Gastrointestinal & Digestive System

Vere et al., J Gastroint Dig Syst 2013, S12

http://dx.doi.org/10.4172/2161-069X.S12-006
Review Article Open Access
J Gastroint Dig Syst Gastrointestinal Cancer ISSN: 2161-069X, an open access journal
Hepatic Stellate Cells in Hepatocellular Carcinogenesis: Possible
Therapeutic Targets?
Cristin Constantin Vere
1,2
, Alin Gabriel Ionescu
1
, Costin Teodor Streba
1,2
* and Otilia Rogoveanu
1
1
University of Medicine and Pharmacy of Craiova, Romania
2
Research Center of Gastroenterology and Hepatology of Craiova, Romania
Abstract
Hepatic stellate cells (HSCs) play a crucial role in liver fbrosis, following infammatory processes within the
parenchyma. Their activation pathways give way to a cascade of phenomena which are potentially dangerous for
the liver metabolism at a cellular level. The changes towards fbrosis pave the way for the evolution of hepatitis
into cirrhosis, the most important etiological entity of hepatocellular carcinoma. In this review, we try to cover a few
of the basic aspects of the intricate mechanisms that govern the complex activation of HSCs, their involvement in
carcinogenesis and how these molecular targets may become valuable in the future therapeutic approaches for
primary liver carcinomas.
*Corresponding author: Costin Teodor Streba, Research Center of Gastroen-
terology and Hepatology, Bvd. 1 Mai nr. 66, Craiova 200638, Romania, E-mail:
costinstreba@gmail.com
Received March 29, 2013; Accepted May 03, 2013; Published May 05, 2013
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic Stellate
Cells in Hepatocellular Carcinogenesis: Possible Therapeutic Targets? J Gastroint
Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006
Copyright: 2013 Vere CC, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Keywords: Hepatocellular carcinoma; Hepatic stellate cells;
Carcinogenesis; Fibrosis; Antifbrotic therapy
Introduction
Activation of hepatic stellate cells (HSCs) following chronic liver
infammation and injury, is a major phenomenon in the initiation
and progression of liver fbrosis - major risk factor for hepatocellular
carcinoma (HCC) [1].
Activated HSCs involved in hepatocarcinogenesis by initiating
autocrine signaling mediated by transforming growth factor-
(TGF- ) and -catenin accumulation in the nucleus of neoplastic
hepatocytes [2,3]. TGF- synthesized by activated HSCs stimulates
tumor progression of neoplastic hepatocytes and also induce epithelial
cell transformation into mesenchymal cells.
One hypothesis regarding the initiation of HCC tumorogenesis
concerns the combined efect of several growth factors synthesized
by activated HSCs: platelet-derived growth factor (PDGF), fbroblast
growth factors (FGF) 1 and 2, as well as the insulin-like growth factor
(IGF) [4].
In CHC, HSCs signifcantly increase the activation of signaling
pathways mediated by nuclear factor kappaB (NF-kB) and extracellular
regulated kinases (ERK). NF-kB pathways and MAP kinase/ERK are
involved in HCC progression by stimulating tumor cell proliferation
and inhibition of apoptosis [5]. Several immunohistochemical studies
have reported an increase in activated HSCs in the tumor sinusoids,
fbrous septa, and tumor capsule [6,7].
Recent studies have highlighted the major role of HSCs both
in inhibiting the immune response in the liver and in stimulating
neoangiogenesis in patients with chronic viral hepatitis infection
[8-11]. It has also been demonstrated experimentally that HSCs
are involved in the development of liver metastases as a result of the
infammatory response generated by stimuli from gastrointestinal
neoplasms, various carcinomas and malignant melanoma [12]. In vitro
studies and murine models based xenografs demonstrated that HSCs
can be activated by HCC cells and contribute via growth factors, both
in progression and increase aggressiveness in HCC [2,13,14]. Enzan
et al., by immunohistochemical studies regarding the involvement of
HSCs in carcinogenesis, demonstrated that activated HSC found in
both intratumoral and peritumoral stroma stimulate the development
of HCC [6,15].
Liver injury initiates fbrogenesis through signaling molecules
released by hepatocytes, infammatory cells and other cells, especially
endothelial sinusoidal and Kupfer cells.
Factors Involved in HSC Activation
Oxidative stress
By generating reactive oxygen species (ROS) plays an important
role in hepatic injury and fbrogenesis initiation. Hepatocyte necrosis
and apoptosis occur due to oxidation of lipids, proteins and DNA,
followed by amplifcation of the infammatory response and the onset
of fbrogenesis [16].
Hypoxia
It occurs in fbrogenesis by stimulating the release of hypoxia
inducible factor (FIH)-1 by CSH. In turn, FIH-1 stimulates cell
growth factor vascular endothelial (VEGF), which increases the
synthesis of collagen type I by CSH [17].
Chronic liver infammation
It leads to activation of hepatic Kupfer cells which release pro-
infammatory cytokines locally, such as tumor necrosis factor
(TNF-), interleukin-1 (IL-1) and interleukin-6 (IL-6) [18,19].
Kupfer cell activation leads to increased NF-kB activity and a
subsequent release of pro-infammatory cytokines, including TNF-
and monocyte-chemoattracting protein-1 (MCP-1), which triggers the
activation of HSCs [20]. CSH, in turn, respond to this stimulation by
releasing macrophage colony stimulating factor (M-CSF), MCP-1 and
IL-6, leading to an increase in acute phase response, accompanied by a
further increase in activated macrophages.
