresistance in HCC [23, 24]. It has further been observed that the anti-apoptotic protein-brain and reproductive organ-expressed protein (BRE), can bind to tumor necrosis factor (TNF) receptor-1 and Fas conferring the ability of chemoresistance to HCC cells by inhibiting death receptor induced apoptosis [25, 26]. FLICE inhibitory protein (c-FLIP), a recently identified intracellular inhibitor of caspase-8 activation that can potentially inhibit death signaling mediated by various death receptors, like Fas, TNF-receptor (TNF-R), and TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) and by NFĸB activation, was found to be constitutively expressed in HCC cell lines and over-expressed in human HCC tissues. An over-expression of c-FLIP was associated with shorter recurrence free survival time in HCC patients [27, 28]. A resistance towards TRAIL induced apoptosis is also reported in HCC by virtue of loss of TRAIL receptor and over activation of NF-κB. Activation of NF-κB, and nuclear localization of NF-κB, p65, p50 and p52 subunits is often found to be associated with cell proliferation and resistance in HCC [29]. Furthermore, Mcl-1, an anti-apoptotic member of the Bcl-2 family, is over-expressed in HCC, which contributes to the malignant phenotype and resistance towards apoptosis and chemotherapeutics. On a similar note, over-expression of Bcl-2 and Bcl-xL has been found in HCC cell lines and is associated with resistance to paclitaxel [30]. An over-expression of a specific set of microRNA, like, miR23a that allow the escape from TGF-β-induced apoptosis has also been observed in HCC [31]. Additionally, the presence of abnormally functioning p53 is also a common finding in many drug-resistant tumor cells and HCC is no exception. It is reported that p53 contributes to cell survival and chemoresistance in HCC under nutrient-deprived conditions by enhancing autophagy [32]. Also, gain of function (GOF) mutations in p53 are reported to impart resistance to doxorubicin and paclitaxel in HCC cells [33]. Overall apoptosis resistance in HCC is the outcome of varied molecular alterations and further research needs to be channelized in this direction to trace the links to individual pathways regulating apoptosis in HCC.

Activation of cell survival signaling and evasion of chemoresistance in HCC

In conjunction with de-regulation of apoptosis, HCC cells simultaneously trigger multiple survival signaling pathways to evade the physicians armory and maintain neoplastic progression. For example constitutive activation of Insulin-like growth factor (IGF) signaling pathway is an important contributor to drug resistance in HCC against sunitinib [34]. Various other growth receptors like epidermal growth factor receptor (EGFR) and connective tissue growth factor (CTGF) are also reported to be upregulated and involved in proliferation and drug resistance of HCC [35, 36]. Also, over-expression of Forkhead box M1 (FoxM1) transcription factor that act as a master regulator of HCC cell growth through regulation of cell cycle, glycolysis and EMT contributes significantly to the development of chemoresistance in HCC [37]. The multiple proliferation signaling pathways that enhance angiogenesis, drug resistance and cell proliferation facilitating HCC cell growth are summarized in Table 4. A targeted therapy by specific inhibition of alternated signaling cascades can therefore be thought upon as one of the options to decelerate HCC progression.
Table 4
Molecular signaling pathways altered in HCC
S. No.
Altered signaling pathways
Relevant molecule
Alteration
Targeted therapies
References
1
Hedgehog
SMO
Activating overexpression
GDC-0449, cyclopomine
2006 [110]
7
Hippo
MST1/2
Down-regulated
2009 [111]
8
Hippo
pYAP
Down-regulated
2009 [111]
3
Notch
NOTCH1
Overexpression
Gamma secretase
2009 [112]
2
Wnt/beta-catenin
APC
Inactivating mutation
2012 [113]
6
PI3K/AKT/mTOR
MTORC1
Up-regulated
Everolimus, rapamycin
2012 [114]

Autophagy as defense to chemotherapeutic stress

Autophagy is an evolutionarily conserved process through which lysosomal degradation of damaged and superfluous cell components are achieved and recycled back into basic bio-molecules in the cytosol. HCC cells can use autophagy as a cellular defense mechanism upon facing stress conditions like, nutrient deprivation, hypoxia and drug insult. Reports of autophagy activation post oxaliplatin treatment and enhanced oxaliplatin induced cell-death upon autophagy inhibition in HCC, supports the pro-survival role of autophagy in HCC cells [38]. Similar to above, the anticancer effects of two other drugs, like, bevacizumab and sorafenib were enhanced upon autophagy inhibition in HCC [39, 40]. Our study, also shows that autophagy plays a pro-tumorigenic role facilitating EMT in HCC cells [41]. Inhibition of autophagy by late stage autophagy inhibitors like, chloroquine showed a marked suppression of liver tumor in vivo studies as well [39]. Furthermore, cisplatin treatment is known to trigger unfolded protein response (UPR) in HCC cells which subsequently inhibits cell apoptosis through activation of autophagy [42]. Accumulation of phosphorylated p62, a protein that is generally degraded through autophagy, was found to stimulate hepatitis C virus induced tumors in HCC. Concurrently, inhibition of p62 phosphorylation suppressed proliferation and anticancer drug tolerance in HCC [43]. In spite of a spur in research articles demonstrating the role of autophagy in cancer, the exact role of autophagy on tumor cells is still controversial and remains to be further elucidated in hepatocellular carcinoma.

Cancer stem cells in HCC chemoresistance

The ‘stem cell model’ of carcinogenesis suggests that cancer originates and is maintained by a rare fraction of cells called the cancer stem cells (CSCs) [44, 45]. They are responsible for the growth of neoplastic tissues and are naturally resistant to chemotherapy. In HCC, CSC markers include epithelial cell adhesion molecule (EpCAM), CD133, CD90, CD44, CD24, CD13, and oval cell marker OV6, some of which confer chemoresistance property to them. CD133+ HCC cells are reported to confer chemoresistance via the preferential activation of the Akt and Bcl-2 survival pathway [46]. The EpCAM+ CSCs in HCC also show chemo-resistance against genotoxic agents like, 5-FU [47]. HCC tumor growth and metastasis are thus undoubtedly driven by CSCs leading to transient effects of the current chemotherapies against HCC.

Evidences for epigenetic regulation of chemoresistance in HCC

The role of epigenetics, has surfaced as an emerging topic in regulation of chemoresistance in the last decade. Amongst the epigenetic modifications, DNA methylation has garnered a great deal of attention recently in terms of development of chemoresistance. HCC tumors exhibit specific DNA methylation signatures that can be associated with tumor progression implying the potential benefit for their identification and subsequent targeting. Hernandez-Vargas et al. were able to identify a set of hypermethylated gene promoters (APC, RASSFIA, CDKN2A and FZD7) which could differentiate HCC tumors from paired surrounding control liver tissues. Specifically, promoter methylation of DNMT1was also found to be significantly associated with poor prognosis [48]. Song et al. further analyzed DNA methylation pattern in HCC tissues from 27 HCC patients, and observed significant enrichment of promoter methylation in various genes involved in cell death and cancer; the top five of them were genes like, BMP4, CDKN2A, GSTP1, and NFATC1 [49]. Also, another study showed that transcriptional repression of miR-193a-3p promoter through hyper methylation is involved in 5-FU resistance in HCC cells [50]. Hence, suppression of DNA methylation was capable of enhancing the sensitivity of HCC cells to 5-fluorouracil (5-FU). Though, 5-aza-2′-deoxycytidine (5-aza-dC), a specific DNA methylation inhibitor alone, did not induce cell death in vitro; however, a combination of 5-aza-dC with 5-FU showed a reduction in cell viability and induction of apoptosis to a greater degree than with 5-FU only [51]. However, in a clinical study with low dose decitabine (5-Aza-2′-deoxycytidine), substantial remission and favorable toxicity profiles were obtained in patients with advanced HCC [52]. Evaluation of another epigenetic aspect- histone methylation has been less explored and correlated with clinico-pathlogical features in HCC. However, high levels of trimethylated histone H3 lysine 4 (H3K4me3), a transcriptional suppressive signature was found to be associated with poor survival, prognosis and aggressive tumor features in HCC [53]. Also, subunits of polycomb repressive complexes-2 (PRC-2)-SUZ12 and EZH2 were found to impart distinct roles during HCC pathogenesis. Over-expression of EZH2 was consistently observed in advanced HCC [54] while in, chronic HBV infection, the HBx protein was found to modulate SUZ12 protein levels, that maintained “stemness” of a sub-population of hepatocyte cells thus contributing to drug refractoriness [55]. Similar to altered DNA methylation and histone modification patterns, aberrant miRNA expression profiles are also linked to drug resistance and liver progression. A list of miRNAs commonly de-regulated in HCC is shown in Table 5. Another sub-population of non-coding RNAs (ncRNAs), the long non-coding RNAs (lncRNAs) have emerged as critical regulators of HCC drug sensitivity thus offering a novel exciting opportunity to treat HCC. LncRNA HOTAIR (HOX antisense intergenic RNA) and MALAT-1 (metastasis-associated lung adenocarcinoma transcript 1) were found to be upregulated in large cohorts of HCC patients and their suppression increased the chemotherapeutic sensitivity of HCC cells to cisplatin and doxorubicin [56, 57]. Alongside DNA methylation inhibitors, HDAC inhibitors have also been investigated in preclinical and clinical studies in HCC. Belinostat, a deacetylase inhibitor was found to stabilize un-resectable advanced HCC [58, 59]. However, more in-depth understanding of epigenetic alterations is required to gain more insights into the in vivo determinants of responses to epigenetic drugs in HCC.
Table 5
List of miRNAs de-regulated in HCC
S. No.
MiRNAs deregulated in HCC
Mechanism
Expression Level
Reference
1
miR-21
Potential biomarker for early stage HCC diagnosis
Up-regulated
[115]
2
miR-338-3p
Suppresses HCC cell invasion by inhibiting metalloproteinase (MMP-9)
Down-regulated
[116]
3
miR-122
Inhibits cycle cyclins & reduces MDR expression
Down-regulated
[117]
4
miR-181& let-7
IL-6 and twist-regulated miRNA expression
Up-regulated
[118]
5
miR-193a-3p
Affects DNA methylation state
Up-regulated
[119]
6
miR-199a/b-3p
Targets mTOR and c-met
Down-regulated
[120]
7
miR-210
Targets apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) in hypoxic HCC
Down-regulated
[121]
8
miR-494
Reduces the expression of PTEN but increases PI3 K and p-Akt expression
Up-regulated
[122]
9
miR-1180
Activates NF-κB pathway by downregulating its negative regulators
Up-regulated
[123]
10
miR-122
Up-regulates IGF-1R that contribute to activation of RAS/RAF/ERK signaling which is associated with drug resistance
Down-regulated
[124]

