Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease

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1 University of Msschusetts Medicl School Open Access Articles Open Access Publictions by UMMS Authors Adult mouse model of erly heptocellulr crcinom promoted by lcoholic liver disese Adity Ambde University of Msschusetts Medicl School Abhishek Stishchndrn University of Msschusetts Medicl School Benedek Gyongyosi University of Msschusetts Medicl School See next pge for dditionl uthors Follow this nd dditionl works t: Prt of the Digestive System Diseses Commons, Gstroenterology Commons, Heptology Commons, nd the Neoplsms Commons Repository Cittion Ambde, Adity; Stishchndrn, Abhishek; Gyongyosi, Benedek; Lowe, Ptrick; nd Szbo, Gyongyi, "Adult mouse model of erly heptocellulr crcinom promoted by lcoholic liver disese" (16). Open Access Articles This mteril is brought to you by It hs been ccepted for inclusion in Open Access Articles by n uthorized dministrtor of escholrship@umms. For more informtion, plese contct Lis.Plmer@umssmed.edu.

2 Adult mouse model of erly heptocellulr crcinom promoted by lcoholic liver disese Authors Adity Ambde, Abhishek Stishchndrn, Benedek Gyongyosi, Ptrick Lowe, nd Gyongyi Szbo Keywords Alph-fetoprotein, Liver tumor, Mcrophge polriztion, Proliferting cell nucler ntigen, Stetoheptitis Cretive Commons License This work is licensed under Cretive Commons Attribution-Noncommercil. License Rights nd Permissions This rticle is n open-ccess rticle which ws selected by n in-house editor nd fully peer-reviewed by externl reviewers. It is distributed in ccordnce with the Cretive Commons Attribution Non Commercil (CC BY-NC.) license, which permits others to distribute, remix, dpt, build upon this work noncommercilly, nd license their derivtive works on different terms, provided the originl work is properly cited nd the use is non-commercil. See: This rticle is vilble t escholrship@umms:

3 Submit Mnuscript: Help Desk: DOI: 1.378/wjg.v.i16.91 World J Gstroenterol 16 April 8; (16): ISSN (print) ISSN 19-8 (online) 16 Bishideng Publishing Group Inc. All rights reserved. Bsic Study Adult mouse model of erly heptocellulr crcinom promoted by lcoholic liver disese ORIGINAL ARTICLE Adity Ambde, Abhishek Stishchndrn, Benedek Gyongyosi, Ptrick Lowe, Gyongyi Szbo Adity Ambde, Abhishek Stishchndrn, Benedek Gyongyosi, Ptrick Lowe, Gyongyi Szbo, Deprtment of Medicine, University of Msschusetts Medicl School, Worcester, MA 165, United Sttes Author contributions: Ambde A nd Szbo G designed reserch nd wrote the mnuscript; Ambde A did the injections nd the Lieber DeCrli lcohol diet feeding, nlyzed nd interpreted ll the dt; Ambde A, Stishchndrn A, Gyongyosi B nd Lowe P performed the niml scrifice; Szbo G obtined the funding nd provided overll study supervision. United Sttes. gyongyi.szbo@umssmed.edu Telephone: Fx: Received: December 16, 15 Peer-review strted: December 17, 15 First decision: Jnury 13, 16 Revised: Mrch 9, 16 Accepted: Mrch 18, 16 Article in press: Mrch 18, 16 Published online: April 8, 16 Supported by NIH/ NIAAA, No. AA11576 to Szbo G. Institutionl review bord sttement: The study protocol ws pproved by the Institutionl Animl Use nd Cre Committee of the University of Msschusetts Medicl School. Institutionl niml cre nd use committee sttement: All procedures were performed in ccordnce with the policies of Institutionl Animl Use nd Cre Committee of the University of Msschusetts Medicl School. The study protocol ws reviewed nd pproved by the Institutionl Animl Use nd Cre Committee of the University of Msschusetts Medicl School. Conflict-of-interest sttement: The uthors do not hve ny conflict-of-interest to declre. Dt shring sttement: No dditionl dt vilble. Open-Access: This rticle is n open-ccess rticle which ws selected by n in-house editor nd fully peer-reviewed by externl reviewers. It is distributed in ccordnce with the Cretive Commons Attribution Non Commercil (CC BY-NC.) license, which permits others to distribute, remix, dpt, build upon this work non-commercilly, nd license their derivtive works on different terms, provided the originl work is properly cited nd the use is non-commercil. See: licenses/by-nc/./ Correspondence to: Gyongyi Szbo, MD, PhD, Deprtment of Medicine, University of Msschusetts Medicl School, 36 Plnttion Street, Worcester, MA 165, Abstrct AIM: to estblish mouse model of lcohol-driven heptocellulr crcinom (HCC) tht develops in livers with lcoholic liver disese (ALD). METHODS: Adult C57BL/6 mle mice received multiple doses of chemicl crcinogen diethyl nitrosmine () followed by 7 wk of % Lieber-DeCrli diet. Serum lnine minotrnsferse (ALT), lph fetoprotein (AFP) nd liver Cype1 were ssessed. Expression of F/8, CD68 for mcrophges nd Ly6G, MPO, E-selectin for neutrophils ws mesured. Mcrophge polriztion ws determined by IL-1β/iNOS (M1) nd Arg-1/IL-1/CD163/CD6 (M) expression. Liver stetosis nd fibrosis were mesured by oil-red-o nd Sirius red stining respectively. HCC development ws monitored by mgnetic resonnce imging, confirmed by histology. Cellulr prolifertion ws ssessed by proliferting cell nucler ntigen (PCNA). RESULTS: Alcohol- mice showed higher ALTs thn pir fed- mice throughout the lcohol feeding without weight gin. Alcohol feeding resulted in incresed ALT, liver stetosis nd inflmmtion compred to pir-fed controls. Alcohol- mice hd reduced stetosis nd incresed fibrosis indicting 91 April 8, 16 Volume Issue 16