Hepatocyte apoptosis
It is involved in fbrogenesis and the pro-infammatory stimulation
through apoptotic bodies phagocytized by the Kupfer cells [21].
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic Stellate Cells in Hepatocellular Carcinogenesis: Possible Therapeutic
Targets? J Gastroint Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006
Page 2 of 6
J Gastroint Dig Syst Gastrointestinal Cancer ISSN: 2161-069X, an open access journal
Fatty liver fbrogenesis
It occurs indirectly by increasing oxidative stress and hepatocyte
susceptibility to enter apoptosis by altering cellular response to injury,
stimulating and activating the peroxisome proliferator-activated
receptor (PPAR), and by altering the synthesis and leptin signaling [22].
HSC activation
It is composed of two major phases: initiation (preinfammatory
stage) and perpetuation, followed by a phase of resolution, where hepatic
aggression ceases [23]. Initiation is the emergence of early genetic and
structural changes of HSCs, followed by emphasizing their response to
cytokine stimulation. Initial paracrine stimulation, including signals
from damaged hepatocytes, Kupfer cells and endothelial cells lead to
early activation of HSCs and changes in the surrounding extracellular
matrix (ECM). Once the activation process is triggered, perpetuating
the result of continuous stimulation leads to the maintenance stage of
activated HSCs.
HSC Involvement in Carcinogenesis
Mechanisms involved in the initiation and progression of
hepatocellular carcinoma intertwine, not being strictly defned. A
number of studies have shown that oxidative stress is induced at the
molecular level in chronic liver aggression of any etiology, thus fulflling
a major role in fbrogenesis and HCC occurrence [24-28].
HSCs are an important source of reactive oxygen species (ROS)
in fbrogenesis [26,29]. In hepatocytes, the main source of ROS is the
cytochrome P450 2E1. In both Kupfer cells and HSCs the main sources
of ROS are the phagocytic and non-phagocytic nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase [26,30,31].
Phagocytic form of NADPH oxidase synthesized in Kupfer cells
intervenes in the defense against bacterial products that reach the
liver through the portal system. ROS have proinfammatory efects
which sensitize hepatocytes to apoptotic stimuli, thus being involved
in fbrogenesis and carcinogenesis. Recent in vitro studies have shown
that activated HSCs synthesize the non-phagocytic form of NADPH
oxidase and thus demonstrated the involvement of ROS in other HSC
activation and fbrogenesis [29-32]. Hence, multiple ROS-generating
parenchymal and nonparenchymal cells contribute directly to the
formation and activation of pathways involved in either fbrogenesis or
carcinogenesis. Several studies in animal models of chronic liver disease
showed the major role of cytokines and growth factors in fbrogenesis
[33,34] and HCC occurrence [28].
TGF-1 is the main cytokine that is involved in hepatic fbrogenesis,
having an important role in activating myofbroblasts [35]. TGF-,
TNF- and matrix metalloprotease-9 (MMP-9) are synthesized by
activated Kupfer cells and fulfll a role in activation, cell proliferation,
increased collagen I synthesis and release of retinoids by HSCs [36-38].
Liver infammation is induced through diferent mechanisms by other
molecules having profbrogenic activity, such as PDGF, which has a
strong mitogen efect [39]. Brenner et al. reported increased levels of
TGF- in HCC correlated with decreased accumulation of collagen and
its degradation, characteristic changes and liver fbrogenesis [35].
Connective tissue growth factor (CTGF) is involved in fbrogenesis
by reshaping MEC due to its ability to stimulate the synthesis of MMP
and tissue inhibitor of metalloproteases (TIMPs), thus having the
potential to enable synthesis and degradation of MEC . Liu et al. [40]
have shown, in animal models of xenografs, increased canonical Wnt
signaling pathway activity/-catenin protein core of hepatitis C virus
(HCV) and HCC cells. Following this signaling, CTGF synthesis is
enhanced, which accelerates tumor growth, invasion and migration, but
not angiogenesis, due to binding of vascular endothelial growth factor
(VEGF), and hence its suppression. Human HCC cell line synthesizes
high levels of CTGF to form stromal rich tumors [40,41].
As a result of paracrine stimulation of neoplastic cells through
TGF-, cancer associated fbroblasts (CAF) synthetize CTGF [42].
CAF originate from endothelial cells and can trigger their endothelial
- mesenchymal transdiferentiation [42]. A recent study demonstrated
the involvement of CAF generated by stellate cells in increasing
resistance to chemotherapy or radiotherapy associated with pancreatic
cancer [43]. By analogy, activated HSCs can be a source of CAF in HCC.
Toll-like receptors (TLRs), TLR2 and especially TLR4, play an
important role in identifying endogenous ligands released from
damaged cells or apoptosis [44,45].
HSCs infammatory signaling involved in triggering innate
immune response through recognition of TLR4 are identifed
immunohistochemically on the surface of activated HSCs and Kupfer
cells. An animal model study showed a reduction of macrophage
infltration and local relief of experimentally induced liver injury and
fbrosis by genetic deletion of TLR4. As a result of blocking the TLR4
ligands, it activates an intracellular signaling pathway that includes the
activation of NF-kB [46,47]. TLR activation can be triggered by hepatitis
B and C viruses, alcoholic liver disease and nonalcoholic steatohepatitis
(NASH), all involved in HCC development [48].