Ribosome biogenesis as HCC resistance mechanism

The cancer cells for prolonged survival can employ excessive ribosome biogenesis and translation initiation. Recently, RACK1, the receptor for activated C-kinase 1, a component of the 40S subunit of ribosome, was found to be upregulated in HCC and contribute to chemoresistance in vitro and in vivo as well. The preferential translation involved in growth and survival was promoted by ribosomal RACK1 coupled with PKCβII by phosphorylating eIF4E. Inhibition of PKCβII or depletion of eIF4E abolished RACK1-mediated resistance in HCC [60]. These results imply that RACK1 may function as a factor promoting chemoresistance in HCC and targeting RACK1 can be an efficacious strategy for HCC cure.

Role of telomerase in HCC chemoresistance

The enzyme telomerase is activated in many malignant tumors; i It is known to bestow anti-apoptotic and chemoresistant properties to cancer cells. In accordance to above, it was observed that siRNA against human telomerase reverse transcriptase (hTERT) and cisplatin therapy act synergistically in suppression of HCC progression compared to individual therapy [61]. Low-dose of cisplatin also activated telomerase activity in SMMC7721 human HCC cell line. NF-κB has been reported to be responsible for cisplatin-induced activation of the telomerase in a dose dependent manner. It was thus observed that upregulation of hTERT expression by cisplatin is NF-κB-dependent which contributes to chemotherapy resistance in HCC cells [62]. Additionally, translocation of telomerase into mitochondria can prevent intrinsic pathway of apoptosis under chemotherapeutic stress. Cisplatin-resistant SK-Hep1 cells showed increased translocation of hTERT to mitochondria resulting in decrease of apoptosis. Mitochondrial translocation of hTERT reduced mtDNA damage though the telomere length of chemoresistant cells was shortened. Drug-resistant HCC cells can thus escape from apoptosis through hTERT-mediated mitochondrial protection [63].

Topoisomerases and HCC chemoresistance

Human DNA topoisomerases are essential enzymes that play a central role in DNA duplex maintenance. In many cancers, aberrant expression of topoisomerase2A (TOP2A) has been reported and is considered to be a valuable prognostic marker for tumor advancements, recurrences and predictor of poor survival [64, 65]. Elevated protein score of TOP2A has also been correlated with non-responsiveness to chemotherapy in in vitro doxorubicin resistant HCC models [66]. Another report further shows a copy number gain in TOP2A locus in doxorubicin resistant HCC cells [67]. Strikingly, the topoisomerase transfected cell lines were around five–tenfold more resistant to cisplatin and other alkylating drugs endorsing its role in drug resistance. As expected, hence combination of Tirapazamine (TPZ), a new anti-cancer drug with Topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several HCC cell types [68]. Targeting topoisomerases can thus be an appropriate strategy for HCC patients who are resistant to conventional cytotoxic therapy.

Altered lipid metabolism

Cancer cells are able to synthesize lipids in a manner similar to embryonic tissues, and an altered lipid metabolism has often been linked to cancer pathogenesis. For example, stearoyl-coA de-saturase (SCD), a rate limiting enzyme and an essential regulator of lipid homeostasis in the liver is strongly over expressed in HCC. Interestingly, administration of 5-FU also resulted in a time dependent, upregulation of SCD through PI3K and JNK-mediated pathways [69]. While, suppression of SCD by genetic or pharmacologic strategies resulted in increased sensitivity to chemotherapy-induced apoptosis suggesting that SCD play a pro-survival role in HCC [69]. Similarly, another enzyme involved in lipid metabolism- carbonyl reductase1 (CBR1), known to protect cells against lipid peroxidation, promoted chemoresistance in HCC through induction of the master transcription regulator and angiogenesis promoter-HIF-1α [70]. Furthermore, isolated mitochondria from HCC with increased cholesterol levels were resistant to release of cytochrome c or Smac/DIABLO in response to various apoptotic stimuli [71]. Thus, altered lipid metabolism can emerge as a novel therapeutic niche in HCC therapy.

Tumor microenvironment

Tumor microenvironment (TME) plays a crucial role in HCC development and maintenance. The critical cellular and non-cellular components of HCC tumor microenvironment are showed in Fig. 1 and their functions are summarized in Table 6 [72]. Unlike normal fibroblasts, cancer-associated fibroblasts (CAFs) are the most abundant type of connective tissue present in the TME of multiple cancer cell types [73, 74]. CAFs play an important role in the HCC microenvironment as most liver cancers are derived from fibrosis and cirrhosis. Chuang et al. in 2012 and 2013 showed that co-culture of CAFs with HCC can enhance proliferation, migration, and invasion by altering the transcriptome of HCC cells [75, 76]. The CAF cells can specifically upregulate pro-inflammatory cytokines like CCL2, CCL26, IL6, and LOXL2, which are correlated with proliferation, invasion and angiogenesis of HCC cells [77]. Another key component of HCC tumor microenvironment is the hepatic stellate cells (HSCs), which are generally involved in the process of liver regeneration mostly in case of injuries [78]. However, in addition to its regenerative property, HSCs can exhibit liver carcinogenesis promoting functions as well. They can secrete growth factors and cytokines like, HGF and IL-6 and can engage in a reciprocal crosstalk with HCC cells [79]. Activated HSCs can promote the migration, proliferation and resistance in HCC cells through modulation of TGF-β signaling [80]. Since HSCs are actively involved in tumor progression, targeting HSCs may represent a prospective therapeutic strategy in HCC. Furthermore, immune cells like, CD4 T cells (Treg) and myeloid-derived suppressor cells (MDSCs), which are also part of TME have been implicated in promoting HCC tumorigenesis [81]. Tumor-associated macrophages (TAMs) can also affect HCC tumor progression through NF-κB, STAT-3, and HIF-1 signaling [81]. Further studies are however required to better understand the function of immune cells in HCC TME for enhancement of immunotherapeutic strategies. Table 7 shows some of the tumor microenvironment targeting drugs that are now under investigation for HCC treatment.
Table 6
List of various components of HCC tumor microenvironment and their role
S. No.
Cellular and non cellular components
Role in tumor microenvironment
Effect of various components
References
1
Tumor associated macrophages (TAMs)
Tumor development by impairing cytotoxic CD8+ T cell mediated immune responses
Chemo resistance in HCC.
[125]
2
Cancer associated fibroblasts (CAFs)
Produces growth factors like hepatocyte growth factor (HGF), members of the epidermal growth factor (EGF), fibroblast growth factor (FGF) and members of Wnt families, and cytokines, such as stromal-derived factor (SDF)-1α and IL-6
Chemo resistance in HCC
[126, 127]
3
Matrix metalloproteinases (MMPs)
Causes tissue remodeling, inflammation, tumor cell growth and metastasis in many cancers. MMP-2,-9, and -14 activate TGF-β1, which reciprocally activates MMP. Upregulation of MMP-9 is connected with provocation of PI3 K/PTEN/AKT/mTOR pathways in human HCCs. MMPs also inhibit apoptosis signaling in cancer cells
Chemo resistance in HCC
[128, 129]
4
Immune cells
CD8+ T cells, NK cells are fooled by cancer cells as an immune evasion mechanism
Poor prognosis in HCC patients
[130, 131]
5
Kupffer cells
Upon activation secrete excessive level of osteopontin
Chemo resistance of cisplatin in small cell lung cancer. It can be postulated to play a role in Hepatocellular carcinoma too
[132]
6
Hepatic stellate cells (HSCs)
Produce collagen in the liver. They get activated upon liver damage and undergo phenotypic changes leading liver fibrosis. They secrete hepatocyte growth factor
Chemo resistance in HCC
[133]
Table 7
Drugs targeting TME in clinical trials for HCC treatment
S. No.
Drug
Molecular targets
Phases of clinical trial
Year and references
1
Sibrotuzumab
FAPs
I
2003 [134]
2
PI-88
HPR
II
2009 [135]
3
Selumetinib
MEK
II
2011 [136]
4
Brivanib
VEGFR, PDGFR
III
2013 [137]
5
Lilifanib
VEGFR
III
2013 [138]
6
Axitinib
VEGFR
II
2015 [139]
7
Galuniserib
TGF-β
I
2015 [140]

