ArticlePDF Available

Potential molecular, cellular and microenvironmental mechanism of Sorafenib resistance in hepatocellular carcinoma

July 2015
Cancer Letters 367(1)

July 2015
367(1)

DOI:10.1016/j.canlet.2015.06.019

Source
PubMed

Authors:

Jiang Chen

Department of General Surgery

Renan Jin

Sir Run Run Shaw Hospital

Jie Zhao

Texas Medical Center

Show all 13 authorsHide

Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports. Copyright © 2015. Published by Elsevier Ireland Ltd.

Role of CSCs in the development of resistance of HCC to sorafenib. Tumors were hypothesized to be organized into a hierarchy of heterogeneous cell populations and CSCs are only a tiny subset of tumor cells. Treated with sorafenib, the majority of tumor cells underwent apoptosis and CSCs were remained, showing their sorafenib resistance. CSCs reconstructed tumor by causing the heterogeneous lineages of cancer cells, leading to relapse of malignant tumors. In addition, sharing similar characteristics with normal stem cells, CSCs migrated, invaded into blood vessels, self-renewed, differentiated and led to tumor metastasis with acquired sorafenib resistance. CSCs possibly contribute to recurrence and metastasis of malignant tumors with acquired drug resistance.

…

Figures - uploaded by Han Yan

Content may be subject to copyright.

Content uploaded by Han Yan

Content may be subject to copyright.

Mini-review

Potential molecular, cellular and microenvironmental mechanism of

sorafenib resistance in hepatocellular carcinoma

Jiang Chen, Renan Jin, Jie Zhao, Jinghua Liu, Hanning Ying, Han Yan, Senjun Zhou,

Yuelong Liang, Diyu Huang, Xiao Liang, Hong Yu, Hui Lin *, Xiujun Cai **

Department of General Surgery, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang, China

ARTICLE INFO

Article history:

Received 4 March 2015

Received in revised form 23 June 2015

Accepted 25 June 2015

Keywords:

Advanced hepatocellular carcinoma (HCC)

Epithelial–mesenchymal transitions (EMT)

and mesenchymal–epithelial transitions

(MET)

Cancer stem cells (CSCs)

Microenvironment

Acquired resistance

ABSTRACT

Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced

hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent

years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance

mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have

made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and mi-

croenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant

previous studies and reports.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common

primary malignant tumors and the largest cancer-related deaths

ranking only second to lung cancer, with a fairly high and increas-

ing incidence, frequently relapse and dismal prognosis [1,2]. Despite

the remarkable progress in the prevention, detection, and treat-

ment of cancer over the last ﬁve decades, no adequate therapy

remains suﬃciently effective due to late stage diagnosis and inad-

equate clinical strategies for inhibiting metastasis and promoting

apoptosis [3–6]. Furthermore, multi-drug resistance of cancer cells

has been implicated as a major challenge considering the irreplace-

able role of chemotherapeutic interventions in anti-cancer treatment

[7]. The resistance was postulated to associate with elevated ex-

pression of drug eﬄux transporters, changes in drug kinetics,

ampliﬁcation of drug targets or tumor heterogeneity comprising of

genetic variation, the microenvironment, and cell plasticity [8].For

patients with HCC diagnosed at advanced stage, sorafenib is the only

choice of systemic therapy when potentially curative treatment, such

as resection and liver transplantation, may be merely applicable for

patients diagnosed at early stage [9]. Recently, the unstable eﬃca-

cy of sorafenib has raised concern of more and more researchers

and ‘sorafenib resistance’ has become a hot term used to describe

the impaired eﬃcacy of sorafenib, especially for patients with ad-

vanced HCC.

Sorafenib, as a multikinase inhibitor, suppresses tumor angio-

genesis and proliferation by inhibiting serine/threonine kinases, as

well as receptor tyrosine kinases. Intracellular Raf serine/threonine

kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-

type B-Raf and mutant B-Raf. Receptor tyrosine kinases inhibited

by sorafenib include vascular endothelial growth factor receptor

(VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor re-

ceptor (PDGFR)-b, c-KIT, FMS-like tyrosine kinase 3 (FLT-3) and RET

[10]. Among these kinases, RAF and VEGFR are presumed to be es-

sential for the anti-proliferative effects evoked by sorafenib. RAF

kinases are present at the level of the cancer cells, while the VEGFR

is present on the surface of endothelial cells [11]. Inhibition of the

VEGFR accounts, at least in part, for the antiangiogenic effects of

sorafenib. In majority of patients with advanced HCC, the RAF–

MEK–ERK cascade is often activated by autocrine and paracrine loops,

involving for example the production of amphiregulin, an agonist

of the Epidermal Growth Factor Receptor (EGFR) [12]. The analysis

of vitro experiments reported that there was a strong correlation

between the inhibition of the RAF–MEK–ERK cascade and the anti-

clonogenesis effect of sorafenib [13]. In addition, cytotoxic effect of

sorafenib is also a crucial role in antitumor treatment. Generally,

apoptosis is the major form of cytotoxicity and it is required for tumor

regression and sustained clinical remissions [14]. The pro-apoptotic

effect of sorafenib in HCC cells had also been studied extensively. In

2008, the SHARP (Sorafenib HCC Assessment Randomised Protocol)

* Corresponding author. Tel.: +8613958084556; fax: +86 057186044817.

E-mail address: 369369@zju.edu.cn (H. Lin).

** Corresponding author. Tel.: +8613805738266; fax: +86 057186006605.

E-mail address: cxjzu@hotmail.com (X. Cai).

http://dx.doi.org/10.1016/j.canlet.2015.06.019

Cancer Letters 367 (2015) 1–11

Contents lists available at ScienceDirect

Cancer Letters

journal homepage: www.elsevier.com/locate/canlet

trials showed an improved overall survival in Child–Pugh class A

patients with advanced HCC upon treatment with the antiangiogenic

and antiproliferative agent sorafenib. In addition, Oriental con-

ﬁrmed the eﬃcacy and safety of sorafenib again in treatment of

advanced hepatocellular carcinoma by another multicenter, ran-

domized, double-blind, placebo-controlled phase III clinical trials.

However, the promising systemic chemotherapeutic agent

sorafenib only demonstrated relatively limited beneﬁts rather than

eradicated the microscopic residual and cured the patients with ad-

vanced HCC. Sorafenib is beneﬁcial in only around 30% of patients,

and acquired resistance often develops within 6 months [15,16], sug-

gesting the existence of primary and acquired sorafenib resistance

in hepatocellular carcinoma cells. So far, some researchers have in-

vestigated the mechanism underlying resistance to sorafenib from

molecular and clinical points of view. Huang et al. have reported

that overexpression of both αB-Crystallin and 14-3-3ζ decreased

hepatoma cells sensitization to sorafenib in clinical by inducing

epithelial–mesenchymal transition (EMT) in HCC cells [17]. Chiou

et al. presented evidence that glucose-regulated protein 78 (GRP78)

is a positive modiﬁer for sorafenib resistance acquisition in HCC and

GRP78 knockdown enhanced the eﬃcacy of sorafenib-mediated cell

death [18]. Chen et al. also conducted experiments to investigate

sorafenib resistance and the results showed that long-term expo-

sure to sorafenib activated the phosphatidylinositol 3-kinase

(PI3K)/Akt signaling pathway and mediate acquired resistance to

sorafenib in HCC cell lines [19]. All the insights into the molecular

and clinical changes involved in sorafenib treatment provided a

greater understanding of the underlying mechanism of primary and

acquired resistance to sorafenib. However, a systemic and compre-

hensive analysis about the mechanism of acquiring resistance to

sorafenib was still elusive [20]. Here, in order to clarify the drug re-

sistance mechanism clearly, we reviewed studies on sorafenib

resistance in liver cancer from different angles, including molecu-

lar markers, signaling pathways, drug resistance principles, regulation

systems, therapeutic implications and recent approaches. Increas-

ing evidence suggested that deeper insight into the formation of

sorafenib resistance would shed light on the speciﬁc drug resis-

tance mechanism and might lead to identiﬁcation of potential clinical

biomarkers for prognosis evaluation and targets for new therapeu-

tic strategies. Therefore, in the present review, by synthesizing the

retrospective studies and reports, we provided potential molecu-

lar, cellular and microenvironmental mechanism underlying impaired

sensitivity to sorafenib in hepatocellular carcinoma, which had pro-

found effect on inhibiting tumor progression, evaluating patient

survival and predicting sorafenib treatment response.

Epithelial–mesenchymal transitions (EMT)

Epithelial–mesenchymal transitions (EMT) are mainly marked

by the loss of cell–cell interactions and of epithelial apico-basal po-

larity with the concomitant acquisition of mesenchymal markers

and enhanced migratory behavior [21,22]. As is well known, EMT

is of paramount relevance for various developmental processes, in-

cluding gastrulation, neural crest formation and carcinoma

progression. In the last decades, EMT has been extensively studied

and validated in the progression of various carcinomas such as HCC

[23,24]. A large body of researches has claimed the important role

of EMT in facilitating tumor development and progression by driving

metastasis, through the acquisition of enhanced migratory and in-

vasive potential [25–30]. Metastasis, induced by EMT, deconvoluted

into several steps including intravasation, circulation, margin-

ation, extravasation and colonization, is a crucial cause of deaths

in cancer therapy [31,32]. It had been reported that intrahepatic me-

tastases were observed in about 30% of cases after surgical removal

of small HCC nodules and in 80% of HCC autopsy cases [33]. Via EMT,

epithelial cells dissolve intercellular connections and acquire

mesenchymal properties and metastasize to the native or distant

sites. Once cancer cells seed the metastatic site, a mesenchymal to

epithelial transition (MET) occurs, inducing colonization and growth

of the metastatic foci with re-expression of cell adhesion mole-

cule E-cadherin, facilitating tumor cells to seed in the metastatic

sites [34–40]. E-cadherin re-expression accompanied by a partial

MET in the metastatic sites increases post-extravasation survival of

the cancer cells and resistance to multi-drugs [35,37]. Additional-

ly, further study found that a variety of biological molecules such

as HIF, TGF and miRNAs involved in the process of MET through dif-

ferent signaling pathways respectively accelerated the formation of

distant tumor metastasis [41–43]. In epithelial cancers, EMT re-

sulted in the loss of E-cadherin and in turn, tumor cells attain

enhanced migratory and invasive potential. E-cadherin, whose down-

regulated expression is a main biomarker for activation of EMT,

shows reverse relationship with drug resistance [44]. By undergo-

ing EMT, the tumor cells acquired resistance to a number of chemo

and radiotherapies [34,45–48]. The relationship between epithelial–

mesenchymal transition (EMT) and drug resistance was ﬁrst

described in connection with cancer stem cells by Mani et al., who

inferred that blocking or reversing EMT might cause chemoresistant

cells to revert to chemosensitive cells [49]. In addition, in breast

cancer therapy, it was reported that epithelial cells acquire some

cancer stem cells properties via EMT, such as anti-apoptosis and drug

resistance [50]. In the process of EMT in tumor cells, some biolog-

ical molecules, such as TGF β, Slug and FOXC2, play very crucial role

in explaining the sensitivity of tumor cells to chemotherapy drugs.

Activation of TGF β or FOXC2 and overexpression of Slug impaired

the sensitivity of tumor tissues to drug [49,51,52]. The drug resis-

tance was also reported in correlation with EMT in HCC [17–19].

Various signaling pathways have been involved in regulation of EMT

program [27], indicating that these signaling pathways and mol-

ecules involved are potentially associated with drug resistance. The

Raf/MEK/ERK pathway represents a dominant signaling network pro-

moting proliferation and metastasis and is the main jamming target

pathway of sorafenib [53–56]. The genetic and molecular network

involved in the signal pathway is very complicated. In fact, some

studies have demonstrated that treatment with Raf kinase inhibi-

tors can even paradoxically induce ERK cascade signaling by

promoting dimerization of Raf family members [57,58]. The

biomarkers for sorafenib eﬃcacy, such as Plasma c-KIT, hepato-

cyte growth factor and angiopoietin-2, are likely to be downregulated

in the sorafenib sensitive cell lines while the phospho-Akt and p85

(a regulatory subunit of PI3K) are upregulated in sorafenib resis-

tant cell lines [19,59,60]. Kunnimalaiyaan et al. hypothesized that

Notch signaling pathway is a potential regulator of EMT program

in HCC and NICD3 protein increased E-cadherin and activated tran-

scription factors Snail, Slug, and MMPs and induced EMT [27], which

might lead to development of sorafenib resistance. Acquired resis-

tance to sorafenib in HCC might also be mediated by the activation

of phosphatidylinositol 3-Kinase/Akt signaling pathway [19,61].