Yu et al. [49] conducted an experimental study on mice with
chemically induced HCC by diethylnitrosamine, which showed a
decrease in the number of TLR4 and genes responsible for myeloid
diferentiation 88 (MyD88), but not TLR2 receptor defciency. In this
study, they reported a decrease in the incidence, size and number of
chemically induced cancer cells, thus demonstrating the important
role of TLR4 in the initiation of hepatocarcinogenesis [50]. Apoptotic
hepatocytes following diethylnitrosamine action activates and
stimulates TLRs through both myeloid cells - Kupfer cells and HSCs to
synthesize proinfammatory cytokines that can initiate the appearance
of HCC.
A recent study showed that activated HSCs promote carcinogenesis
by increasing the activity of NF-kB mediated signaling pathway [5].
Transcription factors of NF-kB play a major role in regulating the
adaptive and innate immune response, infammation and cell survival
[50,51].
Blocking apoptosis leads to initiation of tumor genesis and
occurs due to DNA mutations, with NF-kB signaling initiation. Te
frst argument for NF-kB involvement in carcinogenesis is given by
encoding a subunit of NF-kB by protein c-rel, a cellular homologue of
the v-rel oncogene. Tese proteins share a domain with Rel homologue
that binds to DNA [52]. Oncogenic transformation is favored by
increased synthesis of normal Rel proteins. Recent studies have shown
that activation of NF-kB is involved in the initiation and progression
of HCC. Initiation of carcinogenesis is linked in particular to NF-kB
signaling pathway involved in controlling a number of processes such as
proliferation, apoptosis, angiogenesis, invasion and metastasis [52,53].
TNF-, an important trigger activation of NF-kB, is synthesized
by macrophages and activated HSCs and plays a major role in
infammation and is also an accelerator of cell proliferation factor [53].
Once activated, NF-kB is involved in controlling the synthesis of a high
number of antiapoptotic factors such as cIAPs, c-FLIP and BclX, play a
role in blocking cancer cell apoptosis [54].
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic Stellate Cells in Hepatocellular Carcinogenesis: Possible Therapeutic
Targets? J Gastroint Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006
Page 3 of 6
J Gastroint Dig Syst Gastrointestinal Cancer ISSN: 2161-069X, an open access journal
Both in vivo and in vitro studies have demonstrated the role of NF-kB
inhibition of activated HSC apoptosis through a mechanism involving
blocking JNK signaling cascade and AP-1 pathway responsible for
modulating apoptosis [55,56].
Damaged liver tissue, activated HSCs proliferate following PDGF
stimulation, achieved through mitogen activated proteinkinases
(MAPKs) of JNK, ERK and p38 types. JNK and ERK activation induces
proliferation of activated HSCs, while p38 activation inhibits their
proliferative response [33,57].
By phosphorylation of a number of genes associated with
carcinogenesis, JNK plays an important role in both the initiation and
progression of HCC, by promoting the synthesis of several angiogenic
factors. VEGF stimulates endothelial cell proliferation and migration;
its synthesis by activated HSCs is also mediated by the activation of
JNK [58,59].
Epithelial-Mesenchymal Transformation (EMT) can occur at
hepatic level. Hepatocellular EMT was identifed both in patients and
in animal models by showing epithelial markers synthesized by HCC
cells. In the case of well-diferentiated HCC, E-cadherin was identifed
immunohistochemically in both tumor hepatocyte membrane and in
those noncancerous from adjacent parenchymal tissue. In the case of
poorly diferentiated HCC, E-cadherin is localized in the cytoplasm or is
frequently absent. Impaired E-cadherin complexes/-catenin from the
cell membrane is characteristic of hepatocellular EMT [60]. Decreased
synthesis of E-cadherin is associated with nuclear translocation of
-catenin, with a signifcant correlation with intrahepatic metastasis
and unfavorable prognosis in patients with HCC [60]. Activated
HSCs are indirectly involved in initiating hepatocellular EMT through
autocrine signaling mediated by TGF- and -catenin accumulation in
the nucleus of neoplastic hepatocytes [2].
HSCs activated due to signaling from tumor cells, stimulates
angiogenesis by increasing VEGF synthesis [61,62]. In angiogenesis
associated with tumor progression of HCC, in addition to VEGF
synthesis by activated HSCs, also intervenes VEGF synthesized by
malignant transformed hepatocytes [63]. Cells involved in tumor
progression by afecting EMC remodeling and angiogenesis by
inducing angiopoietin secretion [61,62]. Local hypoxia activates HSC
by stimulating the release of hypoxia inducible factor (FIH)-1, thus
triggering fbrogenesis. In turn, FIH-1 stimulates VEGF synthesis,
leading to an increase in type I collagen synthesis by activated HSCs
[17], enhancing angiogenesis [64].
Activated HSCs synthesize and secrete laminin-5 (Ln-5), thus
activating the signaling pathway MEK/ERK which has a role in
stimulating migration of HCC cells. In vitro experiments have
demonstrated the involvement of HSCs in HCC cell proliferation and
migration through proteins and growth factors synthesized by them,
involved in activation of ERK signaling pathway [5,65].