4 Ambde A et l. Alcoholic liver disese promotes HCC dvnced liver disese. Moleculr chrcteriztion showed highest levels of both neutrophil nd mcrophge mrkers in lcohol- livers. Importntly, M mcrophges were predominntly higher in lcohol- livers. Mgnetic resonnce imging reveled incresed numbers of intrheptic cysts nd liver histology confirmed the presence of erly HCC in lcohol- mice compred to ll other groups. This correlted with incresed serum lphfetoprotein, mrker of HCC, in lcohol- mice. PCNA immunostining reveled significntly incresed heptocyte prolifertion in livers from lcohol- compred to pir fed- or lcohol-fed mice. CONCLUSION: We describe new 1-wk HCC model in dult mice tht develops in livers with lcoholic heptitis nd defines ALD s co-fctor in HCC. Key words: lph-fetoprotein; mcrophge polriztion; stetoheptitis; proliferting cell nucler ntigen; liver tumor The Author(s) 16. Published by Bishideng Publishing Group Inc. All rights reserved. Core tip: Chronic lcohol consumption leds to brod spectrum of disorders from stetosis to stetoheptitis to cirrhosis nd heptocellulr cncer (HCC). Currently there re no niml models of HCC tht evlute effect of lcoholic liver disese (ALD) on HCC ccelertion. We describe new 1-wk HCC model in dult mice tht develops in livers with lcoholic heptitis nd defines ALD s co-fctor in HCC. Our model involves sequentil step-wise progression of ALD to HCC nd highlights the role of lcohol s tumor promoting gent. Importntly, our model shows inflmmtion, cellulr regenertion, nd fibrosis, ll the fetures of humn HCC pthogenesis. Ambde A, Stishchndrn A, Gyongyosi B, Lowe P, Szbo G. Adult mouse model of erly heptocellulr crcinom promoted by lcoholic liver disese. World J Gstroenterol 16; (16): Avilble from: URL: com/17-937/full/v/i16/91.htm DOI: org/1.378/wjg.v.i16.91 INTRODUCTION Heptocellulr crcinom (HCC) is the most common liver cncer, nd worldwide it represents the fifth most common primry cncer dignosed in ptients [1]. HCC is lso the third leding cuse of cncer relted mortlity globlly. In the United Sttes, the incidence of HCC hs tripled over the lst two decdes []. Unlike mny other cncers with known ssocited risk fctors, the underlying moleculr pthophysiology for HCC is still not completely known. Most commonly, the incidence of HCC is linked to known risk fctors including heptitis B nd C, fltoxin nd chronic lcohol drinking [3]. About % of individuls who chroniclly consume lcohol develop ftty liver, the first pthologicl condition tht, with continued lcohol use, cn dvnce to lcoholic heptitis nd cirrhosis []. In humns, lcohol is known cusl gent in the development of HCC [1]. Most HCC ptients hve history of chronic liver disese nd cirrhosis nd cirrhosis remins the single common precursor to HCC development [5]. Incresing evidence suggests tht chronic tissue inflmmtion promotes tumor development [6]. In lcoholic heptitis recruitment of mcrophges nd neutrophils to the liver nd ctivtion of resident Kupffer cells results in high levels of pro-inflmmtory cytokines (TNF, IL-1β, MCP-1, IL-6) both in the liver nd systemic circultion [7]. Becuse lcoholic liver disese (ALD) nd lcoholic heptitis re chrcterized by significnt liver inflmmtion, here we hypothesized tht the lcoholic liver environment my expedite HCC development. Heptocrcinogenesis is multistep, multistge process tht involves genetic nd epigenetic ltertions tht ultimtely led to mlignnt trnsformtion of heptocytes [8]. Severl niml models hve been reported tht mimic different steps leding to HCC. These models hve helped to identify moleculr mechnisms tht underly the development of HCC including geneticlly modified mouse models, trnsgenic models expressing virl genes, trnsgenic mice over-expressing oncogenes nd trnsgenic models over-expressing growth fctors [9,1]. Although vluble in fcilitting detiled investigtion of moleculr pthwys, the geneticlly modified niml models hve been shown to vry significntly in their pttern of HCC development [1]. Of the chemiclly induced HCC niml models, the N-nitrosodiethylmine () bsed models re the most widely used nd ccepted. cts s lkylting gent for DNA bses which initites the formtion of neoplsms [11]. Chronic lcohol consumption cuses morbidity nd leds to brod spectrum of disorders from stetosis to stetoheptitis to cirrhosis nd heptocellulr cncer [1]. Currently there re no niml models of HCC tht evlutes the effect of ALD on HCC ccelertion. In this study, we dministered 6 doses of to wk old dult C57bl/6 mle mice followed by 7 wk of Lieber DeCrli lcohol diet feeding. We report up-regultion of liver inflmmtory cell infiltrtion nd fibrotic mrkers in mice receiving lcohol +. Further, lcohol + mice showed chrcteristic ppernce of intrheptic cysts nd heptic neoplstic foci t the end of the lcohol feeding compred to mice exposed to lcohol lone nd lone, respectively, supporting ccelertion of HCC by ALD. 9 April 8, 16 Volume Issue 16

5 Ambde A et l. Alcoholic liver disese promotes HCC A Experimentl design Serum AFP MRI Serum AFP i.p. : 75 mg/kg 1 mg/kg Scrifice Mouse ge weeks %-% Alcohol % Lieber-DeCrli lcohol diet B 3 Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + C 8 6 Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + Body weight - g 8 16 ALT - IU/L 6 c c c c c Mouse ge (wk) Mouse ge (wk) Figure 1 Chronic lcohol enhnces induced heptic injury. A: Experimentl design of the dult mouse model of erly heptocellulr crcinom. B: Body weight of mice in ech group per week. C: Three - five mice from ech experimentl group were bled every week nd serum ALT ws mesured. The grph represents men ALT levels of ech group. In grphs B nd C, vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; ( p <.5 vs pir fed sline injected mice, c p <.5 vs pir fed injected mice). ALT: Alnine minotrnsferse; : Diethyl nitrosmine; AFP: α-fetoprotein; MRI: Mgnetic resonnce imging. MATERIALS AND METHODS Animl model of HCC To estblish mouse model of heptocellulr cncer bsed on the Lieber-DeCrli lcohol diet, we injected wk old C57bl/6 mle mice with totl 6 doses of (Sigm, MO, United Sttes) intrperitonelly. As shown in figure 1A, dose of 75 mg/kg ws dministered weekly for the first 3 wk followed by dose of 1 mg/kg for next 3 wk. At week 8, the mice were rndomly divided into lcohol nd pir fed (control) groups. Age mtched groups of mice without were included in the study to understnd the effect of chronic lcohol feeding. Depending on the experimentl design, mice were fed % Lieber-Decrli lcohol diet or clorie mtched control diet (Pir fed), (Bio-Serv, Flemington, NJ, United Sttes) for 7 wk (Figure 1A). At scrifice, blood nd liver tissues were collected for further ssys. The study protocol ws pproved by the Institutionl Animl Use nd Cre Committee of the University of Msschusetts Medicl School. Mgnetic resonnce imging Mgnetic resonnce imging (MRI) of liver ws performed to monitor hyperplstic chnges in liver. Imges were obtined using 3T Philips Achiev whole-body MR scnner (Philips Medicl Systems, Best, Netherlnds) with custom-mde solenoid T/ R coil with dimeter of 3 mm. The nimls were nesthetized with 5% isoflurne mixed with crbogen (95% O/5% CO) nd were mintined with 1% to % isofluorne. Coronl T-weighted spin echo imges were cquired with respirtory triggering to reduce the motion rtifcts. The respirtion rte ws monitored with n opticl probe (Model 15T Monitoring nd Gting System, SA Instruments Inc, Stony Brook, NY, United Sttes). The output signl from the respirtion monitor ws used to trigger, in rel time, the MR cquisition. As consequence 93 April 8, 16 Volume Issue 16