Targeted therapy against HCC

For many years, the foundation of HCC treatment has been surgery and non-targeted chemotherapy with conventional drugs like, cisplatin, as discussed earlier. However, over the last decade, partly because of advancements in genomic technologies, targeted therapies with drugs that home into specific cancer cell types and bring about molecular changes have cemented their place as standard treatment for many cancers, HCC is no exception. Sorafenib, a molecular multi-kinase inhibitor has currently been the drug of choice for HCC and is the first molecular targeted agent that has shown survival benefits in HCC patients. However, use of sorafenib has also been hindered by acquisition of resistance [82]; Gao et al. found that elevated fibroblast growth factor 19 (FGF19) expression or hyper-activation of FGF19/FGFR4 signaling was essential for sorafenib resistance in HCC [83]. Hence blocking of FGF19/FGFR4 axis by ponatinib, a third-generation tyrosine–kinase inhibitor, could overcome the resistance of HCC cells to sorafenib [83]. Further, anti-angiogenic drugs like, sunitinib, linifanib and brivanib were tried as independent therapy in HCC but they failed to prove their non-inferiority over sorafenib [84]. Also, HCC patients who are intolerant to sorafenib or have high expression of cellular mesenchymal–epithelial transition factor (c-MET) were found to benefit from Tivantinib therapy, a highly selective inhibitor of c-MET receptor tyrosine kinase [85, 86]. Furthermore, progress in immunotherapy has provided new dimensions to HCC therapy as well. Immune tolerance in HCC is mediated through decreased co-stimulatory signaling that results in immuno-suppression. Hence, anti-human cytotoxic T-lymphocyte antigen 4 (CTLA-4) and anti-programmed death 1 (PD-1) monotherapy have been utilized in HCC treatment but with limited success. Some of the immunomodulators now under investigation for HCC treatment listed in Table 8. Another rapidly emerging immunotherapy approach has been chimeric antigen receptor-engineered (CAR)-T cell therapies that have already demonstrated efficacy against hematologic malignancies. CART technology utilizes the antitumor activity of “domesticated” T cells that have been engineered to express cancer specific antigen-targeted-receptor to treat malignant tumors [87]. However, the major challenge for CAR-T cell therapy in HCC has been the selection of specific antigen to differentiate tumor from normal tissue to prevent off-target effects. The antigens that have till date been used as targets in CAR-T therapy for HCC are mentioned in Table 9. While therapeutic benefit has been achieved in early clinical trials with CAR-T therapy, the use of this therapy is still at its infancy and is limited due to either unique properties of HCC, off-target effects, lack of specific tumor antigens in HCC or cost of production [87].
Table 8
Immune-modulators in clinical trials for HCC treatment
S. No.
Drug
Molecular targets
Phases of clinical trial
Year and references
1
Tremelimumab
CTLA-4
II
2013 [141]
2
Icaritin
IL-6/Jak2/Stat3
II
2015 [142]
3
Lenalidomide
TNF-α, interferon γ, IL-6, IL-10, and IL-12.
II
2015 [143]
4
Codrituzumab
Glypican-3
II
2016 [144]
5
Nivolumab
PD-1
I
2016 [145]
6
Ipilimumab
CTLA-4
II
2017 [146]
7
Tasquinimod
Protein S100A9
II
2017 [147]
Table 9
Application of CAR-T cells for HCC
S. No.
Antigen
Gene transfer vehicle
Phases of clinical trial
Year (Clinicaltrials.gov identifier or reference)
1
Epidermal growth factor receptor
Lentivirus
I/II
2013 [148]
2
Mucin-1
I/II
2015 (NCT02587689)
3
CD133
Retrovirus
I
2015 (NCT02541370)
4
Carcinoembryonic antigen
Retrovirus
Preclinical
2016 [149]
5
Epithelial cell adhesion molecule
I/II
2016 (NCT02729493)
6
Glypican-3
I/II
2016 (NCT02723942)

Conclusion

We believe that drug companies are currently fighting a losing battle against advanced HCC tumors. The various chemotherapeutic drugs currently in use against HCC have shown strong chemoresistance providing a massive setback to therapeutic regimens targeting HCC. Also, liver cancer patients generally have a poor tolerance to chemotherapy due to liver dysfunction. Characterization of molecular strategies underlying chemoresistance is hence essentially needed to identify appropriate targets to effectively sensitize these resistant cells. However, designing such strategies are by no means easy. Till date development of targeted drugs has not yet improved the outcome much significantly. This might be attributed to various factors extending from apoptosis evasion, stem cell activation, enhanced DNA repair, topoisomerase activation, lack of proper targets for immunotherapy to dynamic changes in TME and others, as discussed in this literature (Fig. 2). These factors either independently or in unison contribute to emergence of refractoriness to drug therapy in HCC. To compound the scenario, therapeutic effectiveness may also vary depending on patient properties and at various stages of tumor development. Hence, formulating a unified molecular targeted therapeutic strategy for all HCC patients is unlikely to succeed. Therefore, future therapies targeting HCC should be based on combination of context and stage dependent molecular targeted drugs against resistance with or without conventional drugs to successfully treat HCC.

Authors’ contributions

KL, RC and SM wrote the review. SM and RC conceptualized the content and did corrections as well. All authors read and approved the final manuscript.

Acknowledgements

The authors express their thanks to the funding agency and Birla Institute of Technology and Science, Pilani for all the support and assistance required for the work.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.
Our paper is a review of the literature and we do not need an informed consent.
This review article does not contain any research with human participants or animals performed by any of the authors. Our paper is a review of the literature and we do not need an informed consent.