A recent immunohistochemical study showed the role of activated
HSCs in HCC progression, their presence in peritumoral tissue being
correlated with increased vascular invasion and aggressive forms of
HCC [66]. CSH are involved through several mechanisms modulating
the invasive phenotype of HCC cells. Te frst mechanism is the
synthesis and release by activated HSCs of Ln-5, this isoform of laminin
promoting strong adhesion as well as tumor invasion and migration
[65].
Another mechanism by which activated HSCs induce the
appearance of a tumor with an aggressive phenotype and higher
invasiveness is through secretion of Ln-5 which triggers the TEM of
HCC cells [67]. Ln-5 is involved in carcinogenesis through its G4-5
domain, as demonstrated in a study aimed at the MEK/ERK activation
pathway in squamous cell carcinoma [68].
Te Role Of Inhibition and/or Induction of Apoptosis
CSH and Neoadjuvant Terapy in Prophylaxis of HCC
Reducing oxidative stress, which triggers activation of HSCs,
is a potential therapeutic target in preventing fbrogenesis and thus
HCC occurrence. An experimental study on animal model with liver
cirrhosis induced by common bile duct ligation, reported a reduction of
liver fbrosis by reducing oxidative stress afer administration of IGF-1,
an important regulator of the intermediary metabolism [69].
Another therapeutic target in preventing carcinogenesis is the
blocking cytokine signaling pathways mediated by cytokine receptor
antagonists. Deepening the role of growth factors in fbrogenesis
and carcinogenesis studies Trigger antagonists of cytokines and their
receptors. Highlighting the importance of cytokines in the pathogenesis
of proliferative fbrosis that occur in signaling pathways of HSCs, and
PDGF, fbroblast growth factor, TGF- and response to tyrosine kinase
receptors led to the emergence of inhibitors that block these signaling
pathways. Tus, several inhibitors were discovered, such as the gamma-
linolenic acid, lipo-oxygenaze and PPAR gamma receptor [70,71].
Inhibitory efects of cytokines interferon- and HGF on HSC
were observed in experimental animal models, where the degree of
activation of HSCs was signifcantly reduced [72]. HGFs antifbrotic
mechanism is uncertain, but it appears to act by inhibiting the activity
of TGF-1 [73].
A number of studies have highlighted the major role of signaling
pathways mediated by TGF- and PDGF both in tumorogenesis and
in fbrogenesis and subsequent activation of HSCs [74]. Mikula et al.
reported a decrease in liver fbrosis and tumor progression by inhibiting
cell signaling pathway mediated by TGF- between hepatocytes and
activated HSCs with an antagonist Smad7 [2]. A recent study showed
a decrease in fbrosis and tumorogenesis afer blocking signaling
pathways mediated by PDGF and TGF- from the CSH activated by a
tyrosine kinase inhibitor PTK/ZK [75].
Okuno et al. observed in an animal model that administering
camostat mesylate lowers activated TGF-, followed by a reduction
in the progression of liver fbrosis [76]. A further study, conducted
on mice, showed that imatinib mesylate, a tyrosine kinase receptor
inhibitor, causes a reduction of hepatic fbrosis by a signifcant decrease
in proliferation and migration of HSCs induced by PDGF-BB, and a
decrease in both -SMA and synthesis of 2 - (I)-procollagen mRNA
in activated HSCs [77].
Blocking the signaling pathway mediated by NF-kB is another
potential therapeutic target in preventing carcinogenesis. Pentoxifylline
is a methylxanthine derivative with antifbrotic properties that lowers
I collagen synthesis by activated HSCs by inhibiting degradation of I
kappa b , which in turn blocks the activation of nuclear factor kappa-B
(NF-kB) [78]. Anan et al. showed that bortezomib, a protease inhibitor,
induces apoptosis of HSCs by blocking NFB activity due to increased
half-life of its inhibitors [79].
Apoptosis is the main mechanism responsible for the reduction of
activated HSC during liver lesion healing [80]. Several mediators of
apoptosis such as Fas/FasL, TNF receptors and Bcl/Bax were identifed
in the HSC, so a possible therapeutic target could address through these
mediators triggering apoptosis [81,82].
Activated HSCs synthesize an excess of TIMP-1 and TIMP-250
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic Stellate Cells in Hepatocellular Carcinogenesis: Possible Therapeutic
Targets? J Gastroint Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006
Page 4 of 6
J Gastroint Dig Syst Gastrointestinal Cancer ISSN: 2161-069X, an open access journal
which inhibits interstitial colagenases, reducing degradation of MET
and its buildup. TIMP-1 also exerts an antiapoptotic efect on activated
HSCs [83].
TIME antagonists represent a therapeutic target aimed at inhibiting
the synthesis of collagen I and triggering apoptosis activated HSCs.
TIMP-1 plays an important role in HSC survival by blocking apoptosis
of these cells directly. TIME antagonists induce apoptosis of HSCs,
leading to a decrease in liver fbrosis and a decreased risk of HCC [84].
Natural killer cells (NK), in addition to their role in innate immune
response, are involved in limiting liver fbrosis by neutralization of
activated HSCs [85,86] and antifbrotic cytokine release and INF and
[72,87].