Overexpression of both αB-Crystallin (Cryab) and 14-3-3ζ can induce

epithelial–mesenchymal transition (EMT) in HCC cells through ac-

tivation of the extracellular-regulated protein kinase (ERK) cascade,

a crucial up-stream factor of ERK1/2/Fra-1/slug signaling pathway,

which can counteract the effect of sorafenib [62–67]. Therefore, it

is postulated that sorafenib resistance is closely correlated with the

dynamic changes of numerous molecules, especially their up- or

down-regulated expression, involved in the mutual transition

between epithelial and mesenchymal cell phenotypes and various

signaling pathways. Particularly, epithelial cells are more suscep-

tible to a Raf kinase inhibitor, sorafenib, whereas mesenchymal cells

showed signiﬁcant resistance [68,69]. In addition, PI3K/Akt showed

higher activity and integrin-linked kinase (ILK) exhibit in the mes-

enchymal cells as compared to epithelial cells [70,71]. Many

pathways and molecules involved in these pathways play a crucial

2J. Chen et al./Cancer Letters 367 (2015) 1–11

role in regulation, induction and reversion of EMT, including Wnt,

TGFβ, RTK and other signaling pathways [72–81]. The detailed in-

formation was depicted in Tabl e 1. Therefore, EMT, MET and

concomitant molecules and cell phenotypes are important deter-

minants for the resistance of HCC against sorafenib (Fig. 1).

Cancer stem cells (CSCs)

Cancer stem cells (CSCs) were ﬁrst identiﬁed in the hematopoi-

etic system in 1990s when the cancer stem cells model was

established [85,92]. CSCs are deﬁned as cells within a tumor that

Table 1

Pathways and molecules involved in EMT.

Pathways Molecules

involved

Role Sorafenib

eﬃcacy

References

Wnt Frizzled Promotes tumor cell proliferation and metastasis; induces EMT; increases drug resistance; participates in

crosstalk with other pathways; alters the microenvironment

–[38,62,71,82]

GSK-3β

β-catenin

TCF

TGFβ Smad Regulates cell proliferation, differentiation and apoptosis; induces EMT; promotes tumor invasion and

metastasis

–[21,26,83]

TIP30

RTK-Ras Raf Regulates cell signaling and the tumor microenvironment; drives tumor development and progression – [27,29,42]

MEK

ERK

RTK-PI3K AKT Regulates EMT; promotes motility and metastasis – [50,72,84]

mTOR

Hedgehog Gli Regulates cancer cell proliferation and metastasis; induces EMT; increases stromal ﬁbrosis – [57,85,86]

PTCH1

Snail/Slug

TNFα IκB Induces EMT; promotes metastasis and invasion; increased Twist expression – [28,49,87]

NF-κB

IL-1β IRAK Promotes tumor cell migration and invasion; contributes to higher angiogenesis, tumor growth, tumor

progression; increases inﬂammation; induces EMT

–[28,59,64]

TRAF

NF-κB

IL-6 HSP27 Promotes proliferation; regulates EMT; enhances cancer metastasis; increases inﬂammation – [54,88,89]

STAT3

Notch Snail Upregulates Snail; stimulates Slug; induces EMT; represses E-cadherin expression; promotes tumor cell

migration and invasion; increases chemoresistance

–[17,90,91]

Slug

Jagged1

Note: –, speciﬁc molecules negatively correlated with Sorafenib eﬃcacy.

Fig. 1. Role of EMT, MET and the molecules involved in the two processes in the development of resistance of HCC to sorafenib. During epithelial–mesenchymal transi-

tions, the expression of E-cadherin and cytokeratins, the cell–cell adhesion molecules, was down-regulated and the levels of Snail, Twist and Zeb, the transcriptional repressors

of E-cadherin, were upregulated. Epithelial phenotype was transformed to mesenchymal phenotype. Epithelial cells are more sensitive to sorafenib treatment while mes-

enchymal cells are resistant to sorafenib treatment. MET, the reverse process of EMT, was accompanied by re-expression of E-cadherin and cytokeratins and down-

regulation of Snail, Twist and Zeb. Metastatic tumor cells could seed in the distant or local sites with higher adhesion via MET. In addition, our team has hypothesized that

the tumor cells acquired sorafenib resistance in a way of an upward spiral through EMT and MTE circulation and the evidence has been collected using the experiments

and detailed data but yet not oﬃcial report.

3J. Chen et al./Cancer Letters 367 (2015) 1–11

possess the capacity to self-renew and to cause the heteroge-

neous lineages of cancer cells that comprise the tumor [93,94].

According to cancer stem cell hypothesis, in tumors organized into

a hierarchy of heterogeneous cell populations, CSCs are only a minor

part but real driving force behind tumor growth while the remain-

ing cells, though making up the majority of the cells in the tumor,

lack tumorigenic potential [95]. Moreover, CSCs are able to resist

chemotherapy and spring back months or years which may explain

the tragic relapses after surgical or chemotherapeutic treatment [96].

Chemo and radiotherapies can only shrink bulk tumors with quick

eﬃcacy but fail to kill the tiny subset of cells, CSCs, that seed and

resupply the main tumor directly. Perhaps, the expression of drug

eﬄux pumps and DNA-repair mechanisms are the two main reasons

of resistance of CSCs to various forms of therapy. The preferential

activation of the DNA damage checkpoint response and an in-

crease in DNA-repair capacity have been veriﬁed to be associated

with resistance to radiotherapy of brain cancer stem cells [97].Fur-

thermore, virulent multi drug resistant (MDR) phenotypes were

established in the hierarchy of heterogeneous cell populations in

HCC, which may explain the therapeutic refractoriness and dormant

behavior displayed by CSCs [90,93]. Apart from displaying classi-

cal physiological abnormalities and aberrant blood ﬂow behavior,

MDR cancers exhibit several distinctive features such as higher

apoptotic threshold, aerobic glycolysis, regions of hypoxia, and el-

evated activity of drug-eﬄux transporters, which may function as

safeguards for CSCs from radio- or chemotherapy [90]. Distinc-

tively, Dick et al. suggested that the insensitivity of CSCs to most

treatment such as chemotherapy and radiation perhaps corre-

lated with the relatively more slow growth speed of CSCs as

compared to other rapidly dividing malignant cells [96].

Cancer stem cell (CSC)-like cells could be acquired via EMT with

increased CSC markers on the cell surface. They share common prop-

erties with CSCs, self-renewal ability and drug resistance [98].

Recently, the correlation between EMT and the adoption of cancer

stemness has been extensively studied as a hot research topic. From

the cellular point of view, the involvement of EMT can also be used

to clarify the mechanism under the acquired resistance to sorafenib

[99]. Via EMT, the epithelial cells overexpressed mesenchymal

biomarkers and CSC markers and silenced CSC gain migratory ability

[100]. Moreover, various signaling pathways are bridged between

EMT and CSCs, including Notch, Hedgehog, Wnt, NF-κB and epi-

genetic molecular changes [101,102], which exist in potential

molecular and cellular mechanism underlying the sorafenib resis-

tance but still unclear until now.

In HCC, liver cancer stem cells (LCSCs) display strong prolifer-

ation ability, multi-directional differentiation capacity and high drug

resistance properties, although they merely account for minor pro-

portion in liver cancer tissues [83,103,104]. For advanced HCC treated

with sorafenib, in LRCCs, a novel subpopulation of LCSCs, CSC markers

such as aldehyde dehydrogenase 1 family, wingless-type MMTV-

integration-site family, cell survival and proliferation genes were

observed upregulated, and tumor suppression markers such as apop-

tosis, cell cycle arrest, cell adhesion and stem cells differentiation

genes downregulated, concomitant with non-uniform activation of

speciﬁc isoforms of the sorafenib target proteins extracellular-

signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene

homolog (AKT) [105]. It suggested that acquired resistance of HCC

to sorafenib might be explained by LCSCs, which cannot be com-

pletely killed by sorafenib but proﬁle and differentiate into new

tumor tissues, leading to the metastasis and recurrence of HCC.

Therefore, similar to hepatocytes or even progenitor cells of the liver,

LCSCs can be regarded as the critical subset in the pathogenesis of

HCC [70] and provide a new thought line to understand the mech-

anism underlying sorafenib resistance (Fig. 2).

By understanding the cellular mechanisms underlying drug re-

sistance, especially for CSCs, it may help to identify CSC-speciﬁc

targets and develop CSC-speciﬁc therapies for HCC treatment.

Microenvironment

The liver tumor microenvironment is a complex interaction

network created by non-tumoral cells, molecules and soluble factors

within stroma, supportive and permissive for HCC initiation and pro-

gression. Sorafenib, a multikinase inhibitor with antiangiogenic and

antiproliferative effects for advanced HCC, works on tumor cells and

the stroma. The stroma correlates with diverse critical molecules

Fig. 2. Role of CSCs in the development of resistance of HCC to sorafenib. Tumors were hypothesized to be organized into a hierarchy of heterogeneous cell populations

and CSCs are only a tiny subset of tumor cells. Treated with sorafenib, the majority of tumor cells underwent apoptosis and CSCs were remained, showing their sorafenib

resistance. CSCs reconstructed tumor by causing the heterogeneous lineages of cancer cells, leading to relapse of malignant tumors. In addition, sharing similar character-

istics with normal stem cells, CSCs migrated, invaded into blood vessels, self-renewed, differentiated and led to tumor metastasis with acquired sorafenib resistance. CSCs

possibly contribute to recurrence and metastasis of malignant tumors with acquired drug resistance.

4J. Chen et al./Cancer Letters 367 (2015) 1–11

and signaling pathways responsible for cancer progression, includ-

ing activated Akt, Ras, NF-κB, HIF-1α, myc, hTERT and IRF4 involved

in notch, wnt and hedgehog signaling pathway [39,48,74,106]. The

angiogenic cells, immune cells and cancer associated ﬁbroblastic cells

are three subclasses of stromal components in the liver microen-

vironment. These cells favor tumor progression and promote

resistance to therapy [86,87,106]. Resulting from these cells, an-

giogenesis, inﬂammation, ﬁbrosis, hypoxia, oxidative stress and

autophagy emerged in the precancerous and neoplastic milieu, all

of which play critical roles in the development, progression, recur-

rence and drug resistance of malignant tumors [88,106–108].In

addition, for HCC patients infected chronically by hepatitis B virus

(HBV) or hepatitis C virus (HCV), viral reactivation is a vital mi-

croenvironmental factor. Role of different microenvironmental factors

in the development of resistance of HCC to sorafenib was de-

picted in Fig. 3.

Angiogenesis

HCC is a highly vascularized tumor and angiogenesis plays an

important role in the growth of liver tumor. Vascular endothelial

growth factor (VEGF) is the most critical proangiogenic factor and

the main target of mutikinases inhibitor, sorafenib [109]. VEGF can

function as a cytokine that directly affects hepatic stellate cells,

Kupffer cells and hepatocytes [110,111], and mediates the dissolu-

tion of the vascular basement membrane and the interstitial matrix

[109]. During the growth of tumor tissues, endothelial cells are ac-

tivated and become proliferative to form new vessel within the

stroma, to provide nutrients and oxygen for tumors. Remarkably,

tumor new vasculature is composed largely of immature vessels with

increased permeability, tortuosity and interstitial ﬂuid pressure than

normal, which facilitates immune cell inﬁltration, metastasis and

tumor progression but compromises the delivery of therapeutics

and nutrients [91,106]. Platelet-derived endothelial cell growth factor

(PDGF), secreted by cancer cells, is also involved in cell migration

and new vessel maturation. Integrins and cadherins are other two

important mediators involved in tumor neoagiogenesis and they es-

tablish contacts required for new vascular tube formation by

mediating cell–matrix and cell–cell interactions respectively [112].