Funding

DST-SERB Young Scientist award (SB/YS/LS-97/2013) of Dr. Sudeshna Mukherjee.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
Literatur
1.
Zurück zum Zitat Raoul JL. Natural history of hepatocellular carcinoma and current treatment options. Semin Nucl Med. 2008;37(2):S13–8. Raoul JL. Natural history of hepatocellular carcinoma and current treatment options. Semin Nucl Med. 2008;37(2):S13–8.
2.
Zurück zum Zitat Chuma M, Terashita K, Sakamoto N. New molecularly targeted therapies against advanced hepatocellular carcinoma: from molecular pathogenesis to clinical trials and future directions. Hepatol Res. 2015; 45(10):E1–11. Chuma M, Terashita K, Sakamoto N. New molecularly targeted therapies against advanced hepatocellular carcinoma: from molecular pathogenesis to clinical trials and future directions. Hepatol Res. 2015; 45(10):E1–11.
3.
Zurück zum Zitat Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12(7):408–24.PubMedCrossRef Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12(7):408–24.PubMedCrossRef
5.
Zurück zum Zitat Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, et al. Early-Stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation 1. Radiology. 2005;234(3):961–7.PubMedCrossRef Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, et al. Early-Stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation 1. Radiology. 2005;234(3):961–7.PubMedCrossRef
6.
Zurück zum Zitat Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev. 1988;15(1):1–31.PubMedCrossRef Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev. 1988;15(1):1–31.PubMedCrossRef
7.
Zurück zum Zitat Sanoff HK, Bernard S, Goldberg RM, Morse MA, Garcia R, Woods L, et al. Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma. Gastrointest Cancer Res GCR. 2011;4(3):78.PubMed Sanoff HK, Bernard S, Goldberg RM, Morse MA, Garcia R, Woods L, et al. Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma. Gastrointest Cancer Res GCR. 2011;4(3):78.PubMed
8.
Zurück zum Zitat Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97(20):1532–8.PubMedCrossRef Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97(20):1532–8.PubMedCrossRef
9.
Zurück zum Zitat Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC). Cancer. 2007;109(7):1384–90.PubMedCrossRef Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC). Cancer. 2007;109(7):1384–90.PubMedCrossRef
10.
Zurück zum Zitat Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Can Res. 2006;66(24):11851–8.CrossRef Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Can Res. 2006;66(24):11851–8.CrossRef
11.
Zurück zum Zitat Roodhart JM, Langenberg MH, Witteveen E, Voest EE. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol. 2008;3(2):132–43.PubMedCrossRef Roodhart JM, Langenberg MH, Witteveen E, Voest EE. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol. 2008;3(2):132–43.PubMedCrossRef
12.
Zurück zum Zitat Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008.PubMedPubMedCentralCrossRef Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008.PubMedPubMedCentralCrossRef
13.
Zurück zum Zitat Nies AT, Konig J, Pfannschmidt M, Klar E, Hofmann WJ, Keppler D. Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int J Cancer. 2001;94(4):492–9.PubMedCrossRef Nies AT, Konig J, Pfannschmidt M, Klar E, Hofmann WJ, Keppler D. Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int J Cancer. 2001;94(4):492–9.PubMedCrossRef
14.
Zurück zum Zitat Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Can Res. 1994;54(16):4313–20. Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Can Res. 1994;54(16):4313–20.
15.
Zurück zum Zitat Murray GI, Paterson PJ, Weaver RJ, Ewen SW, Melvin WT, Burke MD. The expression of cytochrome P-450, epoxide hydrolase, and glutathione s-transferase in hepatocellular carcinoma. Cancer. 1993;71(1):36–43.PubMedCrossRef Murray GI, Paterson PJ, Weaver RJ, Ewen SW, Melvin WT, Burke MD. The expression of cytochrome P-450, epoxide hydrolase, and glutathione s-transferase in hepatocellular carcinoma. Cancer. 1993;71(1):36–43.PubMedCrossRef
16.
Zurück zum Zitat Takano M, Otani Y, Tanda M, Kawami M, Nagai J, Yumoto R. Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2. Drug Metab Pharmacokinet. 2009;24(5):418–27.PubMedCrossRef Takano M, Otani Y, Tanda M, Kawami M, Nagai J, Yumoto R. Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2. Drug Metab Pharmacokinet. 2009;24(5):418–27.PubMedCrossRef
17.
Zurück zum Zitat Yang SF, Chang CW, Wei RJ, Shiue YL, Wang SN, Yeh YT. Involvement of DNA damage response pathways in hepatocellular carcinoma. Biomed Res Int. 2014;2014:153867.PubMedPubMedCentral Yang SF, Chang CW, Wei RJ, Shiue YL, Wang SN, Yeh YT. Involvement of DNA damage response pathways in hepatocellular carcinoma. Biomed Res Int. 2014;2014:153867.PubMedPubMedCentral
18.
Zurück zum Zitat Minemura M, Tanimura H, Tabor E. Overexpression of multidrug resistance genes MDR1 and cMOAT in human hepatocellular carcinoma and hepatoblastoma cell lines. Int J Oncol. 1999;15(3):559–63.PubMed Minemura M, Tanimura H, Tabor E. Overexpression of multidrug resistance genes MDR1 and cMOAT in human hepatocellular carcinoma and hepatoblastoma cell lines. Int J Oncol. 1999;15(3):559–63.PubMed
19.
Zurück zum Zitat Jodo S, Kobayashi S, Nakajima Y, Matsunaga T, Nakayama N, Ogura N, et al. Elevated serum levels of soluble Fas/APO-1 (CD95) in patients with hepatocellular carcinoma. Clin Exp Immunol. 1998;112(2):166–71.PubMedPubMedCentralCrossRef Jodo S, Kobayashi S, Nakajima Y, Matsunaga T, Nakayama N, Ogura N, et al. Elevated serum levels of soluble Fas/APO-1 (CD95) in patients with hepatocellular carcinoma. Clin Exp Immunol. 1998;112(2):166–71.PubMedPubMedCentralCrossRef
20.
Zurück zum Zitat Volkmann M, Schiff JH, Hajjar Y, Otto G, Stilgenbauer F, Fiehn W, et al. Loss of CD95 expression is linked to most but not all p53 mutants in European hepatocellular carcinoma. J Mol Med. 2001;79(10):594–600.PubMedCrossRef Volkmann M, Schiff JH, Hajjar Y, Otto G, Stilgenbauer F, Fiehn W, et al. Loss of CD95 expression is linked to most but not all p53 mutants in European hepatocellular carcinoma. J Mol Med. 2001;79(10):594–600.PubMedCrossRef
21.
Zurück zum Zitat Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer. 2001;91(12):2378–85.PubMedCrossRef Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer. 2001;91(12):2378–85.PubMedCrossRef
22.
Zurück zum Zitat Liu Z, Liu R, Qiu J, Yin P, Luo F, Su J, et al. Combination of human Fas (CD95/Apo-1) ligand with adriamycin significantly enhances the efficacy of antitumor response. Cell Mol Immunol. 2009;6(3):167–74.PubMedPubMedCentralCrossRef Liu Z, Liu R, Qiu J, Yin P, Luo F, Su J, et al. Combination of human Fas (CD95/Apo-1) ligand with adriamycin significantly enhances the efficacy of antitumor response. Cell Mol Immunol. 2009;6(3):167–74.PubMedPubMedCentralCrossRef
23.
Zurück zum Zitat Schattenberg JM, Galle PR, Schuchmann M. Apoptosis in liver disease. Liver Int. 2006;26(8):904–11.PubMedCrossRef Schattenberg JM, Galle PR, Schuchmann M. Apoptosis in liver disease. Liver Int. 2006;26(8):904–11.PubMedCrossRef
24.
Zurück zum Zitat Witort E, Lulli M, Carloni V, Capaccioli S. Anticancer activity of an antisense oligonucleotide targeting TRADD combined with proteasome inhibitors in chemoresistant hepatocellular carcinoma cells. J Chemother. 2013;25(5):292–7.PubMedCrossRef Witort E, Lulli M, Carloni V, Capaccioli S. Anticancer activity of an antisense oligonucleotide targeting TRADD combined with proteasome inhibitors in chemoresistant hepatocellular carcinoma cells. J Chemother. 2013;25(5):292–7.PubMedCrossRef
25.
Zurück zum Zitat Chan BC, Ching AK, To KF, Leung JC, Chen S, Li Q, et al. BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma. Oncogene. 2008;27(9):1208–17.PubMedCrossRef Chan BC, Ching AK, To KF, Leung JC, Chen S, Li Q, et al. BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma. Oncogene. 2008;27(9):1208–17.PubMedCrossRef
26.
Zurück zum Zitat Chui YL, Ching AK, Chen S, Yip FP, Rowlands DK, James AE, et al. BRE over-expression promotes growth of hepatocellular carcinoma. Biochem Biophys Res Commun. 2010;391(3):1522–5.PubMedCrossRef Chui YL, Ching AK, Chen S, Yip FP, Rowlands DK, James AE, et al. BRE over-expression promotes growth of hepatocellular carcinoma. Biochem Biophys Res Commun. 2010;391(3):1522–5.PubMedCrossRef
27.
Zurück zum Zitat Du X, Bao G, He X, Zhao H, Yu F, Qiao Q, et al. Expression and biological significance of c-FLIP in human hepatocellular carcinomas. J Exp Clin Cancer Res. 2009;28:24.PubMedPubMedCentralCrossRef Du X, Bao G, He X, Zhao H, Yu F, Qiao Q, et al. Expression and biological significance of c-FLIP in human hepatocellular carcinomas. J Exp Clin Cancer Res. 2009;28:24.PubMedPubMedCentralCrossRef
28.
Zurück zum Zitat Safa AR, Day TW, Wu C-H. Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets. 2008;8(1):37–46.PubMedPubMedCentralCrossRef Safa AR, Day TW, Wu C-H. Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets. 2008;8(1):37–46.PubMedPubMedCentralCrossRef
29.
30.
Zurück zum Zitat Chun E, Lee KY. Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2004;315(3):771–9.PubMedCrossRef Chun E, Lee KY. Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2004;315(3):771–9.PubMedCrossRef
31.
Zurück zum Zitat Huang S, He X, Ding J, Liang L, Zhao Y, Zhang Z, et al. Upregulation of miR-23a approximately 27a approximately 24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells. Int J Cancer. 2008;123(4):972–8.PubMedCrossRef Huang S, He X, Ding J, Liang L, Zhao Y, Zhang Z, et al. Upregulation of miR-23a approximately 27a approximately 24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells. Int J Cancer. 2008;123(4):972–8.PubMedCrossRef