6 Ambde A et l. Alcoholic liver disese promotes HCC of the triggered cquisition, the TR vlue of round ms, corresponding to the respirtion rte of round 3 bpm, ws determined. Other imging prmeters were: echo time (TE) of 7 ms, flip ngel of 9 degrees, TSE-fctor of 8, number of verge =, mtrix size of 18 1, field of view of 3 5 mm, slice thickness of 1 mm with no gp, cquisition time round min for slices. Hyperplstic nodules were distinguished from norml liver tissues on bsis of differences in homogeneity nd signl intensity. Pixel bsed nodule re quntittion ws performed using ImgeJ softwre. Biochemicl ssys Serum lnine minotrnsferse (ALT) ctivity ws determined using kinetic method (D-TEK LLC, PA, United Sttes). Serum AFP ws ssyed by ELISA (R&D systems, Minnepolis, MN, United Sttes). Serum bilirubin ws estimted using bilirubin ssy kit (Abnov, Wlnut, CA, United Sttes) nd the endotoxin levels were mesured using LAL Chromogenic Endotoxin Quntittion Kit (Thermo Scientific, Rockford, IL, United Sttes). Liver triglycerides were ssyed in liver whole cell lystes using L-Type TriGlyceride M kit (Wko Dignostics, Richmond, VA, United Sttes). RNA extrction nd rel-time PCR Totl RNA ws extrcted using the Direct-zol RNA MiniPrep ccording to the mnufcturer s instructions (Zymo Reserch, Irvin, CA, United Sttes). RNA ws quntified using Nnodrop (Thermo Scientific, Wilmington, DE). Complementry DNA (cdna) synthesis ws performed by reverse trnscription of totl RNA using the iscript Reverse Trnscription Supermix (BIO-RAD, Hercules, CA, United Sttes). Rel-time quntittive PCR ws performed using the CFX96 reltime detection system (Bio-Rd Lbortories, Hercules, CA, United Sttes). Primers were synthesized by IDT, Inc. (Corlville, IA, United Sttes). Accumultion of PCR products ws detected by monitoring the increse in fluorescence of double-strnded DNA-binding dye SYBR Green during mplifiction. Reltive gene expression ws clculted by the comprtive cycle threshold (Ct) method. The expression of trget genes ws normlized to the house-keeping gene, 18S rrna, in ech smple nd the fold-chnge in the trget gene expression between experimentl groups ws expressed s rtio. Melt-curve nlysis ws used to confirm the uthenticity of the PCR products. Western blotting Whole cell lystes, were prepred from mouse livers s described previously [13]. Proteins of interest were detected by immunoblotting with specific primry ntibodies ginst: Cype1 (b15 Millipore), β-ctin- HRP (b99; Abcm). Respective horserdish peroxidse-lbeled secondry ntibodies were from Sntcruz Biotechnology (Dlls, TX, United Sttes). The specific immunorective bnds of interest were detected by chemiluminescence (Bio-Rd, Hercules, CA, United Sttes). The immunorective bnds were quntified by densitometric nlysis using the UVP System (Bio-Rd Lbortories, Hercules, CA, United Sttes). Histopthologicl nlysis Sections of formlin-fixed, prffin-embedded livers were stined with hemtoxylin nd eosin, or Sirius Red nd ssessed for histologicl fetures of crcinom nd fibrosis. To ssess stetosis, Oil Red O stining ws performed on cryofrozen liver tissue sections (OCT). Immunohistochemistry stining for PCNA (b9; Abcm), MPO (b9535; Abcm) ws performed on formlin-fixed, prffin-embedded livers ccording to the mnufcturer s instructions. Imges were cquired on Nikon microscope t mgnifiction mentioned in figure legends. The quntittion of the Oil Red O, Sirius Red stining ws performed using ImgeJ softwre. Sttisticl nlysis Sttisticl significnce ws determined using two-tiled t-test; ANOVA nd Dunnett s multiple comprison post-test were used to compre the mens of multiple groups. Dt re shown s men ± SD nd were considered sttisticlly significnt t P <.5. GrphPd Prism 6. (GrphPd Softwre Inc., L Joll, CA, United Sttes) ws used for nlysis. RESULTS Chronic lcohol enhnces -induced heptic injury ALD nd lcoholic cirrhosis re mjor risk fctors for HCC development in humns [1]. Here we hypothesized tht the lcoholic liver environment expedites liver tumor development fter repeted dministrtion of chemicl crcinogen,. In this study, mle C57bl/6 mice received 6 weekly injections, strting t ge of wk followed by 7 wk of chronic lcohol dministrtion (Figure 1A). Weekly body weight monitoring showed tht compred to pir-fed mice, lcohol-fed sline-injected mice gined weight significntly fter 7 wk of lcohol feeding. Both injected pir-fed nd -injected lcohol-fed mice showed ttenuted weight gin during the entire course of experiment compred to mice without injection (Figure 1B). Serum ALT, mrker of heptic injury, ws significntly incresed fter the first dministrtion nd remined elevted fter repeted doses. In ddition, co-dministrtion of nd lcohol further incresed ALT (weeks 8-9) tht remined elevted in lcohol-fed mice. Introduction of lcohol feeding even in the sline injected group resulted in significnt 9 April 8, 16 Volume Issue 16