Inﬂammation

Inﬂammation is an essential element of tumor microenviron-

ment that predisposes to cancer initiation. The inﬂammatory

response in HCC microenvironment is regulated by several growth

factors, in particular, TGF-β, HGF and EGF. TGFβ, a difunctional mol-

ecule, acts as a tumor suppressor in normal and premalignant cells

and paradoxically, an oncogenic growth factor in cancer cells [113].

Epidermal growth factor receptor (EGFR) plays an important role

in tumor-associated angiogenesis by regulating synergistically with

several angiogenic factors [82]. Cytokines and chemokines, se-

creted not only in tumor cells but also in the surrounding tissue,

have been implicated in chronic inﬂammation, which have pro-

found effect on the development and progression of HCC through

mediating evasion of the immune system, angiogenesis, invasion

and dissemination [106,114].

Fibrosis

Fibrogenesis can entail secretion of several pro-angiogenic factors

by stromal cells, especially MMP, PDGF, TGFβ1, FGF and VEGF, which

provokes resistance to blood ﬂow and reduces metabolic ex-

change of oxygen, favoring hypoxia [106]. It has been reported that

stromal ﬁbroblasts may inﬂuence tumor initiation in adjacent epi-

thelia and promote progression [115]. Fibrosis is characterized mainly

by increased stiffness and denser collagen secreted by stromal,

Fig. 3. Role of microenvironment in the development of resistance of HCC to sorafenib. Hepatocellular carcinoma is a highly vascularized tumor. Sorafenib played an antiangiogenic

role by inhibiting VEGF and led to vasculature atrophy, leading to hypoxia. Inadequate oxygen accessibility activated hypoxia-inducible factor 1 (HIF-1α, HIF-2α), whose

expression correlates with angiogenesis, immune evasion, invasion and metastasis, inducing sorafenib resistance. Sorafenib treatment activated mTOR, upregulated expres-

sion of AKT and then caused autophagy, escaping from sorafenib eﬃcacy. In extracellular microenvironment, with the progression of tumors, stromal cells secreted more

and more molecules and the stroma becomes stiffer and denser, affecting delivery and eﬃcacy of sorafenib negatively. TAM are typical inﬂammatory cells, predisposing to

cancer initiation, and can cause oxidative stress. The relationship between inﬂammation, oxidative stress and sorafenib resistance has not been investigated directly until

now (—–). Hypoxia could activate ﬁbroblast and HSC to secrete more collagen and resulted in further stiffened stroma, enhancing insensitivity to sorafenib.

5J. Chen et al./Cancer Letters 367 (2015) 1–11

inﬂammatory and cancer cells, which has a causative impact on the

pathogenesis of liver diseases. In the ﬁbrotic microenvironment, it

is observed that ﬁbrillary collagen types I and II and ﬁbronectin are

deposited excessively in the liver [106]. The situation leads to cel-

lular transformation and metastasis, essential for tumor angiogenesis

and HCC development. The eﬃcacy of sorafenib has been re-

ported to reduce on stiff, collagen-rich microenvironments which

impairs the delivery of chemotherapeutics and promotes aggres-

sive neoplastic cell behavior [84,89].

Hypoxia

Compared to normal liver vasculature, liver tumor vessels have

an abnormal blood ﬂow and are excessively leaky, leading to

hypovascular areas and severe hypoxia. Inadequate oxygen acces-

sibility activates hypoxia-inducible factor 1 (HIF-1), whose expression

correlates with angiogenesis, immune evasion, invasion and me-

tastasis by interacting with several downstream genes [88,107,116].

It has been reported that during exposure to hypoxic condition, HCC

cells tended to experience EMT with increased cell migration and

invasion, and exhibit high resistance to chemotherapy [117]. Chronic

alcohol consumption, sustained antiangiogenic therapy and abnor-

mal metabolic signatures contribute to hypoxia, enhancing

proliferation, angiogenesis, metastasis, chemoresistance, and ra-

dioresistance [33,88,118]. Liang et al. conﬁrmed the hypothesis that

hypoxia caused by the antiangiogenic effects of sustained sorafenib

therapy could induce sorafenib resistance as a cytoprotective adap-

tive response through HIF-1α and NF-κB activation, thereby limiting

sorafenib eﬃciency [118].

Oxidative stress

Oxidative stress caused by tumor-associated macrophages (TAM),

CSCs and cancer cells leads to an increased mutation, genomic in-

stability, epigenetic changes, and protein dysfunction through

interaction with DNA, RNA, lipid and proteins. Tumor-associated mac-

rophages (TAM) are an important component of the leukocytes in

the tumor microenvironment that can inﬁltrate most tumors and

promote migration of endothelial cells, neo-angiogenesis and ﬁ-

brosis, associated with poor prognosis [119]. Oxidative stress can

activate ﬁbroblast, the main source of collagen, and produces several

mediators implicated in tumor progression [106], suggesting that

there is a signiﬁcant correlation between oxidative stress and sorafenib

resistance although no studies have already verify the hypothesis.

Autophagy

Hypoxia in the stroma, together with oxidative stress condi-

tions, can stimulate an evolutionarily conserved self-digestion

pathway, autophagy, an escape phenomenon for cancer cells during

antiangiogenic treatment [108,120]. Sorafenib treatment could lead

to accumulation of autophagosomes as evidenced by conversion from

LC3-I to LC3-II observed by immunoblot in Huh7, HLF and PLC/

PRF/5 cells due to activation of autophagic ﬂux, suggesting that

autophagy is likely to correlate with the underlying sorafenib re-

sistance in HCC [121].

Viral reactivation

Chronic HBV or HCV infection was the major cause of HCC in

either Western or Eastern [122]. Viral reactivation is potentially fatal

and mainly triggers those patients previously exposed to HBV or

HCV [123]. It leads to deterioration of liver function, induces de-

velopment of HCC and signiﬁcantly affects prognosis of patients with

HCC [124]. Zuo et al. reported that viral reactivation was the most

important correlative risk factor for HCC recurrence [125].As

sorafenib resistance becomes a hot topic, some researchers start to

focus on the correlation between viral reactivation and sorafenib

eﬃcacy, with expectation to explore new treatment against HCC

basing their potential correlation. However, until now, the opin-

ions were still controversial.

Two recent studies reported that sorafenib exhibited a potent

anti-replicative eﬃcacy on HCV [126,127]. An opposite result was

shown in another study, which reported that sorafenib impaired the

antiviral effect of interferon alpha on hepatitis C virus replication

[128].In addition, Zhang et al. showed that sorafenib may contrib-

ute to the reactivation of virus by immunosuppressing the

proliferation of NK cells [129]. Therefore, there is no consistent view

about the correlation about viral reactivation and sorafenib treat-

ment. What’s more, further exploration about the correlation about

viral reactivation and sorafenib resistance just took a small step.

HBV infection in HCC may enhance sorafenib resistance by

downregulating miR-193b and its downstream target protein Mcl-1,

inhibiting sorafenib-induced apoptosis [130]. Compared to HBV-

negative patients, HBV-positive HCC patients showed a less survival

beneﬁt according to a phase III RCT from Asia-Paciﬁc region [131].

On the contrary, HCV-positive patients showed an improvement in

median overall survival and time to progression over non-HCV in-

fected patients by a post-hoc retrospective subgroup analysis of HCV-

positive patients in the Sorafenib Hepatocellular Carcinoma

Assessment Randomized Protocol (SHARP) study [132].

Although no consistent view was obtained about the correla-

tion of viral reactivation, sorafenib treatment and sorafenib resistance,

we believe that the unremitting efforts of researchers will pave a

way for the new clinical treatment of HBV/HCV-associated HCC.

In summary, understanding how biological processes and viral

reactivation in tumor stroma interact with cancer cells and the sig-

naling pathways involved could help to illustrate the mechanism

of sorafenib resistance and identify new therapeutic and

chemopreventive targets.

Current and promising

New agents targeting pathways

Tivantinib (ARQ 197) is an oral, selective small MET tyrosine

kinase inhibitor and demonstrates signiﬁcant antitumor activity es-

pecially in MET-high patients [133]. Everolimus, as a mTOR inhibitor,

may be a promising therapeutic drug for advanced HCC though no

consistent ﬁndings of its antitumor effects were observed [134].

Belinostat may induce apoptosis and tumor regression in HCC pop-

ulation by inhibiting HDAC [135].

Moreover, Tovar et al. reported that brivanib demonstrated an-

titumor activity in xenograft HCC models resistant to sorafenib

through suppressing tumorigenesis and angiogenesis via target-

ing vascular endothelial growth factor(VEGF) and ﬁbroblast growth

factor receptors (FGFR) while Llovet et al. reported a negative result

that brivanib did not signiﬁcantly improve OS of patients with HCC

who had received sorafenib treatment [136,137]. Another two new

agents, linifanib, a novel ATP-competitive inhibitor, and bevacizumab,

a monoclonal antibody, both could block the activity of VEGF and

show comparative eﬃcacy with sorafenib, as evidenced by the results

of Phase III trial of linifanib and phase II trial of bevacizumab

[138,139]. In addition, PI-88, another new agent inhibiting

heparanase, may confer signiﬁcant clinical beneﬁts for patients with

HCC by preserving the integrity of the stroma and blocking the ac-

tivity of ﬁbroblastic growth factors (FGF) [140].

Combination of targeted agents

The Raf/(MAPK) signaling pathway is the major targeting source

of sorafenib, whose blockage will inhibit tumorigenesis and

6J. Chen et al./Cancer Letters 367 (2015) 1–11

angiogenesis of HCC. The PI3K/Akt pathway is also involved in the

development and progression of HCC by regulating a large number

of molecules implicated in all aspects of cancer progression. Sorafenib

inhibits the Raf/(MAPK) signaling pathway but activates (PI3K)/

Akt pathway, indicating that there exist cross-talks between the PI3K/

Akt and MAPK/ERK pathways and that the latent compensatory

mechanism of the PI3K/Akt pathway may contribute to sorafenib

resistance in HCC. Therefore, better survival outcomes may be

achieved by using promising combinations of targeted therapies

through inhibiting different pathways involved in HCC. Ras/MAPK

and AKT/mTOR pathways are frequently deregulated in human

hepatocarcinogenesis [141]. The combination of PKI-587, target-

ing PI3K/AKT/mTOR pathway and sorafenib, mainly targeting Ras/

Raf/MAPK signaling pathways, has the advantage over monodrug

therapy on inhibition of HCC cell proliferation by blocking both the

signaling pathways simultaneously [142]. Additionally, results of an

ongoing, randomized, open-label, phase II study are awaited, which

would compare the eﬃcacy of everolimus, targeting PI3K/AKT/

mTOR pathway, combined with sorafenib to sorafenib alone

(ClinicalTrials.gov identiﬁer NCT01005199). However, a recent phase

III, randomized, double-blind, placebo-controlled trial of sorafenib

plus erlotinib (a EGFR inhibitor) in patients with advanced HCC

showed no improved survival compared to sorafenib alone [143].

The horizontal blockades on different pathways by using com-

bination of targeted agents showed a good perspective in HCC

treatment. At the same time, vertical blockades on Ras/MAPK

pathway were also emphasized in exploration of new strategies for

overcoming sorafenib resistance.

The Ras/MAPK pathway is the key pathway in the treatment of

HCC using sorafenib and the inhibition of the RAF kinases is an im-

portant facet of the action of sorafenib in HCC. Combining sorafenib

with other inhibitors active on other kinases or facets of the Ras/

MAPK pathway, such as MEK inhibitors, might achieve a better

eﬃcacy of sorafenib and therefore a better control of tumor growth

[144]. Moreover, refametinib plus sorafenib with reduced doses

showed antitumor activity in patients with HCC. Especially, in pa-

tients with RAS mutations, refametinib/sorafenib combination could

signiﬁcantly improve their overall survival [145].

