chronic liver diseases ( cld ) and its end - stages , cirrhosis and hepatocellular carcinoma ( hcc ) , are leading causes of morbidity and mortality worldwide with enormous socio - economic costs . patients with liver cirrhosis are at high risk of deadly hepatic failure and well over 80% of hcc develop on a cirrhotic background . hcc ranks as the fifth most common cancer and , with over 600,000 deaths per annum , it constitutes a major global health problem ( parkin et al . the main aetiologies of clds are chronic hepatitis c virus ( hcv ) and hepatitis b virus ( hbv ) infections , alcohol abuse and , as a result of metabolic syndrome reaching epidemic proportions , an increasing prevalence of non - alcoholic steatohepatitis ( nash ) . liver transplantation is currently the only available therapy for terminal liver failure . with donor organs being limited , preventive measures and prevention aims at eliminating the source of damage . in alcoholic liver disease , this obviously means avoiding further alcohol consumption . the addictive behaviour of patients , however , puts a serious limitation to the efficiency of this prevention strategy . hbv and hcv infections , representing about one third of cld aetiologies , are combatted with virostatic treatments , thus improving patient conditions to some extent . the infections can , however , not be fully abrogated , severely reducing the efficiency of such therapy for this subset of clds . this liver injury triggers a cascade of molecular and cellular reactions geared towards damage limitation , removal or repair of damaged cells , defence against further infection , tissue repair and regeneration . central to the natural response to injury is inflammation induced by a large battery of signalling molecules and executed by a variety of dedicated cells , repair by activated myofibroblasts , which produce the fibrous tissue and parenchymal cell proliferation , both of which are required for filling the holes caused by damage . together , these cellular and molecular events release the enormous natural regenerative potential of the liver . in cld , hepatocyte damage , wound healing and tissue remodelling go awry , resulting in fibrosis and ultimately cirrhosis , the platform on which hcc and deadly hepatic failure develop . at the cellular and molecular level , the multistep process of progressive cld is reflected in the complex modulation of intracellular signal transduction circuits , altered cell - cell communications and , more drastically , an altered differentiation state of most liver resident cell types . evidently , the dissection of these pathways is critical for the development of drugs and therapies . as is well recognised , the multifunctional cytokine transforming growth factor ( tgf)- plays a pivotal role in the sequence of events leading to end - stage cld , although the complexity of the underlying aberrant responses that , in the various liver cell types and at the organ level , lead to the drastic changes seen in cld and hcc is not understood in detail ( dooley et al . 2009 ; gianelli et al . 2011 ; matsuzaki 2009 ) . to set the stage , we will first discuss the current knowledge of cellular communication and molecular mechanisms associated with cld initiation and progression and thereafter address the role of tgf- therein . the initial event is liver epithelial cell stress , resulting in necrotic and/or apoptotic death . death - mediated signals induce the activation of kupffer and stellate cells , which orchestrate an inflammatory and wound - healing response that might lead to tissue regeneration and repair in an acute setting or to fibrogenesis , cirrhosis and cancer when injury occurs chronically . below , we discuss the diverse phases that trigger disease progression and the process of liver regeneration . cell damage and death clds are characterised by persistent hepatocyte damage and death , induced by either chemical toxicity , metabolic overload resulting in high levels of reactive oxygen species ( ros ) or viral / microbial activity causing metabolic deregulation ( rombouts and marra 2010 ) . in non - alcoholic and alcoholic fatty liver disease , this process is known as steatosis , which is ( highly ) reversible and does not necessarily lead to cell damage . in the case of cholestasis - mediated injury , bile duct epithelial cells ( bdecs ) rather than hepatocytes are the primary target of damage , bile reflux being the major inducer of this type of injury . several modes of cell death have been classified in the damaged liver , including apoptosis and necrosis . hepatocyte death triggers a cascade of reactions initiated actively by specific messengers and signalling molecules or simply by molecules released because of cell damage . the response is aimed towards damage limitation , removal or repair of damaged cells , wound closure , defence against further infection and tissue repair and regeneration . a highly interesting recent observation suggests that , upon liver damage , hedgehog ligand production is upregulated in dying liver epithelial cells to re - initiate a signalling pathway that controls progenitor cell fate and tissue construction during development , thus inducing progenitor cell expansion and liver regeneration ( omenetti et al . 2011 ) . liver regeneration the liver possesses an enormous regenerative capacity . in experimental partial hepatectomy ( phx ) models , full liver mass is restored within 56  days after two - thirds phx in rats or mice . key events and signalling pathways that control hepatocyte proliferation have been extensively investigated and have been summarised ( michalopoulos 2007 ; bohm et al . 