32.
Zurück zum Zitat Guo XL, Hu F, Zhang SS, Zhao QD, Zong C, Ye F, et al. Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy. Cancer Lett. 2014;346(2):278–84.PubMedCrossRef Guo XL, Hu F, Zhang SS, Zhao QD, Zong C, Ye F, et al. Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy. Cancer Lett. 2014;346(2):278–84.PubMedCrossRef
33.
Zurück zum Zitat Chan K-T, Lung ML. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol. 2004;53(6):519–26.PubMedCrossRef Chan K-T, Lung ML. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol. 2004;53(6):519–26.PubMedCrossRef
34.
Zurück zum Zitat Ou DL, Lee BS, Chang YC, Lin LI, Liou JY, Hsu C, et al. Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway. PLoS ONE. 2013;8(6):e66589.PubMedPubMedCentralCrossRef Ou DL, Lee BS, Chang YC, Lin LI, Liou JY, Hsu C, et al. Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway. PLoS ONE. 2013;8(6):e66589.PubMedPubMedCentralCrossRef
35.
Zurück zum Zitat Urtasun R, Latasa MU, Demartis MI, Balzani S, Goni S, Garcia-Irigoyen O, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology. 2011;54(6):2149–58.PubMedCrossRef Urtasun R, Latasa MU, Demartis MI, Balzani S, Goni S, Garcia-Irigoyen O, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology. 2011;54(6):2149–58.PubMedCrossRef
36.
Zurück zum Zitat Huang P, Xu X, Wang L, Zhu B, Wang X, Xia J. The role of EGF-EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment. J Cell Mol Med. 2014;18(2):218–30.PubMedCrossRef Huang P, Xu X, Wang L, Zhu B, Wang X, Xia J. The role of EGF-EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment. J Cell Mol Med. 2014;18(2):218–30.PubMedCrossRef
37.
Zurück zum Zitat Raychaudhuri P, Park HJ. FoxM1: a master regulator of tumor metastasis. Can Res. 2011;71(13):4329–33.CrossRef Raychaudhuri P, Park HJ. FoxM1: a master regulator of tumor metastasis. Can Res. 2011;71(13):4329–33.CrossRef
38.
Zurück zum Zitat Ding ZB, Hui B, Shi YH, Zhou J, Peng YF, Gu CY, et al. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin Cancer Res. 2011;17(19):6229–38.PubMedCrossRef Ding ZB, Hui B, Shi YH, Zhou J, Peng YF, Gu CY, et al. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin Cancer Res. 2011;17(19):6229–38.PubMedCrossRef
39.
Zurück zum Zitat Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011;7(10):1159–72.PubMedCrossRef Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011;7(10):1159–72.PubMedCrossRef
40.
Zurück zum Zitat Guo XL, Li D, Sun K, Wang J, Liu Y, Song JR, et al. Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma. J Mol Med. 2013;91(4):473–83.PubMedCrossRef Guo XL, Li D, Sun K, Wang J, Liu Y, Song JR, et al. Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma. J Mol Med. 2013;91(4):473–83.PubMedCrossRef
41.
Zurück zum Zitat Dash S, Sarashetti PM, Rajashekar B, Chowdhury R, Mukherjee S. TGF-β2-induced EMT is dampened by inhibition of autophagy and TNF-α treatment. Oncotarget. 2018;9(5):6433–49.PubMedPubMedCentralCrossRef Dash S, Sarashetti PM, Rajashekar B, Chowdhury R, Mukherjee S. TGF-β2-induced EMT is dampened by inhibition of autophagy and TNF-α treatment. Oncotarget. 2018;9(5):6433–49.PubMedPubMedCentralCrossRef
42.
Zurück zum Zitat Chen R, Dai RY, Duan CY, Liu YP, Chen SK, Yan DM, et al. Unfolded protein response suppresses cisplatin-induced apoptosis via autophagy regulation in human hepatocellular carcinoma cells. Folia Biol. 2011;57(3):87–95. Chen R, Dai RY, Duan CY, Liu YP, Chen SK, Yan DM, et al. Unfolded protein response suppresses cisplatin-induced apoptosis via autophagy regulation in human hepatocellular carcinoma cells. Folia Biol. 2011;57(3):87–95.
43.
Zurück zum Zitat Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, et al. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun. 2016;7:12030.PubMedPubMedCentralCrossRef Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, et al. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun. 2016;7:12030.PubMedPubMedCentralCrossRef
44.
Zurück zum Zitat Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedCrossRef Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedCrossRef
45.
Zurück zum Zitat Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902.PubMedCrossRef Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902.PubMedCrossRef
46.
Zurück zum Zitat Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008;27(12):1749–58.PubMedCrossRef Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008;27(12):1749–58.PubMedCrossRef
47.
Zurück zum Zitat Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136(3):1012–24.PubMedCrossRef Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136(3):1012–24.PubMedCrossRef
48.
Zurück zum Zitat Hernandez-Vargas H, Lambert M-P, Le Calvez-Kelm F, Gouysse G, McKay-Chopin S, Tavtigian SV, et al. Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors. PLoS ONE. 2010;5(3):e9749.PubMedPubMedCentralCrossRef Hernandez-Vargas H, Lambert M-P, Le Calvez-Kelm F, Gouysse G, McKay-Chopin S, Tavtigian SV, et al. Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors. PLoS ONE. 2010;5(3):e9749.PubMedPubMedCentralCrossRef
49.
Zurück zum Zitat Song M-A, Tiirikainen M, Kwee S, Okimoto G, Yu H, Wong LL. Elucidating the landscape of aberrant DNA methylation in hepatocellular carcinoma. PLoS ONE. 2013;8(2):e55761.PubMedPubMedCentralCrossRef Song M-A, Tiirikainen M, Kwee S, Okimoto G, Yu H, Wong LL. Elucidating the landscape of aberrant DNA methylation in hepatocellular carcinoma. PLoS ONE. 2013;8(2):e55761.PubMedPubMedCentralCrossRef
50.
Zurück zum Zitat Ma K, He Y, Zhang H, Fei Q, Niu D, Wang D, et al. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J Biol Chem. 2012;287(8):5639–49.PubMedCrossRef Ma K, He Y, Zhang H, Fei Q, Niu D, Wang D, et al. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J Biol Chem. 2012;287(8):5639–49.PubMedCrossRef
51.
Zurück zum Zitat Kanda T, Tada M, Imazeki F, Yokosuka O, Nagao K, Saisho H. 5-aza-2′-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines. Oncol Rep. 2005;14(4):975–9.PubMed Kanda T, Tada M, Imazeki F, Yokosuka O, Nagao K, Saisho H. 5-aza-2′-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines. Oncol Rep. 2005;14(4):975–9.PubMed
52.
Zurück zum Zitat Mei Q, Chen M, Lu X, Li X, Duan F, Wang M, et al. An open-label, single-arm, phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma. Oncotarget. 2015;6(18):16698.PubMedPubMedCentralCrossRef Mei Q, Chen M, Lu X, Li X, Duan F, Wang M, et al. An open-label, single-arm, phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma. Oncotarget. 2015;6(18):16698.PubMedPubMedCentralCrossRef
53.
Zurück zum Zitat He C, Xu J, Zhang J, Xie D, Ye H, Xiao Z, et al. High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol. 2012;43(9):1425–35.PubMedCrossRef He C, Xu J, Zhang J, Xie D, Ye H, Xiao Z, et al. High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol. 2012;43(9):1425–35.PubMedCrossRef
54.
Zurück zum Zitat Au SLK, Wong CCL, Lee JMF, Fan DNY, Tsang FH, Ng IOL, et al. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology. 2012;56(2):622–31.PubMedCrossRef Au SLK, Wong CCL, Lee JMF, Fan DNY, Tsang FH, Ng IOL, et al. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology. 2012;56(2):622–31.PubMedCrossRef
55.
Zurück zum Zitat Studach LL, Menne S, Cairo S, Buendia MA, Hullinger RL, Lefrançois L, et al. Subset of Suz12/PRC2 target genes is activated during hepatitis B virus replication and liver carcinogenesis associated with HBV X protein. Hepatology. 2012;56(4):1240–51.PubMedPubMedCentralCrossRef Studach LL, Menne S, Cairo S, Buendia MA, Hullinger RL, Lefrançois L, et al. Subset of Suz12/PRC2 target genes is activated during hepatitis B virus replication and liver carcinogenesis associated with HBV X protein. Hepatology. 2012;56(4):1240–51.PubMedPubMedCentralCrossRef
56.
Zurück zum Zitat Yang Z, Zhou L, Wu L-M, Lai M-C, Xie H-Y, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18(5):1243–50.PubMedCrossRef Yang Z, Zhou L, Wu L-M, Lai M-C, Xie H-Y, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18(5):1243–50.PubMedCrossRef
57.
Zurück zum Zitat M-c Lai, Yang Z, Zhou L, Q-q Zhu, H-y Xie, Zhang F, et al. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol. 2012;29(3):1810–6.CrossRef M-c Lai, Yang Z, Zhou L, Q-q Zhu, H-y Xie, Zhang F, et al. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol. 2012;29(3):1810–6.CrossRef
58.
Zurück zum Zitat Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol. 2012;30(27):3361–7.PubMedPubMedCentralCrossRef Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol. 2012;30(27):3361–7.PubMedPubMedCentralCrossRef
59.
Zurück zum Zitat Ma BB, Sung F, Tao Q, Poon FF, Lui VW, Yeo W, et al. The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs. 2010;28(2):107–14.PubMedCrossRef Ma BB, Sung F, Tao Q, Poon FF, Lui VW, Yeo W, et al. The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs. 2010;28(2):107–14.PubMedCrossRef
60.
Zurück zum Zitat Ruan Y, Sun L, Hao Y, Wang L, Xu J, Zhang W, et al. Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma. J Clin Investig. 2012;122(7):2554–66.PubMedPubMedCentralCrossRef Ruan Y, Sun L, Hao Y, Wang L, Xu J, Zhang W, et al. Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma. J Clin Investig. 2012;122(7):2554–66.PubMedPubMedCentralCrossRef
61.
Zurück zum Zitat Zhao J, Chen J, Lu B, Dong L, Wang H, Bi C, et al. TIP30 induces apoptosis under oxidative stress through stabilization of p53 messenger RNA in human hepatocellular carcinoma. Can Res. 2008;68(11):4133–41.CrossRef Zhao J, Chen J, Lu B, Dong L, Wang H, Bi C, et al. TIP30 induces apoptosis under oxidative stress through stabilization of p53 messenger RNA in human hepatocellular carcinoma. Can Res. 2008;68(11):4133–41.CrossRef