In order to improve the impaired eﬃcacy caused by sorafenib

resistance in advanced HCC, drugs combination is a promising di-

rection but the eﬃcacy of sorafenib combined with other molecular

targeted drugs still needs further exploration.

Combination of cytotoxic chemotherapeutic agents

Extensive efforts have been devoted to evaluation of different cy-

totoxic agents by different methods, including Metronomic

capecitabine [146], gemcitabine [147], cisplatin [148] and doxoru-

bicin [149], for treatment of advanced HCC. But the objective

response rate (ORR) to a single cytotoxic regimen was merely 0–10%

with no signiﬁcant survival beneﬁt [150]. In order to explore new

path to overcome sorafenib resistance and achieve better treat-

ment of advanced HCC, the combination of sorafenib and cytotoxic

agents has attracted focus of researchers. Wang et al. have re-

ported that sorafenib–irinotecan sequential therapy augmented the

anti-tumor eﬃcacy of monotherapy in hepatocellular carcinoma cells

HepG2 [151]. In another study, Liu et al. reported that GEMOX com-

bined with sorafenib as ﬁrst-line therapy followed by sorafenib as

maintenance therapy was effective with manageable toxicity for

treatment of advanced HCC [150]. Furthermore, the combination

of sorafenib and gemcitabine showed modest clinical eﬃcacy with

good toleration in advanced HCC [152]. In addition, compared with

doxorubicin monotherapy, sorafenib plus doxorubicin resulted in

greater median time to progression, overall survival, and progression-

free survival [153]. The effectiveness and the safety of some cytotoxic

chemotherapeutic agents are still in stage III clinical trial. The clinical

application of cytotoxic chemotherapeutic agents combined with

sorafenib still has a long way to go.

Combination with immunotherapeutic drug

Immune checkpoint blockade has been considered as a prom-

ising therapeutic approach for HCC. Immunotherapeutic drugs are

not metabolized in the liver and HCC is typically immunogenic, so

theoretically predictable pharmacokinetic proﬁles may be achieved

in HCC with no severe hepatoxicity [154]. However, immunothera-

peutic drug alone sometimes didn’t demonstrate antitumor activity.

A phase I/II trial of CT-011(anti-PD-1 antibodies) in advanced HCC

was initiated but stopped due to slow accrual (ClinicalTrials.gov iden-

tiﬁer NCT00966251). Therefore, combination of immunotherapeutic

drug and sorafenib has recently emerged as a new treatment method

for advanced HCC. Wang et al. reported that this combinatorial ap-

proach resulted in blockade of programmed death-ligand 1 (PDL1)

and sequential effective natural killer cell responses against hepa-

tocellular carcinoma [155]. Chen et al. reported that combination

of anti-PD-1 immunotherapy with sorafenib showed eﬃcacy con-

comitant with targeting of the hypoxic and immunosuppressive

microenvironment in mice model [156]. In a recent study in vivo

and in vitro, the result showed that targeting CD47 in combina-

tion with sorafenib is an attractive therapeutic regimen for the

treatment of HCC patients [9].

Nevertheless, the successful application of immunotherapy in

HCC will have to take into account the liver cancer-speciﬁc immune

microenvironment and responses.

Personalized therapy

Indeed, differences in etiology, disease stage and pathological

process make HCC a highly dyshomogeneous malignant tumor. In

terms of quality and quantity, individual differences affect sensi-

tiveness of patients with HCC to sorafenib treatment [6]. Selection

of patient candidates more sensitive to sorafenib treatment is fea-

sible in human malignancies according to their tumor molecular

background. Thus, a molecular identiﬁcation is crucial to assess the

levels of new targets, and to customize therapies in patients with

HCC.

Low or high level of miR-425-3p has been postulated respon-

sible for stratifying patients with advanced HCC for sorafenib

treatment [157]. VEGF, VEGFR and VEGFA may represent a valu-

able asset to better identify HCC patients more likely to beneﬁt from

sorafenib treatment [158,159]. Mapk14 inhibition has been re-

ported to be associated with HCC sensitization to sorafenib, indicating

that Mapk14 may be used to classify the HCC population sensitive

or resistant to sorafenib [160]. Other potential biomarkers, still in

exploration, may be essential for personalized therapy, including

pERK [161],STAT3[162], EGFR/HER-3 [163], Nanog [164],JNK[165],

HGF/c-KIT [166], FGF3/FGF4 [167], αB-Crystallin [17] and others.

The exploration of biomarkers is a great step moving toward per-

sonalized therapy in patients with HCC. However, the high genetic

heterogeneity of HCC is diﬃcult to reﬁne due to genome-wide ap-

proaches used for genes identiﬁcation though many progresses have

been made in this regard. With the accelerated progress of clini-

cal management, it is no doubt that the more precise knowledge

of the molecular classes of HCC, better-designed clinical trials, and

more effective blockade of speciﬁc pathways with new therapies

will deﬁnitely implement personalized therapy for HCC.

Conclusion

Hepatocellular carcinoma (HCC), the most common primary liver

tumor, is notoriously resistant to systemic therapies. In particular,

sorafenib resistance of advanced HCC generated during sustained

7J. Chen et al./Cancer Letters 367 (2015) 1–11

drug treatment has raised great concern throughout the world. Un-

derstanding the underlying mechanism is in urgent need in order

to potentiate the antitumor effect of sorafenib and identify new

promising chemotherapeutic therapies. In this review, we present

potential molecular, cellular and microenvironmental mechanism

to explain sorafenib resistance in HCC by synthesizing the retro-

spective studies and report systematically and comprehensively. EMT

and MET, together with the critical growth factors and signaling

pathway involved in the two transition processes, play a pivotal role

in sorafenib resistance. Furthermore, CSCs and CSC-like cells, as the

clonogenic core of the liver tumor, have an important impact on the

generation of sorafenib resistance. Therapeutic approaches target-

ing CSCs or signaling pathways involved in CSCs are hypothesized

as a breakthrough for treating advanced HCC. In addition, the liver

tumor microenvironment functions as an essential part in tumor

development and progression. The biological processes involved in

tumor microenvironment, angiogenesis, inﬂammation, ﬁbrosis,

hypoxia, oxidative stress, autophagy and viral reactivation have been

demonstrated signiﬁcantly or potentially correlated with sorafenib

resistance. This review ﬁrst provides systemic comment on the mech-

anism of sorafenib resistance in HCC and hopes to motivate new

thoughts about the chemotherapeutic targets or approaches. In order

to overcome the impaired eﬃcacy of sorafenib induced by origi-

nal or acquired resistance, immense amount of studies in the ﬁeld

of HCC treatment was done with expectation to explore new ther-

apeutic drugs or approaches with signiﬁcant antitumor activity. These

studies described the state-of-art developments in the ﬁeld and an-

ticipated the problems to be solved.

Funding

This work was supported by National Natural Science Founda-

tion of China (81201942) and Zhejiang Provincial Natural Science

Foundation of China (LZ14H160002, LY15H160039). The funders had

no role in study design, data collection and analysis, decision to

publish, or preparation of the manuscript.

Conﬂict of interest

The authors declare that there are no conﬂicts of interest.

References

[1] G. Yu, Y. Jing, X. Kou, F. Ye, L. Gao, Q. Fan, et al., Hepatic stellate cells secreted

hepatocyte growth factor contributes to the chemoresistance of hepatocellular

carcinoma, PLoS ONE 8 (2013) e73312.

[2] J. Ferlay, I. Soerjomataram, M. Ervik, R. Dikshit, S. Eser, C. Mathers, et al.,

GLOBOCAN 2012 v1. 0, Cancer Incidence and Mortality Worldwide: IARC

CancerBase No. 11 [Internet]. Lyon, Fr Int Agency Res Cancer, 2013. Available

from: <http://globocan.iarc.fr>, (accessed on 12.12.13).

[3] A.J. Page, D.C. Cosgrove, B. Philosophe, T.M. Pawlik, Hepatocellular carcinoma:

diagnosis, management, and prognosis, Surg. Oncol. Clin. N. Am. 23 (2014)

289–311.

[4] A. Pahwa, K. Beckett, S. Channual, N. Tan, D.S. Lu, S.S. Raman, Eﬃcacy of the

American Association for the Study of Liver Disease and Barcelona criteria for

the diagnosis of hepatocellular carcinoma, Abdom. Imaging 39 (2014) 753–760.

[5] L. Wang, M. Yao, Z. Dong, Y. Zhang, D. Yao, Circulating speciﬁc biomarkers in

diagnosis of hepatocellular carcinoma and its metastasis monitoring, Tumour

Biol. 35 (2014) 9–20.

[6] G. Giannelli, B. Rani, F. Dituri, Y. Cao, G. Palasciano, Moving towards

personalised therapy in patients with hepatocellular carcinoma: the role of

the microenvironment, Gut 63 (2014) 1668–1676.

[7] Q. Wu, Z. Yang, Y. Nie, Y. Shi, D. Fan, Multi-drug resistance in cancer

chemotherapeutics: mechanisms and lab approaches, Cancer Lett. 347 (2014)

159–166.

[8] N.A. Saunders, F. Simpson, E.W. Thompson, M.M. Hill, L. Endo-Munoz, G.

Leggatt, et al., Role of intratumoural heterogeneity in cancer drug resistance:

molecular and clinical perspectives, EMBO Mol. Med. 4 (2012) 675–684.

[9] J. Lo, E.Y. Lau, R.H. Ching, B.Y. Cheng, M.K. Ma, I.O. Ng, et al., NF-kappaB

mediated CD47 upregulation promotes sorafenib resistance and its blockade

synergizes the effect of sorafenib in hepatocellular carcinoma, Hepatology

(2015).

[10] G.M. Keating, A. Santoro, Sorafenib a review of its use in advanced

hepatocellular carcinoma, Drugs 69 (2009) 223–240.

[11] A. Galmiche, B. Chauffert, J.C. Barbare, New biological perspectives for the

improvement of the eﬃcacy of sorafenib in hepatocellular carcinoma, Cancer

Lett. 346 (2014) 159–162.

[12] J. Castillo, E. Erroba, M.J. Perugorria, M. Santamaria, D.C. Lee, J. Prieto, et al.,

Amphiregulin contributes to the transformed phenotype of human

hepatocellular carcinoma cells, Cancer Res. 66 (2006) 6129–6138.

[13] Z. Ezzoukhry, C. Louandre, E. Trecherel, C. Godin, B. Chauffert, S. Dupont, et al.,

EGFR activation is a potential determinant of primary resistance of

hepatocellular carcinoma cells to sorafenib, Int. J. Cancer 131 (2012) 2961–

2969.

[14] L. Liu, Y. Cao, C. Chen, X. Zhang, A. McNabola, D. Wilkie, et al., Sorafenib blocks

the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor

cell apoptosis in hepatocellular carcinoma model PLC/PRF/5, Cancer Res. 66

(2006) 11851–11858.

[15] A.-L. Cheng, Y.-K. Kang, Z. Chen, C.-J. Tsao, S. Qin, J.S. Kim, 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. 10 (2009) 25–34.

[16] J.M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.-F. Blanc, et al., Sorafenib

in advanced hepatocellular carcinoma, NEJM 359 (2008) 378–390.

[17] X.Y. Huang, A.W. Ke, G.M. Shi, X. Zhang, C. Zhang, Y.H. Shi, et al., alphaB-

crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal

transition and resistance to sorafenib in hepatocellular carcinoma, Hepatology

57 (2013) 2235–2247.

[18] J.-F. Chiou, C.-J. Tai, M.-T. Huang, P.-L. Wei, Y.-H. Wang, J. An, et al., Glucose-

regulated protein 78 is a novel contributor to acquisition of resistance to

sorafenib in hepatocellular carcinoma, Ann. Surg. Oncol. 17 (2010) 603–612.

[19] K.-F. Chen, H.-L. Chen, W.-T. Tai, W.-C. Feng, C.-H. Hsu, P.-J. Chen, et al.,

Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates

acquired resistance to sorafenib in hepatocellular carcinoma cells, J. Pharmacol.

Exp. Ther. 337 (2011) 155–161.