HSC apoptosis was obtained in the absence of oxidative stress in an
animal model following administration glitoxin, a fungal metabolite,
through mitochondrial cytochrome c release and caspase-3 activation
and ATP depletion, responsible for reducing fbrogenesis [88].
References
1. Elsharkawy AM, Mann DA (2007) Nuclear factor-kappaB and the hepatic
infammation-fbrosis-cancer axis. Hepatology 46: 590-597.
2. Mikula M, Proell V, Fischer AN, Mikulits W (2006) Activated hepatic stellate cells
induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent
fashion. J Cell Physiol 209: 560-567.
3. Zhao W, Zhang L, Yin Z, Su W, Ren G, et al. (2011) Activated hepatic stellate
cells promote hepatocellular carcinoma development in immunocompetent
mice. Int J Cancer 129: 2651-2661.
4. Bataller R, Brenner DA (2005) Liver fbrosis. J Clin Invest 115: 209-218.
5. Amann T, Bataille F, Spruss T, Mhlbauer M, Gbele E, et al. (2009) Activated
hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma.
Cancer Sci 100: 646-653.
6. Enzan H, Himeno H, Iwamura S, Onishi S, Saibara T, et al. (1994) Alpha-smooth
muscle actin-positive perisinusoidal stromal cells in human hepatocellular
carcinoma. Hepatology 19: 895-903.
7. Schmitt-Grff A, Krger S, Bochard F, Gabbiani G, Denk H (1991) Modulation
of alpha smooth muscle actin and desmin expression in perisinusoidal cells of
normal and diseased human livers. Am J Pathol 138: 1233-1242.
8. Yin Z, Jiang G, Fung JJ, Lu L, Qian S (2007) ICAM-1 expressed on hepatic
stellate cells plays an important role in immune regulation. Microsurgery 27:
328-332.
9. Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and
enigmatic cells of the liver. Physiol Rev 88: 125-172.
10. Chen CH, Kuo LM, Chang Y, Wu W, Goldbach C, et al. (2006) In vivo immune
modulatory activity of hepatic stellate cells in mice. Hepatology 44: 1171-1181.
11. Novo E, Cannito S, Zamara E, Valfr di Bonzo L, Caligiuri A, et al. (2007)
Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of
human hepatic stellate cells. Am J Pathol 170: 1942-1953.
12. Gulubova MV (2004) Collagen type IV, laminin, alpha-smooth muscle actin
(alphaSMA), alpha1 and alpha6 integrins expression in the liver with metastases
from malignant gastrointestinal tumours. Clin Exp Metastasis 21: 485-494.
13. Faouzi S, Lepreux S, Bedin C, Dubuisson L, Balabaud C, et al. (1999) Activation
of cultured rat hepatic stellate cells by tumoral hepatocytes. Lab Invest 79: 485-
493.
14. Neaud V, Faouzi S, Guirouilh J, Le Bail B, Balabaud C, et al. (1997) Human
hepatic myofbroblasts increase invasiveness of hepatocellular carcinoma cells:
evidence for a role of hepatocyte growth factor. Hepatology 26: 1458-1466.
15. Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, et al. (2003) ADAM12
in human liver cancers: TGF-beta-regulated expression in stellate cells is
associated with matrix remodeling. Hepatology 37: 1056-1066.
16. Galli A, Svegliati-Baroni G, Ceni E, Milani S, Ridolf F, et al. (2005) Oxidative
stress stimulates proliferation and invasiveness of hepatic stellate cells via a
MMP2-mediated mechanism. Hepatology 41: 1074-1084.
17. Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, et al. (2002) Hypoxia-
induced VEGF and collagen I expressions are associated with angiogenesis
and fbrogenesis in experimental cirrhosis. Hepatology 35: 1010-1021.
18. Capuron L, Miller AH (2011) Immune system to brain signaling:
neuropsychopharmacological implications. Pharmacol Ther 130: 226-238.
19. Lay S, Gheusi G, Cremona S, Combe C, Kelley K, et al. (2000) Endogenous
brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine
expression. Am J Physiol Regul Integr Comp Physiol 279: R93-98.
20. Liu C, Tao Q, Sun M, Wu JZ, Yang W, et al. (2010) Kupffer cells are associated
with apoptosis, infammation and fbrotic effects in hepatic fbrosis in rats. Lab
Invest 90: 1805-1816.
21. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, et al. (2003) Apoptotic
body engulfment by a human stellate cell line is profbrogenic. Lab Invest 83:
655-663.
22. Friedman SL (2003) Liver fbrosis -- from bench to bedside. J Hepatol 38 Suppl
1: S38-53.
23. Friedman SL (2004) Mechanisms of disease: Mechanisms of hepatic fbrosis
and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 1: 98-105.
24. Kisseleva T, Brenner DA (2007) Role of hepatic stellate cells in fbrogenesis and
the reversal of fbrosis. J Gastroenterol Hepatol 22 Suppl 1: S73-78.
25. Brenner DA, Seki E, Taura K, Kisseleva T, Deminicis S, et al. (2011) Non-
alcoholic steatohepatitis-induced fbrosis: Toll-like receptors, reactive oxygen
species and Jun N-terminal kinase. Hepatol Res 41: 683-686.
26. De Minicis S, Brenner DA (2008) Oxidative stress in alcoholic liver disease:
role of NADPH oxidase complex. J Gastroenterol Hepatol 23 Suppl 1: S98-103.