62.
Zurück zum Zitat Guo XL, Ma NN, Zhou FG, Zhang L, Bu XX, Sun K, et al. Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells. Oncol Rep. 2009;22(3):549–56.PubMed Guo XL, Ma NN, Zhou FG, Zhang L, Bu XX, Sun K, et al. Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells. Oncol Rep. 2009;22(3):549–56.PubMed
63.
Zurück zum Zitat Ling X, Wen L, Zhou Y. Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance. Int J Med Sci. 2012;9(7):545–54.PubMedPubMedCentralCrossRef Ling X, Wen L, Zhou Y. Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance. Int J Med Sci. 2012;9(7):545–54.PubMedPubMedCentralCrossRef
64.
65.
Zurück zum Zitat Almeida D, Gerhard R, Leitão D, Davilla C, Damasceno M, Schmitt F. Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer. Pathol-Res Pract. 2014;210(10):675–9.PubMedCrossRef Almeida D, Gerhard R, Leitão D, Davilla C, Damasceno M, Schmitt F. Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer. Pathol-Res Pract. 2014;210(10):675–9.PubMedCrossRef
66.
Zurück zum Zitat Pang E, Hu Y, Chan KY, Lai PB, Squire JA, Macgregor PF, et al. Karyotypic imbalances and differential gene expressions in the acquired doxorubicin resistance of hepatocellular carcinoma cells. Lab Invest. 2005;85(5):664–74.PubMedCrossRef Pang E, Hu Y, Chan KY, Lai PB, Squire JA, Macgregor PF, et al. Karyotypic imbalances and differential gene expressions in the acquired doxorubicin resistance of hepatocellular carcinoma cells. Lab Invest. 2005;85(5):664–74.PubMedCrossRef
67.
Zurück zum Zitat Wong N, Yeo W, Wong WL, Wong NLY, Chan KYY, Mo FKF, et al. TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. Int J Cancer. 2009;124(3):644–52.PubMedCrossRef Wong N, Yeo W, Wong WL, Wong NLY, Chan KYY, Mo FKF, et al. TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. Int J Cancer. 2009;124(3):644–52.PubMedCrossRef
68.
Zurück zum Zitat Cai TY, Liu XW, Zhu H, Cao J, Zhang J, Ding L, et al. Tirapazamine sensitizes hepatocellular carcinoma cells to topoisomerase I inhibitors via cooperative modulation of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2014;13(3):630–42.PubMedCrossRef Cai TY, Liu XW, Zhu H, Cao J, Zhang J, Ding L, et al. Tirapazamine sensitizes hepatocellular carcinoma cells to topoisomerase I inhibitors via cooperative modulation of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2014;13(3):630–42.PubMedCrossRef
69.
Zurück zum Zitat Bansal S, Berk M, Alkhouri N, Partrick DA, Fung JJ, Feldstein A. Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma. J Surg Res. 2014;186(1):29–38.PubMedCrossRef Bansal S, Berk M, Alkhouri N, Partrick DA, Fung JJ, Feldstein A. Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma. J Surg Res. 2014;186(1):29–38.PubMedCrossRef
70.
Zurück zum Zitat Tak E, Lee S, Lee J, Rashid MA, Kim YW, Park JH, et al. Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells. J Hepatol. 2011;54(2):328–39.PubMedCrossRef Tak E, Lee S, Lee J, Rashid MA, Kim YW, Park JH, et al. Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells. J Hepatol. 2011;54(2):328–39.PubMedCrossRef
71.
Zurück zum Zitat Montero J, Morales A, Llacuna L, Lluis JM, Terrones O, Basanez G, et al. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Can Res. 2008;68(13):5246–56.CrossRef Montero J, Morales A, Llacuna L, Lluis JM, Terrones O, Basanez G, et al. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Can Res. 2008;68(13):5246–56.CrossRef
72.
Zurück zum Zitat Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.PubMedCrossRef Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.PubMedCrossRef
73.
Zurück zum Zitat Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.PubMedCrossRef Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.PubMedCrossRef
74.
Zurück zum Zitat Chen L, Qu C, Chen H, Xu L, Qi Q, Luo J, et al. Chinese herbal medicine suppresses invasion-promoting capacity of cancer-associated fibroblasts in pancreatic cancer. PLoS ONE. 2014;9(4):e96177.PubMedPubMedCentralCrossRef Chen L, Qu C, Chen H, Xu L, Qi Q, Luo J, et al. Chinese herbal medicine suppresses invasion-promoting capacity of cancer-associated fibroblasts in pancreatic cancer. PLoS ONE. 2014;9(4):e96177.PubMedPubMedCentralCrossRef
75.
Zurück zum Zitat Lin Z-Y, Chuang Y-H, Chuang W-L. Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells. Biomed Pharmacother. 2012;66(7):525–9.PubMedCrossRef Lin Z-Y, Chuang Y-H, Chuang W-L. Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells. Biomed Pharmacother. 2012;66(7):525–9.PubMedCrossRef
76.
Zurück zum Zitat Lin Z-Y, Chuang W-L. Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts. Kaohsiung J Med Sci. 2013;29(6):312–8.PubMedCrossRef Lin Z-Y, Chuang W-L. Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts. Kaohsiung J Med Sci. 2013;29(6):312–8.PubMedCrossRef
77.
Zurück zum Zitat Jia C-C, Wang T-T, Liu W, Fu B-S, Hua X, Wang G-Y, et al. Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS ONE. 2013;8(5):e63243.PubMedPubMedCentralCrossRef Jia C-C, Wang T-T, Liu W, Fu B-S, Hua X, Wang G-Y, et al. Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS ONE. 2013;8(5):e63243.PubMedPubMedCentralCrossRef
78.
Zurück zum Zitat Yin C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Investig. 2013;123(5):1902–10.PubMedPubMedCentralCrossRef Yin C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Investig. 2013;123(5):1902–10.PubMedPubMedCentralCrossRef
79.
Zurück zum Zitat Sancho-Bru P, Juez E, Moreno M, Khurdayan V, Morales-Ruiz M, Colmenero J, et al. Hepatocarcinoma cells stimulate the growth, migration and expression of pro-angiogenic genes in human hepatic stellate cells. Liver Int. 2010;30(1):31–41.PubMedCrossRef Sancho-Bru P, Juez E, Moreno M, Khurdayan V, Morales-Ruiz M, Colmenero J, et al. Hepatocarcinoma cells stimulate the growth, migration and expression of pro-angiogenic genes in human hepatic stellate cells. Liver Int. 2010;30(1):31–41.PubMedCrossRef
80.
Zurück zum Zitat Shapero K, Wylie-Sears J, Levine RA, Mayer JE, Bischoff J. Reciprocal interactions between mitral valve endothelial and interstitial cells reduce endothelial-to-mesenchymal transition and myofibroblastic activation. J Mol Cell Cardiol. 2015;80:175–85.PubMedPubMedCentralCrossRef Shapero K, Wylie-Sears J, Levine RA, Mayer JE, Bischoff J. Reciprocal interactions between mitral valve endothelial and interstitial cells reduce endothelial-to-mesenchymal transition and myofibroblastic activation. J Mol Cell Cardiol. 2015;80:175–85.PubMedPubMedCentralCrossRef
81.
Zurück zum Zitat Quatromoni JG, Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res. 2012;4(4):376.PubMedPubMedCentral Quatromoni JG, Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res. 2012;4(4):376.PubMedPubMedCentral
82.
Zurück zum Zitat Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, 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(1):25–34.PubMedCrossRef Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, 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(1):25–34.PubMedCrossRef
83.
Zurück zum Zitat Gao L, Wang X, Tang Y, Huang S. Hu C-AA, Teng Y. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Cancer Res. 2017;36(1):8.PubMedPubMedCentralCrossRef Gao L, Wang X, Tang Y, Huang S. Hu C-AA, Teng Y. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Cancer Res. 2017;36(1):8.PubMedPubMedCentralCrossRef
84.
Zurück zum Zitat Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol. 2013;14(7):e283–8.PubMedCrossRef Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol. 2013;14(7):e283–8.PubMedCrossRef
85.
Zurück zum Zitat Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14(1):55–63.PubMedCrossRef Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14(1):55–63.PubMedCrossRef
86.
Zurück zum Zitat Pievsky D, Pyrsopoulos N. Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date. J Hepatocell Carcinoma. 2016;3:69.PubMedPubMedCentralCrossRef Pievsky D, Pyrsopoulos N. Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date. J Hepatocell Carcinoma. 2016;3:69.PubMedPubMedCentralCrossRef
87.
Zurück zum Zitat Li K, Lan Y, Wang J, Liu L. Chimeric antigen receptor—engineered T cells for liver cancers, progress and obstacles. Tumor Biol. 2017;39(3):1010428317692229. Li K, Lan Y, Wang J, Liu L. Chimeric antigen receptor—engineered T cells for liver cancers, progress and obstacles. Tumor Biol. 2017;39(3):1010428317692229.
88.
Zurück zum Zitat Tan CK, Chow PK, Findlay M, Wong C, Machin D. Use of tamoxifen in hepatocellular carcinoma: a review and paradigm shift. J Gastroenterol Hepatol. 2000;15(7):725–9.PubMedCrossRef Tan CK, Chow PK, Findlay M, Wong C, Machin D. Use of tamoxifen in hepatocellular carcinoma: a review and paradigm shift. J Gastroenterol Hepatol. 2000;15(7):725–9.PubMedCrossRef
89.
Zurück zum Zitat Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8.PubMedCrossRef Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8.PubMedCrossRef
90.
Zurück zum Zitat Hsu C, Chen CN, Chen LT, Wu CY, Yang PM, Lai MY, et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology. 2003;65(3):242–9.PubMedCrossRef Hsu C, Chen CN, Chen LT, Wu CY, Yang PM, Lai MY, et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology. 2003;65(3):242–9.PubMedCrossRef
91.
Zurück zum Zitat Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med. 2004;117(7):508–15.PubMedCrossRef Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med. 2004;117(7):508–15.PubMedCrossRef