[20] Y.Y. Lu, F. Feng, F. Zhang, X. Gao, C. Wang, X. Chang, et al., A novel mechanism

of PXR mediated Sorafenib drug resistance in HCC through MDR and CYP3A4,

Hepatology (2013) 1084A.

[21] M.A. Nieto, A. Cano, The epithelial–mesenchymal transition under control:

global programs to regulate epithelial plasticity, Semin. Cancer Biol. 22 (2012)

361–368.

[22] Y.D. Shaul, E. Freinkman, W.C. Comb, J.R. Cantor, W.L. Tam, P. Thiru, et al.,

Dihydropyrimidine accumulation is required for the epithelial-mesenchymal

transition, Cell 158 (2014) 1094–1109.

[23] J.P. Thiery, H. Acloque, R.Y. Huang, M.A. Nieto, Epithelial-mesenchymal

transitions in development and disease, Cell 139 (2009) 871–890.

[24] K. Uchibori, A. Kasamatsu, M. Sunaga, S. Yokota, T. Sakurada, E. Kobayashi, et al.,

Establishment and characterization of two 5-ﬂuorouracil-resistant

hepatocellular carcinoma cell lines, Int. J. Oncol. 40 (2012) 1005–1010.

[25] F.J. Carmona, V. Davalos, E. Vidal, A. Gomez, H. Heyn, Y. Hashimoto, et al., A

comprehensive DNA methylation proﬁle of epithelial-to-mesenchymal

transition, Cancer Res. 74 (2014) 5608–5619.

[26] A. de Reyniès, M.-C. Jaurand, A. Renier, G. Couchy, I. Hysi, N. Elarouci, et al.,

Molecular classiﬁcation of malignant pleural mesothelioma: identiﬁcation of

a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition,

Clin. Cancer Res. 20 (2014) 1323–1334.

[27] S. Kunnimalaiyaan, T.C. Gamblin, M. Kunnimalaiyaan, Role of notch3 in

epithelial-to-mesenchymal transition of HCC, Cancer Res. 74 (2014) 5289.

[28] J.P. Morris, S.C. Wang, M. Hebrok, KRAS, Hedgehog, Wnt and the twisted

developmental biology of pancreatic ductal adenocarcinoma, Nat. Rev. Cancer

10 (2010) 683–695.

[29] S. Lamouille, J. Xu, R. Derynck, Molecular mechanisms of epithelial-

mesenchymal transition, Nat. Rev. Mol. Cell Biol. 15 (2014) 178–196.

[30] Z. Ke, S. Caiping, Z. Qing, W. Xiaojing, Sonic hedgehog-Gli1 signals promote

epithelial-mesenchymal transition in ovarian cancer by mediating PI3K/AKT

pathway, Med. Oncol. 32 (2015) 368.

[31] Z.-J. Zhou, Z. Dai, S.-L. Zhou, Z.-Q. Hu, Q. Chen, Y.-M. Zhao, et al., HNRNPAB

induces epithelial–mesenchymal transition and promotes metastasis of

hepatocellular carcinoma by transcriptionally activating SNAIL, Cancer Res.

74 (2014) 2750–2762.

[32] G. Semenza, Cancer–stromal cell interactions mediated by hypoxia-inducible

factors promote angiogenesis, lymphangiogenesis, and metastasis, Oncogene

32 (2013) 4057–4063.

[33] K. Yuki, S. Hirohashi, M. Sakamoto, T. Kanai, Y. Shimosato, Growth and spread

of hepatocellular carcinoma: a review of 240 consecutive autopsy cases, Cancer

66 (1990) 2174–2179.

[34] J.P. Thiery, Epithelial–mesenchymal transitions in tumour progression, Nat.

Rev. Cancer 2 (2002) 442–454.

[35] F.L. Cousins, A. Murray, A. Esnal, D.A. Gibson, H.O. Critchley, P.T. Saunders,

Evidence from a mouse model that epithelial cell migration and

mesenchymal-epithelial transition contribute to rapid restoration of uterine

tissue integrity during menstruation, PLoS ONE 9 (2014) e86378.

[36] K. Polyak, R.A. Weinberg, Transitions between epithelial and mesenchymal

states: acquisition of malignant and stem cell traits, Nat. Rev. Cancer 9 (2009)

265–273.

[37] Y. Chao, Q. Wu, C. Shepard, A. Wells, Hepatocyte induced re-expression of

E-cadherin in breast and prostate cancer cells increases chemoresistance, Clin.

Exp. Metastasis 29 (2012) 39–50.

8J. Chen et al./Cancer Letters 367 (2015) 1–11

[38] T.S. Gujral, M. Chan, L. Peshkin, P.K. Sorger, M.W. Kirschner, G. MacBeath, A

noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition

and metastasis, Cell 159 (2014) 844–856.

[39] M. Cojoc, C. Peitzsch, I. Kurth, F. Trautmann, L.A. Kunz-Schughart, G.D. Telegeev,

et al., Aldehyde dehydrogenase is regulated by Beta-catenin/TCF and promotes

radioresistance in prostate cancer progenitor cells, Cancer Res. (2015).

[40] H. Liu, J. Yin, H. Wang, G. Jiang, M. Deng, G. Zhang, et al., FOXO3a modulates

WNT/beta-catenin signaling and suppresses epithelial-to-mesenchymal

transition in prostate cancer cells, Cell. Signal. 27 (2015) 510–518.

[41] B. Bao, A.S. Azmi, S. Ali, A. Ahmad, Y. Li, S. Banerjee, et al., The biological kinship

of hypoxia with CSC and EMT and their relationship with deregulated

expression of miRNAs and tumor aggressiveness, Biochim. Biophys. Acta 2012

(1826) 272–296.

[42] S. Lamouille, R. Derynck, Emergence of the phosphoinositide 3-kinase-Akt-

mammalian target of rapamycin axis in transforming growth factor-β-induced

epithelial-mesenchymal transition, Cells Tissues Organs 193 (2010) 8.

[43] M. Korpal, B.J. Ell, F.M. Buffa, T. Ibrahim, M.A. Blanco, T. Celià-Terrassa, et al.,

Direct targeting of Sec23a by miR-200s inﬂuences cancer cell secretome and

promotes metastatic colonization, Nat. Med. 17 (2011) 1101–1108.

[44] J. Gros, C.J. Tabin, Vertebrate limb bud formation is initiated by localized

epithelial-to-mesenchymal transition, Science 343 (2014) 1253–1256.

[45] S. Grünert, M. Jechlinger, H. Beug, Diverse cellular and molecular mechanisms

contribute to epithelial plasticity and metastasis, Nat. Rev. Mol. Cell Biol. 4

(2003) 657–665.

[46] L.A. Timmerman, J. Grego-Bessa, A. Raya, E. Bertran, J.M. Perez-Pomares, J.

Diez, et al., Notch promotes epithelial-mesenchymal transition during

cardiac development and oncogenic transformation, Genes Dev. 18 (2004)

99–115.

[47] K.G. Leong, K. Niessen, I. Kulic, A. Raouf, C. Eaves, I. Pollet, et al., Jagged1-

mediated Notch activation induces epithelial-to-mesenchymal transition

through Slug-induced repression of E-cadherin, J. Exp. Med. 204 (2007)

2935–2948.

[48] C. Sahlgren, M.V. Gustafsson, S. Jin, L. Poellinger, U. Lendahl, Notch signaling

mediates hypoxia-induced tumor cell migration and invasion, Proc. Natl. Acad.

Sci. U.S.A. 105 (2008) 6392–6397.

[49] S.A. Mani, W. Guo, M.-J. Liao, E.N. Eaton, A. Ayyanan, A.Y. Zhou, et al., The

epithelial-mesenchymal transition generates cells with properties of stem cells,

Cell 133 (2008) 704–715.

[50] P. Mallini, T. Lennard, J. Kirby, A. Meeson, Epithelial-to-mesenchymal transition:

what is the impact on breast cancer stem cells and drug resistance, Cancer

Treat. Rev. 40 (2014) 341–348.

[51] P. Bhat-Nakshatri, H. Appaiah, C. Ballas, P. Pick-Franke, R. Goulet, S. Badve, et al.,

SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24-

phenotype, BMC Cancer 10 (2010) 411.

[52] B.G. Hollier, A.A. Tinnirello, S.J. Werden, K.W. Evans, J.H. Taube, T.R. Sarkar,

et al., FOXC2 expression links epithelial–mesenchymal transition and stem

cell properties in breast cancer, Cancer Res. 73 (2013) 1981–1992.

[53] J. Bruix, M. Sherman, Management of hepatocellular carcinoma: an update,

Hepatology 53 (2011) 1020–1022.

[54] D.J. Mulholland, N. Kobayashi, M. Ruscetti, A. Zhi, L.M. Tran, J.T. Huang, et al.,

Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis

initiated from prostate cancer stem/progenitor cells, Cancer Res. 72 (2012)

1878–1889.

[55] J.M. Buonato, M.J. Lazzara, ERK1/2 blockade prevents epithelial-mesenchymal

transition in lung cancer cells and promotes their sensitivity to EGFR inhibition,

Cancer Res. 74 (2014) 309–319.

[56] C.H. Hou, F.L. Lin, S.M. Hou, J.F. Liu, Cyr61 promotes epithelial-mesenchymal

transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/

TWIST-1 signaling pathway, Mol. Cancer 13 (2014) 236.

[57] M.M. McKay, D.A. Ritt, D.K. Morrison, RAF inhibitor-induced KSR1/B-RAF

binding and its effects on ERK cascade signaling, Curr. Biol. 21 (2011) 563–568.

[58] P.I. Poulikakos, C. Zhang, G. Bollag, K.M. Shokat, N. Rosen, RAF inhibitors

transactivate RAF dimers and ERK signalling in cells with wild-type BRAF,

Nature 464 (2010) 427–430.

[59] K. Miyahara, K. Nouso, K. Yamamoto, Chemotherapy for advanced

hepatocellular carcinoma in the sorafenib age, World J. Gastroenterol. 20 (2014)

4151.

[60] N.C. Schlegel, A. von Planta, D.S. Widmer, R. Dummer, G. Christofori, PI3K

signalling is required for a TGF beta-induced epithelial-mesenchymal-like

transition (EMT-like) in human melanoma cells, Exp. Dermatol. 24 (2015)

22–28.

[61] G.Y. Lin, R.H. Gai, Z.B. Chen, Y.J. Wang, S.D. Liao, R. Dong, et al., The dual

PI3K/mTOR inhibitor NVP-BEZ235 prevents epithelial-mesenchymal transition

induced by hypoxia and TGF-beta 1, Eur. J. Pharmacol. 729 (2014) 45–53.

[62] S.K. Gruvberger-Saal, R. Parsons, Is the small heat shock protein αB-crystallin

an oncogene?, J. Clin. Invest. 116 (2006) 30.

[63] S. Seitz, E. Korsching, J. Weimer, A. Jacobsen, N. Arnold, A. Meindl, et al., Genetic

background of different cancer cell lines inﬂuences the gene set involved in

chromosome 8 mediated breast tumor suppression, Genes Chromosomes

Cancer 45 (2006) 612–627.

[64] J.V. Moyano, J.R. Evans, F. Chen, M. Lu, M.E. Werner, F. Yehiely, et al., αB-

crystallin is a novel oncoprotein that predicts poor clinical outcome in breast

cancer, J. Clin. Invest. 116 (2006) 261.

[65] J. Holcakova, L. Hernychová, P. Bouchal, K. Brozkova, J. Zaloudik, D. Valík, et al.,

Identiﬁcation of alphaB-crystallin, a biomarker of renal cell carcinoma by

SELDI-TOF MS, Int. J. Biol. Markers 23 (2007) 48–53.

[66] Q. Tang, Y.-F. Liu, X.-J. Zhu, Y.-H. Li, J. Zhu, J.-P. Zhang, et al., Expression and

prognostic signiﬁcance of the αB-crystallin gene in human hepatocellular

carcinoma, Hum. Pathol. 40 (2009) 300–305.

[67] T. Rajakulendran, M. Sahmi, M. Lefrancois, F. Sicheri, M. Therrien, A

dimerization-dependent mechanism drives RAF catalytic activation, Nature

461 (2009) 542–545.