7 Ambde A et l. Alcoholic liver disese promotes HCC nd sustined increse in ALT compred to pir-fed control diet (Figure 1C). These results suggested tht while nd lcohol, respectively induce liver injury, their combintion results in synergistic heptic injury leding to sustined high serum ALT levels. Mcrophge nd neutrophil ctivtion in the liver is incresed in exposed ALD Previous reports showed tht chronic lcohol feeding results in significnt liver inflmmtion [15]. Humn lcoholic heptitis is chrcterized by liver injury, incresed serum trnsminses, incresed bilirubin nd inflmmtory cell infiltrtion into the liver [16]. Thus, first, we ssessed serum bilirubin which is incresed in lcoholic heptitis s well s in humn HCC [17]. We found tht similr to humn ptients with lcoholic heptitis, serum bilirubin ws incresed in mice fter chronic lcohol dministrtion (Figure A). Serum bilirubin ws lso incresed in mice tht received lone (Figure A). However, the gretest extent of serum bilirubin increse ws found in lcohol-fed injected mice compred to ny other experimentl groups. This ws indictive of dvnced liver disese nd rised the possibility of HCC (Figure A). Chronic lcohol exposure lso induces Kupffer cell ctivtion nd infiltrtion of mcrophges into the liver nd results in secretion of pro-inflmmtory cytokines tht drive inflmmtion in lcoholic heptitis [18]. Kupffer cells nd mcrophges re the most bundnt pro-inflmmtory cell type in the liver nd re known to contribute to ALDs [19]. Thus, next, we ssessed the expression of the mcrophge/kupffer cell mrkers, F/8, CD68 in the liver. The expression of the pn-mcrophge mrker, F/8, ws significntly elevted in ll lcohol-fed mice with or without. The mcrophge ctivtion mrker, CD68, ws up regulted to greter extent in lcohol-fed -injected mice s compred to lcohol-fed sline-injected mice suggesting the presence of ctivted inflmmtory mcrophges in the liver (Figure B). Recent literture suggests tht mcrophges cn be further clssified into pro-inflmmtory M1 or nti-inflmmtory M mcrophges []. These mcrophge subtypes express unique mrkers [1]. We found significnt increse in the expression of M1 mcrophge mrkers, IL- 1β nd inos, (Figure C) in livers of lcohol fed mice. Importntly, inos expression ws significntly higher in lcohol fed- injected mice compred to lcohol lone (Figure C). Livers from lcohol fed mice lso showed higher expression of M mcrophge mrkers, Arg1, CD163, IL-1 nd CD6, compred to non-lcohol controls (Figure D) nd CD6 the highest in lcohol fed- injected mice (Figure D). These observtions suggested incresed mcrophge recruitment to precncerous liver with mixed M1/M phenotype. Neutrophils ply significnt role in lcoholic heptitis nd lso contribute to HCC []. Other studies hve shown tht lcohol lone upregulted expression of the chrcteristic neutrophil mrkers, Ly6G, MPO nd E-selectin [3]. In our study, messenger RNA levels of these neutrophil mrkers were significntly upregulted in lcohol-fed (Figure 3A) compred to pirfed mice. The highest expression of Ly6G, MPO nd E-selectin ws found in lcohol-fed -injected mice s compred to ny other experimentl groups (Figure 3A). lone resulted in no chnge in neutrophil mrker expression compred to sline injected controls (Figure 3A). We lso confirmed the upregultion of MPO t the protein level using MPO immunostining (Figure 3B) tht showed significntly incresed numbers of infiltrting neutrophils in lcohol-fed slineinjected mice compred to pir-fed controls (Figure 3B). Moreover, the highest levels of MPO stining, confirming neutrophil infiltrtion nd ctivtion, were present in the livers of -injected lcohol-fed mice (Figure 3C). Tken together, our dt showed significnt increse in key fetures of lcoholic heptitis including incresed serum bilirubin, cliniclly relevnt dignostic mrker, elevted mcrophge, neutrophil fter lcohol dministrtion nd n even greter elevtion in ll of these indices in the lcohol + treted mice mrkers in our experimentl model. Chronic lcohol synergizes with in induction of liver fibrosis As we found sustined nd incresed liver injury nd inflmmtion fter + lcohol dministrtion, we next nlyzed stetosis nd fibrosis in the livers. There ws significnt increse in stetosis in the livers of lcohol-fed mice compred to the pir-fed control s indicted by Oil-Red-O stining (Figure A). Interestingly, lcohol-induced liver stetosis ws ttenuted in -injected mice compred to slineinjected lcohol-fed mice (Figure A). lone did not induce stetosis (Figure A nd B). Alcohol induced stetosis ws further confirmed by mesuring heptic triglyceride content, which lso showed reduction in lcohol-fed -injected mice s compred to lcohol-fed sline-injected mice (Figure C). While stetosis is n erly presenttion of ALD, prolonged liver disese results in fibrosis tht is considered s sequentil step towrds HCC development []. Hence, we ssessed the extent of fibrosis using Sirius Red stining. As shown in Figure D, lcohol-fed injected mice showed significntly incresed fibrosis by Sirius Red stining indicting the presence of liver fibrosis compred to ll other groups (Figure D). The incresed fibrosis ws quntified in Figure E. Thus, our experimentl model of HCC with + lcohol 95 April 8, 16 Volume Issue 16

8 Ambde A et l. Alcoholic liver disese promotes HCC A.5 Serum bilirubin Pir fed Alcohol fed Totl Bilirubin - mg/dl Sline B F/8 CD mrna - fold chnge 1 mrna - fold chnge 8 6 Sline Sline C IL-1β inos mrna - fold chnge 8 6 mrna - fold chnge Sline Sline D Arg1 CD163 mrna - fold chnge 8 6 mrna - fold chnge 3 1 Sline Sline 96 April 8, 16 Volume Issue 16