27. Tanaka S, Mogushi K, Yasen M, Ban D, Noguchi N, et al. (2011) Oxidative
stress pathways in noncancerous human liver tissue to predict hepatocellular
carcinoma recurrence: a prospective, multicenter study. Hepatology 54: 1273-
1281.
28. Aoyama T, Inokuchi S, Brenner DA, Seki E (2010) CX3CL1-CX3CR1 interaction
prevents carbon tetrachloride-induced liver infammation and fbrosis in mice.
Hepatology 52: 1390-1400.
29. De Minicis S, Seki E, Paik YH, Osterreicher CH, Kodama Y, et al. (2010) Role
and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in
hepatic fbrosis. Hepatology 52: 1420-1430.
30. Paik YH, Iwaisako K, Seki E, Inokuchi S, Schnabl B, et al. (2011) The
nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues
NOX1 and NOX2/gp91(phox) mediate hepatic fbrosis in mice. Hepatology 53:
1730-1741.
31. Marzioni M, Saccomanno S, Candelaresi C, Rychlicki C, Agostinelli L, et al.
(2010) Clinical implications of novel aspects of biliary pathophysiology. Dig
Liver Dis 42: 238-244.
32. Svegliati-Baroni G, De Minicis S, Marzioni M (2008) Hepatic fbrogenesis
in response to chronic liver injury: novel insights on the role of cell-to-cell
interaction and transition. Liver Int 28: 1052-1064.
33. Kodama Y, Kisseleva T, Iwaisako K, Miura K, Taura K, et al. (2009) c-Jun
N-terminal kinase-1 from hematopoietic cells mediates progression from
hepatic steatosis to steatohepatitis and fbrosis in mice. Gastroenterology 137:
1467-1477.
34. Lin W, Tsai WL, Shao RX, Wu G, Peng LF, et al. (2010) Hepatitis C virus
regulates transforming growth factor beta1 production through the generation
of reactive oxygen species in a nuclear factor kappaB-dependent manner.
Gastroenterology 138: 2509-2518, 2518.
35. Brenner DA (2009) Molecular pathogenesis of liver fbrosis. Trans Am Clin
Climatol Assoc 120: 361-368.
36. Gressner AM, Lotf S, Gressner G, Haltner E, Kropf J (1993) Synergism
between hepatocytes and Kupffer cells in the activation of fat storing cells
(perisinusoidal lipocytes). J Hepatol 19: 117-132.
37. Matsuoka M, Tsukamoto H (1990) Stimulation of hepatic lipocyte collagen
production by Kupffer cell-derived transforming growth factor beta: implication
for a pathogenetic role in alcoholic liver fbrogenesis. Hepatology 11: 599-605.
38. Winwood PJ, Schuppan D, Iredale JP, Kawser CA, Docherty AJ, et al. (1995)
Kupffer cell-derived 95-kd type IV collagenase/gelatinase B: characterization
and expression in cultured cells. Hepatology 22: 304-315.
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic Stellate Cells in Hepatocellular Carcinogenesis: Possible Therapeutic
Targets? J Gastroint Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006
Page 5 of 6
J Gastroint Dig Syst Gastrointestinal Cancer ISSN: 2161-069X, an open access journal
39. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE (1989) Effects of platelet-
derived growth factor and other polypeptide mitogens on DNA synthesis and
growth of cultured rat liver fat-storing cells. J Clin Invest 84: 1786-1793.
40. Liu J, Ding X, Tang J, Cao Y, Hu P, et al. (2011) Enhancement of canonical
Wnt/-catenin signaling activity by HCV core protein promotes cell growth of
hepatocellular carcinoma cells. PLoS One 6: e27496.
41. Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, et al. (2002)
Connective tissue growth factor binds vascular endothelial growth factor
(VEGF) and inhibits VEGF-induced angiogenesis. FASEB J 16: 219-221.
42. Wang B, Haldar SM, Lu Y, Ibrahim OA, Fisch S, et al. (2008) The Kruppel-
like factor KLF15 inhibits connective tissue growth factor (CTGF) expression in
cardiac fbroblasts. J Mol Cell Cardiol 45: 193-197.
43. Walter K, Omura N, Hong SM, Griffth M, Vincent A, et al. (2010) Overexpression
of smoothened activates the sonic hedgehog signaling pathway in pancreatic
cancer-associated fbroblasts. Clin Cancer Res 16: 1781-1789.
44. Kluwe J, Pradere JP, Gwak GY, Mencin A, De Minicis S, et al. (2010) Modulation
of hepatic fbrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 138:
347-359.
45. Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, et al. (2007)
Chronic infammation associated with hepatitis C virus infection perturbs
hepatic transforming growth factor beta signaling, promoting cirrhosis and
hepatocellular carcinoma. Hepatology 46: 48-57.
46. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, et al. (2003) Toll-like
receptor 4 mediates infammatory signaling by bacterial lipopolysaccharide in
human hepatic stellate cells. Hepatology 37: 1043-1055.
47. Szabo G, Dolganiuc A, Mandrekar P (2006) Pattern recognition receptors: a
contemporary view on liver diseases. Hepatology 44: 287-298.