[68] J.S. Bae, S.J. Noh, K.M. Kim, K.Y. Jang, M.J. Chung, D.G. Kim, et al., Serum

response factor induces epithelial to mesenchymal transition with resistance

to sorafenib in hepatocellular carcinoma, Int. J. Oncol. 44 (2014) 129–136.

[69] J. Fernando, A. Malfettone, E.B. Cepeda, R. Vilarrasa-Blasi, E. Bertran, G.

Raimondi, et al., A mesenchymal-like phenotype and expression of CD44

predict lack of apoptotic response to sorafenib in liver tumor cells, Int. J. Cancer

136 (2015) E161–E172.

[70] F. van Zijl, G. Zulehner, M. Petz, D. Schneller, C. Kornauth, M. Hau, et al.,

Epithelial-mesenchymal transition in hepatocellular carcinoma, Future Oncol.

5 (2009) 1169–1179.

[71] P.Gulhati, K.A. Bowen, J.Y. Liu, P.D.Stevens, P.G. Rychahou,M. Chen, et al., mTORC1

and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via

RhoA and Rac1 signaling pathways, Cancer Res. 71 (2011) 3246–3256.

[72] C.W. Li, W. Xia, L. Huo, S.O. Lim, Y. Wu, J.L. Hsu, et al., Epithelial-mesenchymal

transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional

upregulation of Twist1, Cancer Res. 72 (2012) 1290–1300.

[73] K. Hao, X.D. Tian, C.F. Qin, X.H. Xie, Y.M. Yang, Hedgehog signaling pathway

regulates human pancreatic cancer cell proliferation and metastasis, Oncol.

Rep. 29 (2013) 1124–1132.

[74] Y. Bai, H. Lu, C. Wu, Y. Liang, S. Wang, C. Lin, et al., Resveratrol inhibits

epithelial-mesenchymal transition and renal ﬁbrosis by antagonizing the

hedgehog signaling pathway, Biochem. Pharmacol. 92 (2014) 484–493.

[75] L. Yu, Y. Mu, N. Sa, H. Wang, W. Xu, Tumor necrosis factor alpha induces

epithelial-mesenchymal transition and promotes metastasis via NF-kappaB

signaling pathway-mediated TWIST expression in hypopharyngeal cancer,

Oncol. Rep. 31 (2014) 321–327.

[76] A.G. Pantschenko, I. Pushkar, K.H. Anderson, Y. Wang, L.J. Miller, S.H. Kurtzman,

et al., The interleukin-1 family of cytokines and receptors in human breast

cancer: implications for tumor progression, Int. J. Oncol. 23 (2003) 269–284.

[77] T. Leibovich-Rivkin, Y. Liubomirski, B. Bernstein, T. Meshel, A. Ben-Baruch,

Inﬂammatory factors of the tumor microenvironment induce plasticity in

nontransformed breast epithelial cells: EMT, invasion, and collapse of normally

organized breast textures, Neoplasia 15 (2013) 1330–1346.

[78] S. Lindsey, S.A. Langhans, Crosstalk of oncogenic signaling pathways during

epithelial-mesenchymal transition, Front. Oncol. 4 (2014) 358.

[79] M. Shiota, J.L. Bishop, K.M. Nip, A. Zardan, A. Takeuchi, T. Cordonnier, et al.,

Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating

tumor cells in prostate cancer, Cancer Res. 73 (2013) 3109–3119.

[80] P. Li, R. Yang, W.Q. Gao, Contributions of epithelial-mesenchymal transition

and cancer stem cells to the development of castration resistance of prostate

cancer, Mol. Cancer 13 (2014) 55.

[81] N. Sheshadri, J.M. Catanzaro, A.J. Bott, Y. Sun, E. Ullman, E.I. Chen, et al.,

SCCA1/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition

via the unfolded protein response and IL6 signaling, Cancer Res. 74 (2014)

6318–6329.

[82] A. De Luca, A. Carotenuto, A. Rachiglio, M. Gallo, M.R. Maiello, D. Aldinucci,

et al., The role of the EGFR signaling in tumor microenvironment, J. Cell. Physiol.

214 (2008) 559–567.

[83] N. Oishi, T. Yamashita, S. Kaneko, Molecular biology of liver cancer stem cells,

Liver Cancer 3 (2014) 71.

[84] K.R. Levental, H. Yu, L. Kass, J.N. Lakins, M. Egeblad, J.T. Erler, et al., Matrix

crosslinking forces tumor progression by enhancing integrin signaling, Cell

139 (2009) 891–906.

[85] J.E. Dick, Tumor archaeology: tracking leukemic evolution to its origins, Sci.

Trans. Med. 6 (2014) 238fs223.

[86] D.W. McMillin, J. Delmore, E. Weisberg, J.M. Negri, D.C. Geer, S. Klippel, et al.,

Tumor cell-speciﬁc bioluminescence platform to identify stroma-induced

changes to anticancer drug activity, Nat. Med. 16 (2010) 483–489.

[87] C.S. Mitsiades, N. Mitsiades, N.C. Munshi, K.C. Anderson, Focus on multiple

myeloma, Cancer Cell 6 (2004) 439–444.

[88] H.-M. Ni, A. Bhakta, S. Wang, Z. Li, S. Manley, H. Huang, et al., Role of hypoxia

inducing factor-1β in alcohol-induced autophagy, steatosis and liver injury

in mice, PLoS ONE 9 (2014) e115849.

[89] T.V. Nguyen, M. Sleiman, T. Moriarty, W.G. Herrick, S.R. Peyton, Extracellular

matrix stiffness protects carcinoma cells from sorafenib via JNK signaling, in:

Northeast Bioengineering Conference (NEBEC), 2014 40th Annual, IEEE, 2014,

pp. 1–2.

[90] A.K. Iyer, A. Singh, S. Ganta, M.M. Amiji, Role of integrated cancer nanomedicine

in overcoming drug resistance, Adv. Drug Deliv. Rev. 65 (2013) 1784–1802.

[91] R.K. Jain, Normalizing tumor vasculature with anti-angiogenic therapy: a new

paradigm for combination therapy, Nat. Med. 7 (2001) 987–989.

[92] D. Bonnet, J.E. Dick, Human acute myeloid leukemia is organized as a hierarchy

that originates from a primitive hematopoietic cell, Nat. Med. 3 (1997)

730–737.

[93] Z. Zhu, X. Hao, M. Yan, M. Yao, C. Ge, J. Gu, et al., Cancer stem/progenitor cells

are highly enriched in CD133+CD44+population in hepatocellular carcinoma,

Int. J. Cancer 126 (2010) 2067–2078.

[94] M.F. Clarke, J.E. Dick, P.B. Dirks, C.J. Eaves, C.H. Jamieson, D.L. Jones, et al., Cancer

stem cells – perspectives on current status and future directions: AACR

Workshop on cancer stem cells, Cancer Res. 66 (2006) 9339–9344.

9J. Chen et al./Cancer Letters 367 (2015) 1–11

[95] L.E. Ailles, I.L. Weissman, Cancer stem cells in solid tumors, Curr. Opin.

Biotechnol. 18 (2007) 460–466.

[96] J.A. Kennedy, F. Barabé, A.G. Poeppl, J.C. Wang, J.E. Dick, Comment on “Tumor

growth need not be driven by rare cancer stem cells”, Science 318 (2007) 1722.

[97] S. Bao, Q. Wu, R.E. McLendon, Y. Hao, Q. Shi, A.B. Hjelmeland, et al., Glioma

stem cells promote radioresistance by preferential activation of the DNA

damage response, Nature 444 (2006) 756–760.

[98] K.-J. Wu, M.-H. Yang, Epithelial-mesenchymal transition and cancer stemness:

the Twist1-Bmi1 connection, Biosci. Rep. 31 (2011) 449–455.

[99] Z.F. Bielecka, A.M. Czarnecka, W. Solarek, A. Kornakiewicz, C. Szczylik,

Mechanisms of acquired resistance to tyrosine kinase inhibitors in clear-cell

renal cell carcinoma (ccRCC), Curr. Signal Transduct. Ther. 8 (2014) 218.

[100] A. Biddle, I.C. Mackenzie, Cancer stem cells and EMT in carcinoma, Cancer

Metastasis Rev. 31 (2012) 285–293.

[101] C. Chang, M. Hung, The role of EZH2 in tumour progression, Br. J. Cancer 106

(2012) 243–247.

[102] T. Kiesslich, D. Neureiter, Advances in targeting the Hedgehog signaling

pathway in cancer therapy, Expert Opin. Ther. Targets 16 (2012) 151–156.

[103] J.-J. Zhou, X.-G. Deng, X.-Y. He, Y. Zhou, M. Yu, W.-C. Gao, et al., Knockdown

of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by

reducing MDR1 expression, Int. J. Oncol. 44 (2014) 2034–2040.

[104] R. Gedaly, R. Galuppo, Y. Musgrave, P. Angulo, J. Hundley, M. Shah, et al.,

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer

stem cell proliferation, J. Surg. Res. 185 (2013) 225–230.

[105] H.-W. Xin, C.M. Ambe, D.M. Hari, G.W. Wiegand, T.C. Miller, J.-Q. Chen, et al.,

Label-retaining liver cancer cells are relatively resistant to sorafenib, Gut 62

(2013) 1777–1786.

[106] V. Hernandez-Gea, S. Toffanin, S.L. Friedman, J.M. Llovet, Role of the

microenvironment in the pathogenesis and treatment of hepatocellular

carcinoma, Gastroenterology 144 (2013) 512–527.

[107] Z. Von Marschall, T. Cramer, M. Höcker, G. Finkenzeller, B. Wiedenmann, S.

Rosewicz, Dual mechanism of vascular endothelial growth factor upregulation

by hypoxia in human hepatocellular carcinoma, Gut 48 (2001) 87–96.

[108] Y.-H. Shi, Z.-B. Ding, J. Zhou, B. Hui, G.-M. Shi, A.-W. Ke, et al., Targeting

autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER

stress-related apoptosis, Autophagy 7 (2011) 1159–1172.

[109] A.X. Zhu, D.G. Duda, D.V. Sahani, R.K. Jain, HCC and angiogenesis: possible

targets and future directions, Nat. Rev. Clin. Oncol. 8 (2011) 292–301.

[110] J. LeCouter, D.R. Moritz, B. Li, G.L. Phillips, X.H. Liang, H.-P. Gerber, et al.,

Angiogenesis-independent endothelial protection of liver: role of VEGFR-1,

Science 299 (2003) 890–893.

[111] B.M. Lichtenberger, P.K. Tan, H. Niederleithner, N. Ferrara, P. Petzelbauer, M.

Sibilia, Autocrine VEGF signaling synergizes with EGFR in tumor cells to

promote epithelial cancer development, Cell 140 (2010) 268–279.

[112] S. Coulon, F. Heindryckx, A. Geerts, C. Van Steenkiste, I. Colle, H.

Van Vlierberghe, Angiogenesis in chronic liver disease and its complications,

Liver Int. 31 (2011) 146–162.

[113] S.J. Faivre, A. Santoro, R.K. Kelley, P. Merle, E. Gane, J.-Y. Douillard, et al., A phase

2 study of a novel transforming growth factor-beta (TGF-{beta} 1) receptor I

kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced

hepatocellular carcinoma (HCC), in: ASCO Annual Meeting Proceedings, 2014,

p. LBA173.

[114] E.T. Roussos, J.S. Condeelis, A. Patsialou, Chemotaxis in cancer, Nat. Rev. Cancer

11 (2011) 573–587.

[115] A.J. Trimboli, C.Z. Cantemir-Stone, F. Li, J.A. Wallace, A. Merchant, N. Creasap,

et al., Pten in stromal ﬁbroblasts suppresses mammary epithelial tumours,

Nature 461 (2009) 1084–1091.

[116] X.Z. Wu, G.R. Xie, D. Chen, Hypoxia and hepatocellular carcinoma: the

therapeutic target for hepatocellular carcinoma, J. Gastroenterol. Hepatol. 22

(2007) 1178–1182.