9 Ambde A et l. Alcoholic liver disese promotes HCC IL-1 CD6.5 5 mrna - fold chnge mrna - fold chnge 3 1. Sline Sline Figure Alcoholic heptitis induces mcrophge polriztion. A: Serum bilirubin ws mesured in serum smples t week 15; B: Liver mrna levels of mcrophge mrkers, F/8, CD68; C: Liver mrna levels of M1 mcrophge mrkers, IL-1β, inos; D: Liver mrna levels of M mcrophge mrkers, Arg1, CD163, IL-1, nd CD6. In grphs, vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; p <.5. : not significnt; : Diethyl nitrosmine; IL: Interleukin; inos: Inducible nitric oxide synthse. showed miniml stetosis nd significnt fibrosis indictive of dvnced liver disese. Chronic lcohol induces serum endotoxin nd ctivtes Cype1 Chronic lcohol exposure leds to n increse in levels of circulting endotoxin, which cn ctivte the immune cells in the liver cusing inflmmtion [5]. TLR signling hs been shown to contribute to HCC [6]. We observed significnt increse in serum endotoxin levels fter lcohol feeding while there ws no significnt difference between the endotoxin levels of lcohol-fed injected mice nd lcohol lone fed mice, t the time of scrifice (Figure 5A). Cype1, the enzyme tht metbolizes lcohol in liver, ws upregulted t both mrna nd liver protein levels in lcohol fed mice (Figure 5B nd C) s compred to pir fed or lone mice. Interestingly, the liver protein levels of Cype1 in lcohol + mice were significntly lower thn lcohol lone fed mice (Figure 5D). This dt supported the hypothesis of incresed inflmmtion nd Cype1 ctivtion fter lcohol exposure in our experimentl model. Chronic lcohol induces cellulr prolifertion nd expedites HCC To scertin the liver tumor nd HCC development, we performed MRI on ll experimentl groups before scrifice, t week 13 of ge. The liver MRI reveled few bright spots, chrcteristics of intrheptic cysts, in treted mice, however significntly higher numbers of heptic cysts were present in the + lcohol mice (Figure 6A). The incresed numbers of intrheptic cysts in + lcohol mice were further confirmed by histology (Figure 6B). Livers of pir-fed or lcohol lone fed mice showed no lesions on MRI. The re of cysts from MRI dt ws quntified using ImgeJ nd shown in figure 6C. In ddition to heptic cysts, histology evlution reveled the presence of numerous liver nodules chrcterized by heptic hyperplsi exclusively in lcohol-fed -injected mice compred to ll other experimentl groups (Figure 6D). The pir-fed -injected mice hd very few intrheptic cysts nd no heptic hyperplstic nodules. None of the lcohol fed or pir fed mice hd cysts or hyperplstic nodules. These results indicted tht lcoholic heptitis expedited erly liver tumor development. Next, we ssessed the expression of chrcteristic HCC mrkers. The expression of AFP is directly ssocited with heptocyte differentition nd HCC progression [7]. More importntly, AFP is the most commonly used noninvsive mrker for HCC dignosis [17]. We mesured serum AFP levels t week 8 (t the beginning of lcohol feeding) nd t week 15 (t the end of lcohol feeding). lone incresed serum AFP t both 8 nd 15 wk while lcohol lone incresed AFP only t 15 wk (Figure 7A). Importntly, there ws significnt increse in serum AFP in lcohol + mice compred to the lone or lcohol lone groups not only t 8 but lso t 15 wk, indicting erly regenertion nd potentilly, HCC development (Figure 7A nd B). Chronic lcohol feeding is reported to induce heptic prolifertion [8]. Thus, to estimte cell prolifertion, we performed PCNA stining on liver tissue sections (Figure 7C). Immunohistochemistry stining for PCNA showed significntly higher number of PCNA positive nuclei in lcohol-fed -injected mice compred to ll other groups (Figure 7C). Of note, both lcoholfed sline-injected nd pir-fed -injected mice showed incresed numbers of PCNA positive nuclei compred to pir-fed sline-injected controls (Figure 7D). Tken together, our experimentl model showed heptic hyperplsi confirmed on histology, significnt up regultion in AFP nd cell prolifertion, providing evidence for the synergistic ction of lcohol s tumor promoting gent in -induced erly HCC. 97 April 8, 16 Volume Issue 16

10 Ambde A et l. Alcoholic liver disese promotes HCC A Ly6G Pir fed Alcohol fed MPO mrna - fold chnge 3 1 mrna - fold chnge Sline Sline E-selectin 6 mrna - fold chnge Sline B MPO - immunohistochemistry Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + 98 April 8, 16 Volume Issue 16

11 Ambde A et l. Alcoholic liver disese promotes HCC C MPO score MPO positive cells per field Sline Figure 3 Alcoholic heptitis induces neutrophil infiltrtion. A: Liver mrna levels of neutrophil mrkers, Ly6G, MPO nd E-selectin; B: Representtive myeloperoxidse (MPO) immunohistochemistry of heptic sections (mgnifiction ) from ll experimentl groups t 15 wk. Blck rrows point to the positive stining; C: MPO positive cells were scored in t lest 3 different microscopic fields for ech mouse nd plotted s br grph. (n 5 mice per group). In grphs, vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; p <.5. : not significnt; : Diethyl nitrosmine. A Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + B Pir fed Alcohol fed C Oil red O positive re Liver TG Are (%) Triglycerides - mg/g liver 8 6 Sline Sline 99 April 8, 16 Volume Issue 16

12 Ambde A et l. Alcoholic liver disese promotes HCC D Sirius red stining Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + E Sirius red quntittion 5 Are (%) 3 1 Sline Figure Chronic lcohol synergizes with diethyl nitrosmine in heptocellulr crcinom development. A: Representtive Oil Red O stining of heptic sections ( mgnifiction) from ll experimentl groups t 15 wk; B: Br grph shows percent Oil Red O stined re in groups tht ws quntified using ImgeJ softwre. For quntifiction, t lest 3 different microscope fields were scored for ech mouse (n 5 mice per group); C: Liver triglycerides were estimted t week 15; D: Representtive Sirius Red stining of heptic sections (mgnifiction 1) from ll experimentl groups t 15 wk. E: For quntifiction of fibrosis, t lest 3 different microscope fields t 1x mgnifiction were scored for ech mouse (n 5 mice per group). Br grph shows percent Sirius Red positive re quntified using ImgeJ. In grphs, vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; p <.5. : not significnt; : Diethyl nitrosmine. DISCUSSION Chronic lcohol use leds to lcoholic heptitis nd cirrhosis [1]. Epidemiologicl dt suggests tht chronic hevy lcohol consumption nd ALD is significnt risk fctor towrds the development of HCC [9]. In this study, we introduce mouse model tht demonstrtes tht chronic lcohol feeding resulting in lcoholic heptitis in dult mice, expedites (chemicl) induced erly liver tumor development. We found tht fetures of humn lcoholic heptitis including inflmmtion, stetosis nd fibrosis were ll present in -injected mice fter lcohol feeding nd resulted in present numbers of erly HCC neoplstic foci (Figure 8). Our dt indicte tht incresed neutrophil nd mcrophge ctivtion is triggered in the lcoholic liver tissue microenvironment nd my contribute to ccelertion of HCC (Figure 8). In ddition to stetoheptitis, liver fibrosis ws lso present in + lcohol treted mice s indicted by Sirius Red stining. Further, our model showed incresed numbers of intrheptic cysts by the MRI tht were confirmed s heptobiliry cysts by histology nd re fetures of erly heptobiliry cncer. Our model lso 1 April 8, 16 Volume Issue 16