48. Sne D, Levasseur F, Abel M, Lambert M, Camous X, et al. (2010) Hepatitis
C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-
mediated imbalance of infammatory cytokines. PLoS Pathog 6: e1001184.
49. Yu LX, Yan HX, Liu Q, Yang W, Wu HP, et al. (2010) Endotoxin accumulation
prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in
rodents. Hepatology 52: 1322-1333.
50. Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G (2001) The bcl,
NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis
and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic
stellate cells. Eur J Cell Biol 80: 554-561.
51. Khnel F, Zender L, Paul Y, Tietze MK, Trautwein C, et al. (2000) NFkappaB
mediates apoptosis through transcriptional activation of Fas (CD95) in
adenoviral hepatitis. J Biol Chem 275: 6421-6427.
52. Factor P (2001) Role and regulation of lung Na,K-ATPase. Cell Mol Biol (Noisy-
le-grand) 47: 347-361.
53. Calvisi DF, Pascale RM, Feo F (2007) Dissection of signal transduction
pathways as a tool for the development of targeted therapies of hepatocellular
carcinoma. Rev Recent Clin Trials 2: 217-236.
54. Kaisho T, Takeda K, Tsujimura T, Kawai T, Nomura F, et al. (2001) IkappaB
kinase alpha is essential for mature B cell development and function. J Exp
Med 193: 417-426.
55. Oakley F, Meso M, Iredale JP, Green K, Marek CJ, et al. (2005) Inhibition
of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and
accelerated recovery from rat liver fbrosis. Gastroenterology 128: 108-120.
56. Czaja MJ (2003) The future of GI and liver research: editorial perspectives.
III. JNK/AP-1 regulation of hepatocyte death. Am J Physiol Gastrointest Liver
Physiol 284: G875-879.
57. Schnabl B, Bradham CA, Bennett BL, Manning AM, Stefanovic B, et al.
(2001) TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells.
Hepatology 34: 953-963.
58. Kanematsu M, Osada S, Amaoka N, Goshima S, Kondo H, et al. (2006)
Expression of vascular endothelial growth factor in hepatocellular carcinoma
and the surrounding liver: correlation with MR imaging and angiographically
assisted CT. Abdom Imaging 31: 78-89.
59. Limaye PB, Bowen WC, Orr AV, Luo J, Tseng GC, et al. (2008) Mechanisms
of hepatocyte growth factor-mediated and epidermal growth factor-mediated
signaling in transdifferentiation of rat hepatocytes to biliary epithelium.
Hepatology 47: 1702-1713.
60. Zhai B, Yan HX, Liu SQ, Chen L, Wu MC, et al. (2008) Reduced expression
of E-cadherin/catenin complex in hepatocellular carcinomas. World J
Gastroenterol 14: 5665-5673.
61. Thret N, Musso O, Turlin B, Lotrian D, Bioulac-Sage P, et al. (2001) Increased
extracellular matrix remodeling is associated with tumor progression in human
hepatocellular carcinomas. Hepatology 34: 82-88.
62. Wirz W, Antoine M, Tag CG, Gressner AM, Korff T, et al. (2008) Hepatic stellate
cells display a functional vascular smooth muscle cell phenotype in a three-
dimensional co-culture model with endothelial cells. Differentiation 76: 784-794.
63. Torimura T, Sata M, Ueno T, Kin M, Tsuji R, et al. (1998) Increased expression
of vascular endothelial growth factor is associated with tumor progression in
hepatocellular carcinoma. Hum Pathol 29: 986-991.
64. Olaso E, Salado C, Egilegor E, Gutierrez V, Santisteban A, et al. (2003)
Proangiogenic role of tumor-activated hepatic stellate cells in experimental
melanoma metastasis. Hepatology 37: 674-685.
65. Giannelli G, Fransvea E, Bergamini C, Marinosci F, Antonaci S (2003)
Laminin-5 chains are expressed differentially in metastatic and nonmetastatic
hepatocellular carcinoma. Clin Cancer Res 9: 3684-3691.
66. Ju MJ, Qiu SJ, Fan J, Xiao YS, Gao Q, et al. (2009) Peritumoral activated
hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma
after curative resection. Am J Clin Pathol 131: 498-510.
67. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S (2005) Laminin-5
with transforming growth factor-beta1 induces epithelial to mesenchymal
transition in hepatocellular carcinoma. Gastroenterology 129: 1375-1383.
68. Tran M, Rousselle P, Nokelainen P, Tallapragada S, Nguyen NT, et al. (2008)
Targeting a tumor-specifc laminin domain critical for human carcinogenesis.
Cancer Res 68: 2885-2894.
69. Cantrk NZ, Cantrk Z, Ozden M, Dalik H, Yardimoglu M, et al. (2003)
Protective effect of IGF-1 on experimental liver cirrhosis-induced common bile
duct ligation. Hepatogastroenterology 50: 2061-2066.
70. Beno DW, Mullen J, Davis BH (1995) Lipoxygenase inhibitors block PDGF-
induced mitogenesis: a MAPK-independent mechanism that blocks fos and
egr. Am J Physiol 268: C604-610.
71. Galli A, Crabb D, Price D, Ceni E, Salzano R, et al. (2000) Peroxisome
proliferator-activated receptor gamma transcriptional regulation is involved in
platelet-derived growth factor-induced proliferation of human hepatic stellate
cells. Hepatology 31: 101-108.