[117] M. Jiao, K.-J. Nan, Activation of PI3 kinase/Akt/HIF-1α pathway contributes

to hypoxia-induced epithelial-mesenchymal transition and chemoresistance

in hepatocellular carcinoma, Int. J. Oncol. 40 (2012) 461–468.

[118] Y. Liang, T. Zheng, R. Song, J. Wang, D. Yin, L. Wang, et al., Hypoxia-mediated

sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau

tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma,

Hepatology 57 (2013) 1847–1857.

[119] K. Shirabe, Y. Mano, J. Muto, R. Matono, T. Motomura, T. Toshima, et al., Role

of tumor-associated macrophages in the progression of hepatocellular

carcinoma, Surg. Today 42 (2012) 1–7.

[120] M.D. Bareford, M.A. Park, A. Yacoub, H.A. Hamed, Y. Tang, N. Cruickshanks,

et al., Sorafenib enhances pemetrexed cytotoxicity through an autophagy-

dependent mechanism in cancer cells, Cancer Res. 71 (2011) 4955–4967.

[121] S. Shimizu, T. Takehara, H. Hikita, T. Kodama, H. Tsunematsu, T. Miyagi, et al.,

Inhibition of autophagy potentiates the antitumor effect of the multikinase

inhibitor sorafenib in hepatocellular carcinoma, Int. J. Cancer 131 (2012)

548–557.

[122] C. Berasain, J. Castillo, M.J. Perugorria, M.U. Latasa, J. Prieto, M.A. Avila,

Inﬂammation and liver cancer: new molecular links, Ann. N. Y. Acad. Sci. 1155

(2009) 206–221.

[123] V. Pattullo, Hepatitis B reactivation in the setting of chemotherapy and

immunosuppression – prevention is better than cure, World J. Hepatol. 7

(2015) 954–967.

[124] S. D’Angelo, M. Secondulfo, R. De Cristofano, P. Sorrentino, Sorafenib and

entecavir: the dioscuri of treatment for advanced hepatocellular carcinoma?,

World J. Gastroenterol. 19 (2013) 2141–2143.

[125] C. Zuo, M. Xia, Q. Wu, H. Zhu, J. Liu, C. Liu, Role of antiviral therapy in reducing

recurrence and improving survival in hepatitis B virus-associated

hepatocellular carcinoma following curative resection (Review), Oncol. Lett.

9 (2015) 527–534.

[126] V. Descamps, F. Helle, C. Louandre, E. Martin, E. Brochot, L. Izquierdo, et al.,

The kinase-inhibitor sorafenib inhibits multiple steps of the Hepatitis C Virus

infectious cycle in vitro, Antiviral Res. 118 (2015) 93–102.

[127] R. Cabrera, A.R. Limaye, P. Horne, R. Mills, C. Soldevila-Pico, V. Clark, et al.,

The anti-viral effect of sorafenib in hepatitis C-related hepatocellular

carcinoma, Aliment. Pharmacol. Ther. 37 (2013) 91–97.

[128] K. Himmelsbach, E. Hildt, The kinase inhibitor Sorafenib impairs the antiviral

effect of interferon alpha on hepatitis C virus replication, Eur. J. Cell Biol. 92

(2013) 12–20.

[129] Q.B. Zhang, H.C. Sun, K.Z. Zhang, Q.A. Jia, Y. Bu, M. Wang, et al., Suppression

of natural killer cells by sorafenib contributes to prometastatic effects in

hepatocellular carcinoma, PLoS ONE 8 (2013) e55945.

[130] K. Mao, J. Zhang, C. He, K. Xu, J. Liu, J. Sun, et al., Restoration of miR-193b

sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib,

Cancer Lett. 352 (2014) 245–252.

[131] A.L. Cheng, Z. Guan, Z. Chen, C.J. Tsao, S. Qin, J.S. Kim, et al., Eﬃcacy and safety

of sorafenib in patients with advanced hepatocellular carcinoma according

to baseline status: subset analyses of the phase III Sorafenib Asia-Paciﬁc trial,

Eur. J. Cancer 48 (2012) 1452–1465.

[132] L. Bolondi, W. Caspary, J. Bennouna, W. Thomson, F. Van Steenbergen, M. Degos,

et al., Clinical beneﬁt of sorafenib in hepatitis C patients with hepatocellular

carcinoma (HCC): subgroup analysis of the SHARP trial.[Abstract]. Presented

at the 2008 Gastrointestinal Cancers Symposium; Orlando, FL, 2008, pp. 25–

27.

[133] E. Rota Caremoli, R. Labianca, Tivantinib: critical review with a focus on

hepatocellular carcinoma, Expert Opin. Investig. Drugs 23 (2014) 1563–1574.

[134] K. Yamanaka, M. Petrulionis, S. Lin, C. Gao, U. Galli, S. Richter, et al., Therapeutic

potential and adverse events of everolimus for treatment of hepatocellular

carcinoma – systematic review and meta-analysis, Cancer Med. 2 (2013)

862–871.

[135] W. Yeo, H.C. Chung, S.L. Chan, L.Z. Wang, R. Lim, J. Picus, 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. 30 (2012) 3361–3367.

[136] V. Tovar, Cornella, A. Villanueva, FGF signaling is involved in acquired resistance

to sorafenib in an in vivo model of hepatocellular carcinoma, Presented at the

International Liver Cancer Association Conference, Hong Kong, China,

September 2–4, 2011 (abstr 0–006).

[137] J.M. Llovet, T. Decaens, J.L. Raoul, E. Boucher, M. Kudo, C. Chang, et al., Brivanib

in patients with advanced hepatocellular carcinoma who were intolerant to

sorafenib or for whom sorafenib failed: results from the randomized phase

III BRISK-PS study, J. Clin. Oncol. 31 (2013) 3509–3516.

[138] C. Cainap, S.K. Qin, W.T. Huang, I.J. Chung, H.M. Pan, Y. Cheng, et al., Phase III

trial of linifanib versus sorafenib in patients with advanced hepatocellular

carcinoma (HCC), J. Clin. Oncol. 31 (2013).

[139] P. Fang, J.H. Hu, Z.G. Cheng, Z.F. Liu, J.L. Wang, S.C. Jiao, Eﬃcacy and safety of

bevacizumab for the treatment of advanced hepatocellular carcinoma: a

systematic review of phase II trials, PLoS ONE 7 (2012).

[140] C.J. Liu, J. Chang, P.H. Lee, D.Y. Lin, C.C. Wu, L.B. Jeng, et al., Adjuvant heparanase

inhibitor PI-88 therapy for hepatocellular carcinoma recurrence, World J.

Gastroenterol. 20 (2014) 11384–11393.

[141] C.M. Wang, A. Cigliano, S. Delogu, J. Armbruster, F. Dombrowski, M. Evert, et al.,

Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in

hepatocarcinogenesis Implications for the treatment of human liver cancer,

Cell Cycle 12 (2013) 1999–2010.

[142] R. Gedaly, P. Angulo, J. Hundley, M.F. Daily, C. Chen, B.M. Evers, PKI-587 and

sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways

synergistically inhibit HCC cell proliferation, J. Surg. Res. 176 (2012) 542–548.

[143] A.X. Zhu, O. Rosmorduc, T.R. Evans, P.J. Ross, A. Santoro, F.J. Carrilho, et al.,

SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of

sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma,

J. Clin. Oncol. 33 (2015) 559–566.

[144] H. Huynh, V.C. Ngo, H.N. Koong, D. Poon, S.P. Choo, H.C. Toh, et al., AZD6244

enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models

of human hepatocellular carcinoma (HCC), J. Hepatol. 52 (2010) 79–87.

[145] H.Y. Lim, J. Heo, H.J. Choi, C.Y. Lin, J.H. Yoon, C. Hsu, et al., A phase II study of

the eﬃcacy and safety of the combination therapy of the MEK inhibitor

refametinib (BAY 86–9766) plus sorafenib for Asian patients with unresectable

hepatocellular carcinoma, Clin. Cancer Res. 20 (2014) 5976–5985.

[146] G. Brandi, F. de Rosa, V. Agostini, S. di Girolamo, P. Andreone, L. Bolondi, et al.,

Metronomic capecitabine in advanced hepatocellular carcinoma patients: a

phase II study, Oncologist 18 (2013) 1256–1257.

[147] J.S. Hammond, J. Franko, S.E. Holloway, J.T. Heckman, P.D. Orons, T.C. Gamblin,

Gemcitabine transcatheter arterial chemoembolization for unresectable

hepatocellular carcinoma, Hepatogastroenterology 61 (2014) 1339–1343.

[148] Y. Wang, Y. Liu, Y. Liu, W. Zhou, H. Wang, G. Wan, et al., A polymeric prodrug

of cisplatin based on pullulan for the targeted therapy against hepatocellular

carcinoma, Int. J. Pharm. 483 (2015) 89–100.

[149] W.W. Qi, H.Y. Yu, H. Guo, J. Lou, Z.M. Wang, P. Liu, et al., Doxorubicin-loaded

glycyrrhetinic acid modiﬁed recombinant human serum albumin nanoparticles

for targeting liver tumor chemotherapy, Mol. Pharm. 12 (2015) 675–683.

10 J. Chen et al./Cancer Letters 367 (2015) 1–11

[150] Y. Liu, H. Yue, S. Xu, F. Wang, N. Ma, K. Li, et al., First-line gemcitabine and

oxaliplatin (GEMOX) plus sorafenib, followed by sorafenib as maintenance

therapy, for patients with advanced hepatocellular carcinoma: a preliminary

study, Int. J. Clin. Oncol. (2015).

[151] Z. Wang, Z. Zhao, T. Wu, L. Song, Y. Zhang, Sorafenib-irinotecan sequential

therapy augmented the anti-tumor eﬃcacy of monotherapy in hepatocellular

carcinoma cells HepG2, Neoplasma 62 (2015) 172–179.

[152] V. Srimuninnimit, V. Sriuranpong, S. Suwanvecho, Eﬃcacy and safety of

sorafenib in combination with gemcitabine in patients with advanced

hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study,

Asia Pac. J. Clin. Oncol. 10 (2014) 255–260.

[153] G.K. Abou-Alfa, P. Johnson, J.J. Knox, M. Capanu, I. Davidenko, J. Lacava, et al.,

Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced

hepatocellular carcinoma: a randomized trial, JAMA 304 (2010) 2154–2160.

[154] T. Hato, L. Goyal, T.F. Greten, D.G. Duda, A.X. Zhu, Immune checkpoint blockade

in hepatocellular carcinoma: current progress and future directions,

Hepatology 60 (2014) 1776–1782.

[155] Y. Wang, H. Li, Q. Liang, B. Liu, X. Mei, Y. Ma, Combinatorial immunotherapy

of sorafenib and blockade of programmed death-ligand 1 induces effective

natural killer cell responses against hepatocellular carcinoma, Tumour Biol.

(2014).

[156] Y. Chen, R.R. Ramjiawan, T. Reiberger, M.R. Ng, T. Hato, Y. Huang, et al., CXCR4

inhibition in tumor microenvironment facilitates anti-programmed death

receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in

mice, Hepatology 61 (2015) 1591–1602.

[157] V. Vaira, M. Roncalli, C. Carnaghi, A. Faversani, M. Maggioni, C. Augello, et al.,

MicroRNA-425-3p predicts response to sorafenib therapy in patients with

hepatocellular carcinoma, Liver Int. 35 (2015) 1077–1086.

[158] M. Scartozzi, L. Faloppi, G. Svegliati Baroni, C. Loretelli, F. Piscaglia, M. Iavarone,

et al., VEGF and VEGFR genotyping in the prediction of clinical outcome for

HCC patients receiving sorafenib: the ALICE-1 study, Int. J. Cancer 135 (2014)

1247–1256.

[159] X. Luo, G.S. Feng, VEGFA genomic ampliﬁcation tailors treatment of HCCs with

sorafenib, Cancer Discov. 4 (2014) 640–641.

[160] R. Rudalska, D. Dauch, T. Longerich, K. McJunkin, T. Wuestefeld, T.W. Kang, et al.,

In vivo RNAi screening identiﬁes a mechanism of sorafenib resistance in liver

cancer, Nat. Med. 20 (2014) 1138–1146.