13 Ambde A et l. Alcoholic liver disese promotes HCC A Pir fed Alcohol fed B Serum endotoxin Liver Cype1 Endotoxin - EU/mL mrna - fold chnge 3 1. Sline Sline C D 1 Cype1 β-ctin Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + Cype1 reltive density 8 6 Sline Figure 5 Chronic lcohol increses serum endotoxin levels nd ctivtes Cype1. A: Serum endotoxin; B: Liver Cype1 mrna levels; C: Representtive western blot showing liver Cype1 protein levels. β-ctin ws used s loding control for western blot; D: Reltive density of Cype1 western blot signl. In grphs, vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; p <.5. : not significnt; : Diethyl nitrosmine. A Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + 11 April 8, 16 Volume Issue 16

14 Ambde A et l. Alcoholic liver disese promotes HCC B Pir fed + Alcohol fed + C 6 MRI quntittion Pir fed Alcohol fed pixels (1 3 ) ND ND Sline D Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + Figure 6 Chronic lcohol expedites heptocellulr crcinom development. A: T-weighted MRI of liver in coronl section t week 13. Arrows denote intrheptic cysts. B: Representtive HE stined intrheptic cysts observed in ll injected mice (1X mgnifiction). Note the higher number of cysts in lcohol + mice. C: Quntifiction of cyst re using ImgeJ. D: Representtive HE stined liver sections from ll tretment groups (mgnifiction 1) t week 15. The heptic hyperplsi (encircled in blck dotted line) ws exclusively observed in lcohol + mice. In grph (C), vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; p <.5, pir fed vs lcohol fed. ND: not detected; : Diethyl nitrosmine. 1 April 8, 16 Volume Issue 16

15 Ambde A et l. Alcoholic liver disese promotes HCC A Serum AFP - ng/ml Pir fed + sline Pir fed + Alcohol fed + sline Alcohol fed + Pir fed Alcohol fed Pir fed Alcohol fed Week 8 Week 15 B mrna - fold chnge 8 6 Sline AFP Pir fed Alcohol fed C Pir fed + sline Alcohol fed + sline Pir fed + Alcohol fed + D PCNA positive cells per field PCNA score Sline Pir fed Alcohol fed Figure 7 Chronic lcohol induces serum AFP nd cellulr prolifertion. A: Fold chnges in serum AFP levels t week 8 nd week 15; B: Liver AFP mrna levels t week 15; C: Representtive immunostining imges for proliferting cell nucler ntigen (PCNA) t week 15 (mgnifiction ). Arrows point to positive stining; D: PCNA positive nuclei were scored in t lest 3 different microscopic fields for ech mouse nd plotted s br grph on the right. (n 5 mice per group). In grphs, vlues re given s men ± SD, Dunnett s multiple comprison were used to compre the mens of multiple groups; p <.5. : not significnt; : Diethyl nitrosmine; AFP: α-fetoprotein. 13 April 8, 16 Volume Issue 16

16 Ambde A et l. Alcoholic liver disese promotes HCC Ethnol ROS Stetosis Prolifertion Inflmmtion Heptocytes Mcrophges M1/M Neutrophils HCC Figure 8 Multi-fctoril effects of ethnol in heptocellulr crcinom ccelertion. HCC: Heptocellulr crcinom. showed significnt induction in serum AFP, one of the well-estblished mrkers of HCC, upon lcohol feeding in the -injected mice. Finlly, our dt showed enhnced cellulr prolifertion in response to chronic lcohol feeding which promoted progression to HCC. hs been used since the 196s to induce HCCs in lbortory nimls, nd is the most widely used chemicl to induce liver cncer in mice [1]. undergoes metbolic ctivtion in heptocytes by enzymes of the cytochrome P5 fmily nd cts s complete crcinogen, if injected in mice younger thn wk, when heptocytes re still ctively proliferting [3]. When dministered to dult mice, tumor promotion is required nd cn be chieved by phenobrbitl, crbon tetrchloride, prtil heptectomy. Our experimentl model used wk old mle mice nd provided evidence for the role of lcohol s tumor promoting gent in dult mice. In our study, mle mice were chosen becuse of the higher prevlence of HCC in mles compred to femles in humns [3]. Irrespective of the promoting gent used, bsed HCC models tke t lest 5 mo to show the first signs of tumor. Our model using lcohol s tumor promoting gent demonstrted the first signs of erly HCC in much shorter time of 3 mo. Although severl crcinogen initited HCC niml models hve been described, none of them so fr evluted lcoholic heptitis nd ALD s tumor promoting fctor in wild-type mice [9]. A recent study performed in neonte mice combined chronic lcohol exposure in the drinking wter with injection nd showed tumors t 8 wk [1]. However, lcohol dministrtion in the drinking wter does not cuse ALD [31]. In our study, we employed the Lieber-DeCrli lcohol feeding model tht results in fetures of humn ALD including stetosis, inflmmtion nd liver fibrosis [3]. By utilizing dult mice nd the Lieber- DeCrli lcohol diet, our model shows ccelertion of erly heptobiliry tumors fter chemicl crcinogen exposure with some histopthologicl resemblnce to humn ALD. Chemicl toxins nd virl gents re the two well known etiologies of heptocellulr cncer [1]. Irrespective of the underlying etiology, cellulr inflmmtion is the common feture tht hs been shown to be present in humn HCC ptients s well s niml models [33]. It is lso known tht persistent inflmmtion in the bsence of infection increses the risk nd expedites the development of cncer. Inflmmtion in the liver is one of the hllmrks of lcoholic heptitis [33] nd it ws prominent in our model with the highest level in lcohol-fed treted mice. Activtion nd recruitment of neutrophils nd mcrophges to the liver is well-known feture of lcoholic heptitis [19,], stetoheptitis nd ALD [3]. In our experiments, we found incresed expression nd ctivtion of neutrophils nd mcrophges in lcohol-fed mice nd mrkers of inflmmtion were even higher in mice with liver tumors fter + lcohol feeding. Alcohol-induced sensitiztion of liver mcrophges to portl endotoxin is hllmrk of ALD [35]. LPS recognition by TLR on mcrophges nd other cell types in the liver, ctivtion of downstrem signling pthwys culminting in ctivtion of trnscription fctors such s NF-κB, AP-1 leds to incresed inflmmtory cytokine production in ALD. Recent literture suggests tht mcrophges cn be further clssified into pro-inflmmtory M1 or ntiinflmmtory M mcrophges []. The M1 phenotype is chrcterized by the expression of high levels of proinflmmtory cytokines, high production of rective nitrogen nd oxygen intermedites, promotion of Th1 response, nd strong microbicidl nd tumoricidl ctivity [,36]. The lterntively ctivted or M mcrophges re often referred to s tumor ssocited mcrophges (TAMs) []. We observed significnt induction of both M1 (TNFα, inos) nd M mrkers (Arg1, CD163, CD6) in our experimentl model. The presence of M1 mcrophges is consistent with the incresed proinflmmtory ctivtion in ALD. This 1 April 8, 16 Volume Issue 16