72. Rockey DC, Chung JJ (1994) Interferon gamma inhibits lipocyte activation
and extracellular matrix mRNA expression during experimental liver injury:
implications for treatment of hepatic fbrosis. J Investig Med 42: 660-670.
73. Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, et al. (1999) Hepatocyte
growth factor gene therapy of liver cirrhosis in rats. Nat Med 5: 226-230.
74. Liu X, Hu H, Yin JQ (2006) Therapeutic strategies against TGF-beta signaling
pathway in hepatic fbrosis. Liver Int 26: 8-22.
75. Liu Y, Wen XM, Lui EL, Friedman SL, Cui W, et al. (2009) Therapeutic targeting
of the PDGF and TGF-beta-signaling pathways in hepatic stellate cells by
PTK787/ZK22258. Lab Invest 89: 1152-1160.
76. Okuno M, Akita K, Moriwaki H, Kawada N, Ikeda K, et al. (2001) Prevention of
rat hepatic fbrosis by the protease inhibitor, camostat mesilate, via reduced
generation of active TGF-beta. Gastroenterology 120: 1784-1800.
77. Yoshiji H, Noguchi R, Kuriyama S, Ikenaka Y, Yoshii J, et al. (2005) Imatinib
mesylate (STI-571) attenuates liver fbrosis development in rats. Am J Physiol
Gastrointest Liver Physiol 288: G907-913.
78. Hernndez E, Bucio L, Souza V, Escobar MC, Gmez-Quiroz LE, et al. (2008)
Pentoxifylline downregulates alpha (I) collagen expression by the inhibition of
Ikappabalpha degradation in liver stellate cells. Cell Biol Toxicol 24: 303-314.
79. Anan A, Baskin-Bey ES, Bronk SF, Werneburg NW, Shah VH, et al. (2006)
Proteasome inhibition induces hepatic stellate cell apoptosis. Hepatology 43:
335-344.
80. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, et al. (1998)
Mechanisms of spontaneous resolution of rat liver fbrosis. Hepatic stellate cell
apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J
Clin Invest 102: 538-549.
81. Oakley F, Trim N, Constandinou CM, Ye W, Gray AM, et al. (2003) Hepatocytes
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic Stellate Cells in Hepatocellular Carcinogenesis: Possible Therapeutic
Targets? J Gastroint Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006
Page 6 of 6
J Gastroint Dig Syst Gastrointestinal Cancer ISSN: 2161-069X, an open access journal
express nerve growth factor during liver injury: evidence for paracrine regulation
of hepatic stellate cell apoptosis. Am J Pathol 163: 1849-1858.
82. Fallowfeld JA, Iredale JP (2004) Targeted treatments for cirrhosis. Expert Opin
Ther Targets 8: 423-435.
83. Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, et al. (2002)
Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor
of metalloproteinase-1 is mediated via effects on matrix metalloproteinase
inhibition: implications for reversibility of liver fbrosis. J Biol Chem 277: 11069-
11076.
84. Parsons CJ, Bradford BU, Pan CQ, Cheung E, Schauer M, et al. (2004)
Antifbrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on
established liver fbrosis in rats. Hepatology 40: 1106-1115.
85. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, et al. (2006) Natural killer
cells ameliorate liver fbrosis by killing activated stellate cells in NKG2D-
dependent and tumor necrosis factor-related apoptosis-inducing ligand-
dependent manners. Gastroenterology 130: 435-452.
86. Melhem A, Muhanna N, Bishara A, Alvarez CE, Ilan Y, et al. (2006) Anti-fbrotic
activity of NK cells in experimental liver injury through killing of activated HSC.
J Hepatol 45: 60-71.
87. Inagaki Y, Nemoto T, Kushida M, Sheng Y, Higashi K, et al. (2003) Interferon
alfa down-regulates collagen gene transcription and suppresses experimental
hepatic fbrosis in mice. Hepatology 38: 890-899.
88. Anselmi K, Stolz DB, Nalesnik M, Watkins SC, Kamath R, et al. (2007) Gliotoxin
causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the
absence of oxidative stress: exacerbation by caspase and serine protease
inhibition. J Hepatol 47: 103-113.
Submit your next manuscript and get advantages of OMICS
Group submissions
Unique features:
User friendly/feasible website-translation of your paper to 50 worlds leading languages
Audio Version of published paper
Digital articles to share and explore
Special features:
250 Open Access Journals
20,000 editorial team
21 days rapid review process
Quality and quick editorial, review and publication processing
Indexing at PubMed (partial), Scopus, EBSCO, Index Copernicus and Google Scholar etc
Sharing Option: Social Networking Enabled
Authors, Reviewers and Editors rewarded with online Scientifc Credits
Better discount for your subsequent articles
Submit your manuscript at: http://omicsonline.com/editorialtracking/
This article was originally published in a special issue, Gastrointestinal
Cancer handled by Editor(s). Dr. Aliasger Amin, James Cook University
Hospital Middlesbrough, United Kingdom
Citation: Vere CC, Ionescu AG, Streba CT, Rogoveanu O (2013) Hepatic
Stellate Cells in Hepatocellular Carcinogenesis: Possible Therapeutic Targets?
J Gastroint Dig Syst S12: 006. doi:10.4172/2161-069X.S12-006