[161] D. Chen, P. Zhao, S.Q. Li, W.K. Xiao, X.Y. Yin, B.G. Peng, et al., Prognostic impact

of pERK in advanced hepatocellular carcinoma patients treated with sorafenib,

Eur. J. Surg. Oncol. 39 (2013) 974–980.

[162] W.T. Tai, A.L. Cheng, C.W. Shiau, H.P. Huang, J.W. Huang, P.J. Chen, et al., Signal

transducer and activator of transcription 3 is a major kinase-independent

target of sorafenib in hepatocellular carcinoma, J. Hepatol. 55 (2011) 1041–

1048.

[163] M.J. Blivet-Van Eggelpoel, H. Chettouh, L. Fartoux, L. Aoudjehane, V. Barbu,

C. Rey, et al., Epidermal growth factor receptor and HER-3 restrict cell response

to sorafenib in hepatocellular carcinoma cells, J. Hepatol. 57 (2012) 108–

115.

[164] J.J. Shan, J.J. Shen, L.M. Liu, F. Xia, C. Xu, G.J. Duan, et al., Nanog regulates self-

renewal of cancer stem cells through the insulin-like growth factor pathway

in human hepatocellular carcinoma, Hepatology 56 (2012) 1004–1014.

[165] S. Hagiwara, M. Kudo, T. Nagai, T. Inoue, K. Ueshima, N. Nishida, et al., Activation

of JNK and high expression level of CD133 predict a poor response to sorafenib

in hepatocellular carcinoma, Br. J. Cancer 106 (2012) 1997–2003.

[166] J.M. Llovet, C.E.A. Pena, C.D. Lathia, M. Shan, G. Meinhardt, J. Bruix, et al., Plasma

biomarkers as predictors of outcome in patients with advanced hepatocellular

carcinoma, Clin. Cancer Res. 18 (2012) 2290–2300.

[167] T. Arao, K. Ueshima, K. Matsumoto, T. Nagai, H. Kimura, S. Hagiwara, et al.,

FGF3/FGF4 ampliﬁcation and multiple lung metastases in responders to

sorafenib in hepatocellular carcinoma, Hepatology 57 (2013) 1407–1415.

11J. Chen et al./Cancer Letters 367 (2015) 1–11

Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma

Article

Full-text available

May 2024

Background Advanced hepatocellular carcinoma (HCC) can be treated with sorafenib, which is the primary choice for targeted therapy. Nevertheless, the effectiveness of sorafenib is greatly restricted due to resistance. Research has shown that exosomes and circular RNAs play a vital role in the cancer’s malignant advancement. However, the significance of exosomal circular RNAs in the development of resistance to sorafenib in HCC remains uncertain. Methods Ultracentrifugation was utilized to isolate exosomes (Exo-SR) from the sorafenib-resistant HCC cells’ culture medium. Transcriptome sequencing and differential expression gene analysis were used to identify the targets of Exo-SR action in HCC cells. To identify the targets of Exo-SR action in HCC cells, transcriptome sequencing and analysis of differential expression genes were employed. To evaluate the impact of exosomal circUPF2 on resistance to sorafenib in HCC, experiments involving gain-of-function and loss-of-function were conducted. RNA pull-down assays and mass spectrometry analysis were performed to identify the RNA-binding proteins interacting with circUPF2. RNA immunoprecipitation (RIP), RNA pull-down, electrophoretic mobility shift assay (EMSA), immunofluorescence (IF) -fluorescence in situ hybridization (FISH), and rescue assays were used to validate the interactions among circUPF2, IGF2BP2 and SLC7A11. Finally, a tumor xenograft assay was used to examine the biological functions and underlying mechanisms of Exo-SR and circUPF2 in vivo. Results A novel exosomal circRNA, circUPF2, was identified and revealed to be significantly enriched in Exo-SR. Exosomes with enriched circUPF2 enhanced sorafenib resistance by promoting SLC7A11 expression and suppressing ferroptosis in HCC cells. Mechanistically, circUPF2 acts as a framework to enhance the creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex contributing to the stabilization of SLC7A11 mRNA. Consequently, exosomal circUPF2 promotes SLC7A11 expression and enhances the function of system Xc- in HCC cells, leading to decreased sensitivity to ferroptosis and resistance to sorafenib. Conclusions The resistance to sorafenib in HCC is facilitated by the exosomal circUPF2, which promotes the formation of the circUPF2-IGF2BP2-SLC7A11 ternary complex and increases the stability of SLC7A11 mRNA. Focusing on exosomal circUPF2 could potentially be an innovative approach for HCC treatment. Graphical Abstract

Tmem39b promotes tumor progression and sorafenib resistance by inhibiting ferroptosis in hepatocellular carcinoma

Article

Jan 2024
ONCOL RES

REVIEWING ADVANCES IN UNDERSTANDING AND TARGETING THE MAPK SIGNALING PATHWAY IN HEPATOCELLULAR CARCINOMA PROGRESSION AND THERAPEUTICS

Article

Full-text available

Feb 2024

Yusra Zarlashat

Hepatocellular carcinoma (HCC) is a severe and increasingly prevalent health issue affecting individuals globally. Recent research endeavors in the clinical domains have lately focused more on the MAPK signaling pathway in HCC. Activating mutations in the RAS and RAF genes, which greatly activate the MAPK pathway in malignancies, are rare in HCC patients, yet over 50% of them have activated the pathway. This suggests that other factors may be responsible for the activation of the signaling pathway in HCC. MAPK signaling is important to carcinogenesis, and it is often altered in human cancers. The drug resistance in targeted therapy against RTKs in HCC may arise from mutations in downstream components (RAS, RAF, MEK, ERK), resistant mutations within RTKs, and additional alternative pathways like PI3K and YAP may also develop the resistance. Epigenetic processes and chromatin remodeling are crucial to pharmacological tolerance to MAPK regulation. This review will focus on the latest developments in our knowledge of the cellular and molecular processes to activate the MAPK signaling pathway, as well as possible treatment approaches that specifically target this pathway in relation to HCC. The study also investigates the clinical efficacy of molecular-targeted treatments, including tyrosine kinase inhibitors and immunological checkpoint inhibitors and highlights the use of combination therapy for HCC.

Signaling pathways in liver cancer: pathogenesis and targeted therapy

Article

May 2024

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

Lenvatinib in hepatocellular carcinoma: Resistance mechanisms and strategies for improved efficacy

Article

May 2024
LIVER INT

Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes of cancer‐related deaths worldwide, approximately 70% of patients with HCC exhibit advanced disease at diagnosis, limiting the potential for radical treatment. For such patients, lenvatinib, a long‐awaited alternative to sorafenib for first‐line targeted therapy, has become a key treatment. Unfortunately, despite some progress, the prognosis for advanced HCC remains poor because of drug resistance development. However, the molecular mechanisms underlying lenvatinib resistance and ways to relief drug resistance in HCC are largely unknown and lack of systematic summary; thus, this review not only aims to explore factors contributing to lenvatinib resistance in HCC, but more importantly, summary potential methods to conquer or mitigate the resistance. The results suggest that abnormal activation of pathways, drug transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial–mesenchymal transition, and other mechanisms are involved in the development of lenvatinib resistance in HCC and subsequent HCC progression. To improve the therapeutic outcomes of lenvatinib, inhibiting acquired resistance, combined therapies, and nano‐delivery carriers may be possible approaches.

Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma

Article

Apr 2024

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity

Article

Apr 2024

Pharmacokinetics and apparent Michaelis constant for metabolite conversion of sorafenib in healthy and hepatocellular carcinoma-bearing rats

Article

Mar 2024

Aim: Investigation of the pharmacokinetics of sorafenib (SRF) in rats with hepatocellular carcinoma (HCC). Methods: A reproducible ultra-HPLC–MS method for simultaneous determination of serum SRF, N-hydroxymethyl sorafenib and N-demethylation sorafenib. Results: Both the maximum serum concentrations (2.5-times) and the area under the serum concentration–time curve from 0 h to infinity (4.5-times) of SRF were observed to be significantly higher, with a greater than 3.0-fold decrease in the clearance rate in the HCC-bearing rats compared with these values in healthy animals. Further study revealed approximately 3.8- and 3.2-times increases in the apparent Michaelis constant for N-hydroxymethyl sorafenib and N-demethylation sorafenib conversions in the HCC-bearing rats. Conclusion: The low efficiency for the SRF conversions was a key contributor to the increased serum concentrations of SRF.

Long-term di-(2-ethylhexyl) phthalate exposure reduces sorafenib treatment efficacy by enhancing mesenchymal transition in hepatocellular carcinoma

Article

Mar 2024
ECOTOX ENVIRON SAFE

A codelivery system loaded with PDL1-siRNA and sorafenib enhances the therapeutic effect of sorafenib on hepatocellular carcinoma via TAT-poly-SS-lysine modified chitosan

Article

Feb 2024
INT J BIOL MACROMOL

Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells

Article

Jan 2011

Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): subgroup analysis of the sharp trial

Article

Jan 2008

Management of hepatocellular carcinoma: an update. american association for the study of liver diseases (AASLD) practice guideline

Article

Jan 2011
HEPATOLOGY

GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC cancer base no. 11 [Internet]. International Agency for Research on Cancer, Lyon

Article

Jan 2014

Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin

Article

Nov 2007

A phase 2 study of a novel transforming growth factor-beta (TGF-beta 1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC)

Conference Paper

Jan 2014

Sorafenib in Advanced Hepatocellular Carcinoma

Article

Jan 2008
NEW ENGL J MED

No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P

Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC)

Article

Feb 2013

249 Background: Linifanib (ABT-869; Lin) is a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase families. In a phase II trial in patients (pts) with advanced HCC, Lin showed clinical activity (objective response rate [ORR] 10.5% in Child-Pugh A [CPA] pts). This open-label, global phase 3 trial evaluated Lin versus sorafenib (Sor) as first-line therapy in pts with advanced CPA HCC (NCT01009593). Methods: Pts were randomized 1:1 to Lin 17.5 mg QD or Sor 400 mg BID and stratified by region (non-Asia/Japan/rest of Asia), ECOG performance status (0/1), vascular invasion or extrahepatic spread (yes/no) and HBV infection (yes/no). The primary efficacy endpoint was overall survival (OS); both non-inferiority (margin 1.0491) and superiority hypotheses were to be tested. Secondary efficacy endpoints included time to progression (TTP) and ORR, using RECIST v1.1. AE severity was graded using NCI-CTCAE v4.0. Results: 1035 ...

Extracellular matrix stiffness protects carcinoma cells from sorafenib via JNK signaling

Conference Paper

Apr 2014

Tumor progression is coincident with mechanochemical changes in the extracellular matrix (ECM). We hypothesized that tumor stroma stiffening, alongside a shift in the ECM composition from a basement membrane-like microenvironment toward a dense network of collagen-rich fibers during tumorigenesis, confers resistance to otherwise powerful chemotherapeutics. We created a high-throughput drug screening platform based on our poly(ethylene glycol)-phosphorylcholine (PEG-PC) hydrogel system, and customized it to capture the stiffness and integrin-binding profile of in vivo tumors. We report that the efficacy of a Raf kinase inhibitor, sorafenib, is reduced on stiff, collagen-rich microenvironments, independent of ROCK activity. Instead, sustained activation of JNK mediated this resistance, and combining a JNK inhibitor with sorafenib eliminated stiffness-mediated resistance in triple negative breast cancer cells. Overall, we discovered that β1 integrin and its downstream effector JNK mediate sorafenib resistance during tumor stiffening. These results also highlight the need for more advanced cell culture platforms, such as our high-throughput PEG-PC system, with which to screen chemotherapeutics.

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

Article

Jan 2009

Potential molecular, cellular and microenvironmental mechanism of Sorafenib resistance in hepatocellular carcinoma

Abstract and Figures

Recommended publications

Hepatocellular Carcinoma Metastasis and Circulating Tumor Cells

Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies

Establishment of a novel system for the culture and expansion of hepatic stem-like cancer cells

Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posth...