92.
Zurück zum Zitat Blaker M, Schmitz M, Gocht A, Burghardt S, Schulz M, Broring DC, et al. Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas. J Hepatol. 2004;41(1):112–8.PubMedCrossRef Blaker M, Schmitz M, Gocht A, Burghardt S, Schulz M, Broring DC, et al. Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas. J Hepatol. 2004;41(1):112–8.PubMedCrossRef
93.
Zurück zum Zitat Cebon J, Findlay M, Hargreaves C, Stockler M, Thompson P, Boyer M, et al. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer. 2006;95(7):853–61.PubMedPubMedCentralCrossRef Cebon J, Findlay M, Hargreaves C, Stockler M, Thompson P, Boyer M, et al. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer. 2006;95(7):853–61.PubMedPubMedCentralCrossRef
94.
Zurück zum Zitat Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009;27(18):3027–35.PubMedPubMedCentralCrossRef Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009;27(18):3027–35.PubMedPubMedCentralCrossRef
95.
Zurück zum Zitat Finn RS, Zhu AX. Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther. 2009;9(4):503–9.PubMedCrossRef Finn RS, Zhu AX. Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther. 2009;9(4):503–9.PubMedCrossRef
96.
Zurück zum Zitat Llovet JM, Bruix J. Testing molecular therapies in hepatocellular carcinoma: the need for randomized phase II trials. J Clin Oncol. 2009;27(6):833–5.PubMedCrossRef Llovet JM, Bruix J. Testing molecular therapies in hepatocellular carcinoma: the need for randomized phase II trials. J Clin Oncol. 2009;27(6):833–5.PubMedCrossRef
97.
Zurück zum Zitat Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, et al. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun. 2013;4:1908.PubMedPubMedCentralCrossRef Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, et al. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun. 2013;4:1908.PubMedPubMedCentralCrossRef
98.
Zurück zum Zitat Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.PubMedCrossRef Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.PubMedCrossRef
99.
Zurück zum Zitat Zhang X, Xu P, Ni W, Fan H, Xu J, Chen Y, et al. Downregulated DYRK2 expression is associated with poor prognosis and Oxaliplatin resistance in hepatocellular carcinoma. Pathol-Res Pract. 2016;212(3):162–70.PubMedCrossRef Zhang X, Xu P, Ni W, Fan H, Xu J, Chen Y, et al. Downregulated DYRK2 expression is associated with poor prognosis and Oxaliplatin resistance in hepatocellular carcinoma. Pathol-Res Pract. 2016;212(3):162–70.PubMedCrossRef
100.
Zurück zum Zitat Chenivesse X, Franco D, Brechot C. MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis. J Hepatol. 1993;18(2):168–72.PubMedCrossRef Chenivesse X, Franco D, Brechot C. MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis. J Hepatol. 1993;18(2):168–72.PubMedCrossRef
101.
Zurück zum Zitat Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004;447(5):653–65.PubMedCrossRef Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004;447(5):653–65.PubMedCrossRef
102.
Zurück zum Zitat van Montfoort JE, Hagenbuch B, Groothuis GM, Koepsell H, Meier PJ, Meijer DK. Drug uptake systems in liver and kidney. Curr Drug Metab. 2003;4(3):185–211.PubMedCrossRef van Montfoort JE, Hagenbuch B, Groothuis GM, Koepsell H, Meier PJ, Meijer DK. Drug uptake systems in liver and kidney. Curr Drug Metab. 2003;4(3):185–211.PubMedCrossRef
103.
Zurück zum Zitat Zollner G, Wagner M, Fickert P, Silbert D, Fuchsbichler A, Zatloukal K, et al. Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int. 2005;25(2):367–79.PubMedCrossRef Zollner G, Wagner M, Fickert P, Silbert D, Fuchsbichler A, Zatloukal K, et al. Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int. 2005;25(2):367–79.PubMedCrossRef
104.
Zurück zum Zitat Goswami S, Gong L, Giacomini K, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for SLC22A1. Pharmacogenet Genom. 2014;24(6):324.CrossRef Goswami S, Gong L, Giacomini K, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for SLC22A1. Pharmacogenet Genom. 2014;24(6):324.CrossRef
105.
Zurück zum Zitat Youn CK, Kim MH, Cho HJ, Kim HB, Chang IY, Chung MH, et al. Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents. Can Res. 2004;64(14):4849–57.CrossRef Youn CK, Kim MH, Cho HJ, Kim HB, Chang IY, Chung MH, et al. Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents. Can Res. 2004;64(14):4849–57.CrossRef
106.
Zurück zum Zitat Ding H, Chen D, Zhao C, Shang H, Zhou L, Zhang J, et al. Flap endonuclease-1 plays double roles in cisplatin-based chemoresistance and cell apoptosis resulted from enhanced long patch DNA repair and a gap endonuclease activity. Cancer Res. 2006;66(8 Supplement):1164. Ding H, Chen D, Zhao C, Shang H, Zhou L, Zhang J, et al. Flap endonuclease-1 plays double roles in cisplatin-based chemoresistance and cell apoptosis resulted from enhanced long patch DNA repair and a gap endonuclease activity. Cancer Res. 2006;66(8 Supplement):1164.
107.
Zurück zum Zitat Chae S, Kim YB, Lee JS, Cho H. Resistance to paclitaxel in hepatoma cells is related to static JNK activation and prohibition into entry of mitosis. Am J Physiol Gastrointest Liver Physiol. 2012;302(9):G1016–24.PubMedCrossRef Chae S, Kim YB, Lee JS, Cho H. Resistance to paclitaxel in hepatoma cells is related to static JNK activation and prohibition into entry of mitosis. Am J Physiol Gastrointest Liver Physiol. 2012;302(9):G1016–24.PubMedCrossRef
108.
Zurück zum Zitat Fujimaki S, Matsuda Y, Wakai T, Sanpei A, Kubota M, Takamura M, et al. Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling. Cancer Lett. 2012;319(1):98–108.PubMedCrossRef Fujimaki S, Matsuda Y, Wakai T, Sanpei A, Kubota M, Takamura M, et al. Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling. Cancer Lett. 2012;319(1):98–108.PubMedCrossRef
109.
Zurück zum Zitat Cun Y, Dai N, Xiong C, Li M, Sui J, Qian C, et al. Silencing of APE1 enhances sensitivity of human hepatocellular carcinoma cells to radiotherapy in vitro and in a xenograft model. PLoS ONE. 2013;8(2):e55313.PubMedPubMedCentralCrossRef Cun Y, Dai N, Xiong C, Li M, Sui J, Qian C, et al. Silencing of APE1 enhances sensitivity of human hepatocellular carcinoma cells to radiotherapy in vitro and in a xenograft model. PLoS ONE. 2013;8(2):e55313.PubMedPubMedCentralCrossRef
110.
Zurück zum Zitat Patil MA, Zhang J, Ho C, Cheung S-T, Fan S-T, Chen X. Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther. 2006;5(1):111–7.PubMedCrossRef Patil MA, Zhang J, Ho C, Cheung S-T, Fan S-T, Chen X. Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther. 2006;5(1):111–7.PubMedCrossRef
111.
Zurück zum Zitat Zhou D, Conrad C, Xia F, Park J-S, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16(5):425–38.PubMedPubMedCentralCrossRef Zhou D, Conrad C, Xia F, Park J-S, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16(5):425–38.PubMedPubMedCentralCrossRef
112.
Zurück zum Zitat Giovannini C, Gramantieri L, Chieco P, Minguzzi M, Lago F, Pianetti S, et al. Selective ablation of Notch3 in HCC enhances doxorubicin’s death promoting effect by a p53 dependent mechanism. J Hepatol. 2009;50(5):969–79.PubMedCrossRef Giovannini C, Gramantieri L, Chieco P, Minguzzi M, Lago F, Pianetti S, et al. Selective ablation of Notch3 in HCC enhances doxorubicin’s death promoting effect by a p53 dependent mechanism. J Hepatol. 2009;50(5):969–79.PubMedCrossRef
113.
Zurück zum Zitat Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694.PubMedPubMedCentralCrossRef Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694.PubMedPubMedCentralCrossRef
115.
Zurück zum Zitat Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A, Kobayashi S, et al. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 2010;103(10):1617–26.PubMedPubMedCentralCrossRef Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A, Kobayashi S, et al. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 2010;103(10):1617–26.PubMedPubMedCentralCrossRef
116.
Zurück zum Zitat Huang XH, Chen JS, Wang Q, Chen XL, Wen L, Chen LZ, et al. miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened. J Pathol. 2011;225(3):463–72.PubMedCrossRef Huang XH, Chen JS, Wang Q, Chen XL, Wen L, Chen LZ, et al. miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened. J Pathol. 2011;225(3):463–72.PubMedCrossRef
117.
Zurück zum Zitat Xu Y, Xia F, Ma L, Shan J, Shen J, Yang Z, et al. MicroRNA-122 sensitizes HCC cancer cells to adriamycin and vincristine through modulating expression of MDR and inducing cell cycle arrest. Cancer Lett. 2011;310(2):160–9.PubMed Xu Y, Xia F, Ma L, Shan J, Shen J, Yang Z, et al. MicroRNA-122 sensitizes HCC cancer cells to adriamycin and vincristine through modulating expression of MDR and inducing cell cycle arrest. Cancer Lett. 2011;310(2):160–9.PubMed
118.
Zurück zum Zitat Meng F, Glaser SS, Francis H, DeMorrow S, Han Y, Passarini JD, et al. Functional analysis of microRNAs in human hepatocellular cancer stem cells. J Cell Mol Med. 2012;16(1):160–73.PubMedCrossRef Meng F, Glaser SS, Francis H, DeMorrow S, Han Y, Passarini JD, et al. Functional analysis of microRNAs in human hepatocellular cancer stem cells. J Cell Mol Med. 2012;16(1):160–73.PubMedCrossRef
119.
Zurück zum Zitat Ma K, He Y, Zhang H, Fei Q, Niu D, Wang D, et al. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J Biol Chem. 2012;287(8):5639–49.PubMedCrossRef Ma K, He Y, Zhang H, Fei Q, Niu D, Wang D, et al. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J Biol Chem. 2012;287(8):5639–49.PubMedCrossRef
120.