17 Ambde A et l. Alcoholic liver disese promotes HCC increse in M mcrophge is likely suggestive of the presence of TAMs in the liver. TAMs represent the mjor inflmmtory component of the strom of liver cncer nd cn ffect different spects of the neoplstic trnsformtion of the tissue. Mny observtions indicte tht TAMs express severl M-ssocited pro-tumourl functions, including promotion of ngiogenesis, mtrix remodeling nd suppression of dptive immunity. The pro-tumourl role of TAMs in cncer is further supported by clinicl studies tht found correltion between the high mcrophge content of tumors nd poor ptient prognosis. TAMs represent unique nd distinct M-skewed myeloid popultion nd re now recognized s potentil trget for nti-cncer therpy [37]. Therefore, we mixed M1/M MΦ presence with the increse in M mcrophge mrkers observed in our model my be responsible for promoting tumor development in the exposed lcohol-fed mice. Alcohol is primrily metbolized in heptocytes nd its metbolites generte ROS, cuse inflmmtion nd stetosis. Long term lcohol exposure induces stte of chronic inflmmtion in the liver [38]. Both nd lcohol induce CypE1, nd the chronic lcoholic injury induced in our model synergized with the chemicl injury to increse heptocyte prolifertion leding to ppernce of erly neoplstic foci found in our experimentl model. In the context of cncer-relted inflmmtion, key intrcellulr signl trnsducers hve been identified both in preneoplstic cells s well s in inflmmtory cells. Among these signling pthwys, sustined ctivtion of trnscription fctors including NF-κB, p53, HIF-1, β-ctenin/wnt, nd Nrf in liver leds to chronic inflmmtion tht is responsible for cncer progression [39]. Thus, the inflmmtion ssocited with lcoholic heptitis my be significnt contributing fctor to HCC development in lcohol fed injected mice. In ddition to cellulr inflmmtion, the lcohol fed injected mice showed sustined higher ALT levels. Incresed ALT levels re indictor of heptocyte dmge nd cn be used relibly s mrker of liver injury []. Initilly in our experimentl model, the ALT levels were significntly higher in ll injected mice nd ALT returned to bseline fter cesstion of dministrtion. However, the lcohol fed mice showed sustined the higher ALT levels suggesting sustined liver injury. cts s n lkylting gent for DNA bses which initites the formtion of neoplsms [11]. It hs been proposed tht the chrged nucleophilic intermedites of ttck DNA bses thereby leding to muttions which initite cellulr trnsformtion [11]. Chemicl crcinogens including exert their effect by generting ROS during their metbolism in the liver, which is responsible for DNA dmge ssocited with incresed risk of cncer development [39]. Importntly, is metbolized in the liver by CypE1, the sme enzyme tht metbolizes lcohol [1]. We lso observed significntly higher TBARS in lcohol fed injected mice, compred to lcohol lone mice (dt not shown). Hence, it is possible tht the heptocytes from lcohol fed injected mice re exposed to extremely higher ROS in ddition to DNA dmge which my expedite their trnsformtion into erly HCC observed in this group exclusively. The expression of AFP is directly ssocited with heptocyte differentition [7]. Elevted levels of serum AFP re reported in lcoholic heptitis ptients []. However, s compred to lcoholic heptitis ptients, the AFP levels re much higher in humn HCC ptients [3]. Some reports show clinicl correltion between serum AFP nd severity of liver disese []. Our dt of serum AFP levels t week 8 nd 15 clerly show the role of lcohol in stimulting AFP expression which cn be correlted to dvnced liver disese such s HCC. In ddition to heptocytes, the liver progenitor cells (LPC) lso produce AFP during their cellulr differentition [5]. The LPCs ply n importnt role in liver regenertion nd homeostsis [6,7]. Incresed serum AFP in our experimentl model is lso indictive of enhnced prolifertion of LPCs which my be responding to chronic liver injury cused by lcohol feeding. This regenertive response by LPCs my lso contribute to HCC development. Chronic lcohol feeding is reported to induce Cyclin D1 protein tht corresponds with enhnced heptic prolifertion [8]. More recently, Lnthier et l [8] reported tht lcoholic heptitis ptients demonstrted significnt invsion of LPC nd higher number of proliferting heptocytes compred to controls. This study on humn lcoholic heptitis ptients suggests tht heptic cell prolifertion plys pivotl role in the prognosis of lcoholic heptitis nd HCC. A significntly higher number of PCNA positive cells in + lcohol mice provide nother evidence for the role of lcohol s inducer of heptocyte nd LPC prolifertion. Chronic liver injury such s long term lcohol exposure leds to stetoheptitis, heptitis which cn progress to fibrosis []. Heptic fibrosis is n injury heling process in which excessive connective tissue ccumultes in the liver [9]. The profibrotic fctors like collgen re overproduced to ssist the expnsion of new heptocytes. Heptic fibrosis cn progress to cirrhosis nd in few cses to HCC []. In our experimentl model of HCC, the lcohol fed injected mice showed significntly higher fibrosis s compred to lcohol fed (lone) or injected (lone) mice. The moleculr pthwys ssocited with fibrosis re very similr to liver regenertion, cellulr process in which mture terminlly differentited heptocytes proliferte to replce the injured cells [5]. In dult mice, mture heptocytes exist in growth-rrested (G) stte which, fter liver injury, leve their G stte nd enter the prolifertive stges of the cell cycle during which they duplicte necessry components nd 15 April 8, 16 Volume Issue 16