Zurück zum Zitat Zhang J, Wang Y, Zhen P, Luo X, Zhang C, Zhou L, et al. Genome-wide analysis of miRNA signature differentially expressed in doxorubicin-resistant and parental human hepatocellular carcinoma cell lines. PLoS ONE. 2013;8(1):e54111.PubMedPubMedCentralCrossRef Zhang J, Wang Y, Zhen P, Luo X, Zhang C, Zhou L, et al. Genome-wide analysis of miRNA signature differentially expressed in doxorubicin-resistant and parental human hepatocellular carcinoma cell lines. PLoS ONE. 2013;8(1):e54111.PubMedPubMedCentralCrossRef
122.
Zurück zum Zitat Liu K, Liu S, Zhang W, Jia B, Tan L, Jin Z, et al. miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN. Oncol Rep. 2015;34(2):1003–10.PubMedCrossRef Liu K, Liu S, Zhang W, Jia B, Tan L, Jin Z, et al. miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN. Oncol Rep. 2015;34(2):1003–10.PubMedCrossRef
123.
Zurück zum Zitat Tan G, Wu L, Tan J, Zhang B, Tai WC, Xiong S, Chen W, Yang J, Li H. MiR-1180 promotes apoptotic resistance to human hepatocellular carcinoma via activation of NF-κB signaling pathway. Sci Rep. 2016;6:22328.PubMedPubMedCentralCrossRef Tan G, Wu L, Tan J, Zhang B, Tai WC, Xiong S, Chen W, Yang J, Li H. MiR-1180 promotes apoptotic resistance to human hepatocellular carcinoma via activation of NF-κB signaling pathway. Sci Rep. 2016;6:22328.PubMedPubMedCentralCrossRef
124.
Zurück zum Zitat Xu Y, Huang J, Ma L, Shan J, Shen J, Yang Z, et al. MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. Cancer Lett. 2016;371(2):171–81.PubMedCrossRef Xu Y, Huang J, Ma L, Shan J, Shen J, Yang Z, et al. MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. Cancer Lett. 2016;371(2):171–81.PubMedCrossRef
125.
Zurück zum Zitat Barajas M, Mazzolini G, Genove G, Bilbao R, Narvaiza I, Schmitz V, et al. Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology. 2001;33(1):52–61.PubMedCrossRef Barajas M, Mazzolini G, Genove G, Bilbao R, Narvaiza I, Schmitz V, et al. Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology. 2001;33(1):52–61.PubMedCrossRef
127.
Zurück zum Zitat Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324–31.PubMedCrossRef Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324–31.PubMedCrossRef
128.
Zurück zum Zitat Cheng JC, Chou CH, Kuo ML, Hsieh CY. Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway. Oncogene. 2006;25(53):7009–18.PubMedCrossRef Cheng JC, Chou CH, Kuo ML, Hsieh CY. Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway. Oncogene. 2006;25(53):7009–18.PubMedCrossRef
129.
Zurück zum Zitat Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res. 2009;39(2):177–86.PubMedCrossRef Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res. 2009;39(2):177–86.PubMedCrossRef
130.
Zurück zum Zitat Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25(18):2586–93.PubMedCrossRef Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25(18):2586–93.PubMedCrossRef
131.
Zurück zum Zitat Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–39.PubMedCrossRef Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–39.PubMedCrossRef
132.
Zurück zum Zitat Gu T, Ohashi R, Cui R, Tajima K, Yoshioka M, Iwakami S, et al. Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer. Lung Cancer. 2009;66(2):176–83.PubMedCrossRef Gu T, Ohashi R, Cui R, Tajima K, Yoshioka M, Iwakami S, et al. Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer. Lung Cancer. 2009;66(2):176–83.PubMedCrossRef
133.
Zurück zum Zitat Thompson AI, Conroy KP, Henderson NC. Hepatic stellate cells: central modulators of hepatic carcinogenesis. BMC Gastroenterol. 2015;15(1):1.CrossRef Thompson AI, Conroy KP, Henderson NC. Hepatic stellate cells: central modulators of hepatic carcinogenesis. BMC Gastroenterol. 2015;15(1):1.CrossRef
134.
Zurück zum Zitat Scott AM, Wiseman G, Welt S, Adjei A, Lee F-T, Hopkins W, et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003;9(5):1639–47.PubMed Scott AM, Wiseman G, Welt S, Adjei A, Lee F-T, Hopkins W, et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003;9(5):1639–47.PubMed
135.
Zurück zum Zitat Liu C-J, Lee P-H, Lin D-Y, Wu C-C, Jeng L-B, Lin P-W, et al. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol. 2009;50(5):958–68.PubMedCrossRef Liu C-J, Lee P-H, Lin D-Y, Wu C-C, Jeng L-B, Lin P-W, et al. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol. 2009;50(5):958–68.PubMedCrossRef
136.
Zurück zum Zitat O’Neil BH, Goff LW, Kauh JSW, Strosberg JR, Bekaii-Saab TS, R-m Lee, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2011;29(17):2350–6.PubMedPubMedCentralCrossRef O’Neil BH, Goff LW, Kauh JSW, Strosberg JR, Bekaii-Saab TS, R-m Lee, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2011;29(17):2350–6.PubMedPubMedCentralCrossRef
137.
Zurück zum Zitat Johnson PJ, Qin S, Park J-W, Poon RT, Raoul J-L, Philip PA, et al. 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(28):3517–24.PubMedCrossRef Johnson PJ, Qin S, Park J-W, Poon RT, Raoul J-L, Philip PA, et al. 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(28):3517–24.PubMedCrossRef
138.
Zurück zum Zitat Cainap C, Qin S, Huang W-T, Chung I-J, Pan H, Cheng Y, et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). Am Soc Clin Oncol. 2013;31:249. Cainap C, Qin S, Huang W-T, Chung I-J, Pan H, Cheng Y, et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). Am Soc Clin Oncol. 2013;31:249.
139.
Zurück zum Zitat McNamara MG, Le LW, Horgan AM, Aspinall A, Burak KW, Dhani N, et al. A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma. Cancer. 2015;121(10):1620–7.PubMedCrossRef McNamara MG, Le LW, Horgan AM, Aspinall A, Burak KW, Dhani N, et al. A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma. Cancer. 2015;121(10):1620–7.PubMedCrossRef
140.
Zurück zum Zitat Serova M, Tijeras-Raballand A, Dos Santos C, Albuquerque M, Paradis V, Neuzillet C, et al. Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients. Oncotarget. 2015;6(25):21614.PubMedPubMedCentralCrossRef Serova M, Tijeras-Raballand A, Dos Santos C, Albuquerque M, Paradis V, Neuzillet C, et al. Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients. Oncotarget. 2015;6(25):21614.PubMedPubMedCentralCrossRef
141.
Zurück zum Zitat Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.PubMedCrossRef Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.PubMedCrossRef
142.
Zurück zum Zitat Zhao H, Guo Y, Li S, Han R, Ying J, Zhu H, et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway. Oncotarget. 2015;6(31):31927.PubMedPubMedCentral Zhao H, Guo Y, Li S, Han R, Ying J, Zhu H, et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway. Oncotarget. 2015;6(31):31927.PubMedPubMedCentral
143.
Zurück zum Zitat Safran H, Charpentier KP, Kaubisch A, Mantripragada K, Dubel G, Perez K, et al. Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University Oncology Group Phase II Study. Am J Clin Oncol. 2015;38(1):1–4.PubMedCrossRef Safran H, Charpentier KP, Kaubisch A, Mantripragada K, Dubel G, Perez K, et al. Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University Oncology Group Phase II Study. Am J Clin Oncol. 2015;38(1):1–4.PubMedCrossRef
144.
Zurück zum Zitat Abou-Alfa GK, Puig O, Daniele B, Kudo M, Merle P, Park J-W, et al. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J Hepatol. 2016;65(2):289–95.PubMedCrossRef Abou-Alfa GK, Puig O, Daniele B, Kudo M, Merle P, Park J-W, et al. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J Hepatol. 2016;65(2):289–95.PubMedCrossRef
145.
Zurück zum Zitat El-Khoueiry AB, Sangro B, Yau TC, Crocenzi TS, Welling TH, Yeo W, et al. Phase I/II safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): interim analysis of the CheckMate-040 dose escalation study. Am Soc Clin Oncol. 2016;34:4012. El-Khoueiry AB, Sangro B, Yau TC, Crocenzi TS, Welling TH, Yeo W, et al. Phase I/II safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): interim analysis of the CheckMate-040 dose escalation study. Am Soc Clin Oncol. 2016;34:4012.
146.
Zurück zum Zitat Kudo M. Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials. Oncology. 2017;92(Suppl. 1):50–62.PubMedCrossRef Kudo M. Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials. Oncology. 2017;92(Suppl. 1):50–62.PubMedCrossRef
147.
Zurück zum Zitat Escudier B, Faivre S, Van Cutsem E, Germann N, Pouget J-C, Plummer R, et al. A phase II multicentre, open-label, proof-of-concept study of tasquinimod in hepatocellular, ovarian, renal cell, and gastric cancers. Target Oncol. 2017;12(5):655–61.PubMedCrossRef Escudier B, Faivre S, Van Cutsem E, Germann N, Pouget J-C, Plummer R, et al. A phase II multicentre, open-label, proof-of-concept study of tasquinimod in hepatocellular, ovarian, renal cell, and gastric cancers. Target Oncol. 2017;12(5):655–61.PubMedCrossRef
148.
Zurück zum Zitat K-c Feng, Y-l Guo, Liu Y, H-r Dai, Wang Y, H-y Lv, et al. Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol. 2017;10(1):4.CrossRef K-c Feng, Y-l Guo, Liu Y, H-r Dai, Wang Y, H-y Lv, et al. Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol. 2017;10(1):4.CrossRef
149.
Zurück zum Zitat Katz S, Point GR, Cunetta M, Thorn M, Guha P, Espat NJ, et al. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther. 2016;23(5):142.PubMedPubMedCentralCrossRef Katz S, Point GR, Cunetta M, Thorn M, Guha P, Espat NJ, et al. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther. 2016;23(5):142.PubMedPubMedCentralCrossRef
Metadaten
Titel
Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight
verfasst von
K. Lohitesh
Rajdeep Chowdhury
Sudeshna Mukherjee
Publikationsdatum
01.12.2018
Verlag
BioMed Central
Erschienen in
Cancer Cell International / Ausgabe 1/2018
Elektronische ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0538-7

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