18 Ambde A et l. Alcoholic liver disese promotes HCC synthesize new prolifertion-specific molecules (G1 phse), replicte their DNA (S phse), nd divide (M phse) [51]. It is conceivble tht in our experimentl model, heptocytes with dmged DNA undergo multiple rounds of prolifertion to complete the regenertion response. However, due to their dmged DNA, continue to proliferte leding to HCC. Other probble explntion could be tht the heptocytes with induced DNA dmge re exposed to incresed mount of ROS nd inflmmtion due to chronic lcohol exposure, which leds to their constnt prolifertion resulting in HCC development. These hypotheses cn be the focus of future studies. In conclusion, by combining multiple injections of prior to chronic Lieber-DeCrli lcohol diet feeding, we developed mouse model tht displys the fetures of erly HCC. Importntly, our model involves dult mice with lcoholic heptitis, liver inflmmtion, cellulr regenertion, nd fibrosis, ll the fetures ssocited with pthogenesis of humn HCC. We believe tht vilbility of such model will provide unique opportunities to understnd lcohol ssocited moleculr nd cellulr mechnisms relted to HCC. ACKNOWLEDGMENTS The uthors would like to thnk members of the Szbo lb for their stimulting intellectul discussions nd scientific input. The help provided by Sho-kun Zheng (Deprtment of Rdiology) in cquisition of MRI dt is cknowledged. We thnk Merin McDonld nd Cndice Dufour for ssistnce with formtting the mnuscript. The uthors re grteful to services provided by DERC (histology nd immunostining) nd CFAR (Primer Synthesis) core fcilities t UMASS Medicl School. CFAR core fcility is supported by the University of Msschusetts Center for AIDS Reserch (P3 AI85). COMMENTS Bckground Heptocellulr crcinom (HCC) is the most common liver cncer, nd worldwide it represents the fifth most common primry cncer dignosed in ptients. Chronic lcohol consumption cuses morbidity nd leds to brod spectrum of disorders from stetosis to stetoheptitis to cirrhosis nd heptocellulr cncer. Reserch frontiers Severl niml models hve been reported tht mimic different steps leding to HCC. Currently there re no niml models of HCC tht evlute the effect of lcoholic liver disese on HCC ccelertion. Innovtions nd brekthrough In this study, the uthors dministered 6 doses of diethyl nitrosmine () to wk old dult C57bl/6 mle mice followed by 7 wk of Lieber-DeCrli lcohol diet feeding. They found tht fetures of humn lcoholic heptitis including inflmmtion, stetosis nd fibrosis were ll present in -injected mice fter lcohol feeding nd resulted in higher numbers of erly HCC neoplstic foci. The dt indicte tht incresed neutrophil nd mcrophge ctivtion is triggered in the lcoholic liver tissue microenvironment nd my contribute to ccelertion of HCC. Applictions This combintion of crcinogen pre-exposure nd chronic lcohol consumption presents one of the most unique phenomenons of chronic lcohol leding to progression of HCC tht occurs in humns. This vilbility of such model will provide unique opportunities to understnd lcohol ssocited moleculr nd cellulr mechnisms relted to HCC. Terminology Lieber-DeCrli diet, commercilly vilble, crefully designed nd well chrcterized rodent diet intended to mimic the clinicl sitution in which the vrious effects of lcohol occur in the setting of liver chnges chrcterized by ftty liver nd inflmmtion. Peer-review This is n interesting mnuscript devoted to incresed -induced HCC development by lcohol. 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Rective oxygen species: role in the development of cncer nd vrious chronic conditions. J Crcinog 6; 5: 1 [PMID: DOI: / ] Kim WR, Flmm SL, Di Bisceglie AM, Bodenheimer HC; Public Policy Committee of the Americn Assocition for the Study of Liver Disese. Serum ctivity of lnine minotrnsferse (ALT) s n indictor of helth nd disese. Heptology 8; 7: [PMID: DOI: 1.1/hep.19] 1 Chowdhury G, Clcutt MW, Ngy LD, Guengerich FP. Oxidtion of methyl nd ethyl nitrosmines by cytochrome P5 E1 nd B1. Biochemistry 1; 51: [PMID: DOI: 1.11/bi319c] Mendenhll CL, Chedid A, French SW, Ry M, Roselle GA, Grossmn CJ, Weesner RE, Grtside PS. Alph-fetoprotein ltertions in lcoholics with liver disese. V.A. Coopertive Study Groups. Alcohol Alcohol 1991; 6: [PMID: 17517] 3 Gowd S, Desi PB, Hull VV, Mth AA, Vernekr SN, Kulkrni SS. A review on lbortory liver function tests. Pn Afr Med J 9; 3: 17 [PMID: 15376] Frinti F, Mrino D, De Giorgio M, Bldn A, Cntrini M, Cursro C, Rpccini G, Del Poggio P, Di Nolfo MA, Benvegnù L, Zoli M, Borzio F, Bernrdi M, Trevisni F. Dignostic nd prognostic role of lph-fetoprotein in heptocellulr crcinom: both or neither? Am J Gstroenterol 6; 11: 5-53 [PMID: DOI: /j x] 5 Sell S, Leffert HL. Liver cncer stem cells. J Clin Oncol 8; 6: 8-85 [PMID: DOI: 1.1/JCO ] 6 Itoh T, Miyjim A. Liver regenertion by stem/progenitor cells. Heptology 1; 59: [PMID: DOI: 1.1/ hep.6753] 7 Miyjim A, Tnk M, Itoh T. Stem/progenitor cells in liver development, homeostsis, regenertion, nd reprogrmming. Cell Stem Cell 1; 1: [PMID: 7911 DOI: 1.116/ j.stem.1..1] 8 Lnthier N, Rubbi-Brndt L, Lin-Mrq N, Clément S, Frossrd JL, Goossens N, Hdengue A, Sphr L. Heptic cell prolifertion plys pivotl role in the prognosis of lcoholic heptitis. J Heptol 15; 63: [PMID: DOI: 1.116/j.jhep.15..3] 17 April 8, 16 Volume Issue 16

20 Ambde A et l. Alcoholic liver disese promotes HCC 9 Brenner DA. Moleculr pthogenesis of liver fibrosis. Trns Am Clin Climtol Assoc 9; 1: [PMID: ] 5 Mrqurdt JU, Seo D, Gómez-Quiroz LE, Uchid K, Gillen MC, Kitde M, Kposi-Novk P, Conner EA, Fctor VM, Thorgeirsson SS. Loss of c-met ccelertes development of liver fibrosis in response to CCl() exposure through deregultion of multiple moleculr pthwys. Biochim Biophys Act 1; 18: [PMID: DOI: 1.116/j.bbdis.1..1] 51 Diehl AM. Alcohol nd liver regenertion. Clin Liver Dis 1998; : [DOI: 1.116/S (5)738-6] P- Reviewer: Osn NA, Tkhshi T S- Editor: Gong ZM L- Editor: A E- Editor: Liu XM 18 April 8, 16 Volume Issue 16

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