2010 ) . however , in some settings , the potency of the toxic xenobiotic or the amount of damaged cells might cause the death of a large number of hepatocytes and cholangiocytes . then , hepatic progenitor cells ( hpcs ) with bi - potential capacity , residing in the ductules and canals of hering , differentiate into either hepatocytes or cholangiocytes , depending on the cell compartment that is damaged the most ( michalopoulos 2011 ) . rapid hepatic failure occurs if hepatic regeneration based on mature hepatocytes / cholangiocytes and hpc proliferation can not replenish dead liver cells and liver architecture ( duncan et al . inflammation hepatitis is a central mechanism of disease progression and a marker of serious liver disease ( weber et al . it encompasses a complex inflammatory response induced by a battery of signalling molecules and is executed by a variety of cells . the process is initiated by mutual activation of stellate and kupffer cells that together provide a cytokine milieu triggering massive infiltration of mononuclear cells , which include macrophages , lymphocytes , eosinophils and plasma cells . lymphocytes are mobilised and stimulated by contact with antigen to produce lymphokines that further activate macrophages . cytokines and chemokines from activated macrophages , in turn , stimulate lymphocytes , thus setting the stage for a persistent inflammatory response ( wynn 2004 ; heymann et al . 2009).evidence is accumulating for the plasticity of liver macrophages , including kupffer cells , depending on the surrounding cytokine milieu : nf-b- and ap1-driven pro - inflammatory ( m1 ) or stat6 and peroxisome proliferation - activated receptor - directed anti - inflammatory ( m2 ) phenotypes are generated and correspondingly impact on subsequent cellular processes ( vats et al . fibrosis the activated ( myo)fibroblast is the cell type responsible for wound closure and fibrosis ( reflecting persistent wound - healing activity attributable to chronic damage ) in any cld . several potential sources for this critical mediator exist , including bone - marrow - derived fibrocytes or circulating mesenchymal cells , which can migrate through the injured liver and become myofibroblasts ( friedman 2008 ; bataller and brenner 2005 ) . resident cells , e.g. tissue fibroblasts located in the portal tract of the liver or quiescent hepatic stellate cells ( hsc ) located in the space of disse , might also be activated to become myofibroblasts ( friedman 2000 ) . whether hepatocytes , cholangiocytes or even endothelial cells undergo a transition into activated fibroblasts under certain circumstances remains controversial ( popov and schuppan 2010 ) . the predominance of evidence still supports a central role for the quiescent hsc becoming activated by cytokine signalling , turning into myofibroblasts and then producing the fibrous scar that can be found in cld.cirrhosis is not simply extensive fibrosis but is characterised by architectural disruption , aberrant hepatocyte regeneration , nodule formation and vascular changes . the chance of a reversal from a cirrhotic to normal liver architecture remains controversial and corresponding data are discussed , for example by iredale ( 2007 ) . on the other hand , no doubt exists that the resolution of liver fibrosis can occur , e.g. it is initiated by apoptosis and senescence as orchestrated biological processes to eliminate fibrogenic cells ( friedman 2010 ; 2008).based on a multitude of data from rat or mouse hscs and animal models of liver damage , several conclusive statements about liver fibrosis can be drawn : ( 1 ) oxidative stress induces hepatocyte damage and hsc and kupffer cell activation , resulting in liver fibrosis , ( 2 ) tgf- is required for liver fibrosis and ( 3 ) the blunting of tgf- signalling reduces fibrogenesis . carcinogenesis in cirrhotic livers , macroregenerative nodules that display foci of hepatocyte dysplasia are considered to be pre - neoplastic lesions of hcc . histologically , these dysplastic lesions are classified as small cell or large cell lesions or as foci of adenomatous hyperplasia , whereby small cell dysplasia and adenomatous hyperplasia are the predominant preneoplastic lesions ( roskams and kojiro 2010 ) . our present lack of a unified comprehensive understanding of liver carcinogenesis is partially attributable to hcc being initiated in multiple genetic and environmental contexts and almost certainly emerging as a consequence of multiple pathways ( whittaker et al . this limitation regarding the pathogenesis of hcc has also prevented the development of effective , targeted , preventive or therapeutic interventions.recent analyses by using genome - wide approaches and improved animal models have initiated new and promising attempts at subclassifying the apparently highly heterogeneous hcc into distinct molecular and prognostic subtypes ( lee and thorgeirsson 2006 ) . the generally accepted paradigm of hepatocarcinogenesis is that malignant transformation occurs through the stepwise accumulation of genetic and epigenetic alterations that lead to the progressive acquisition of cancer phenotypes . on the other hand , more recent studies have led to the concept that a minimum number of molecular alterations leads to the acquisition of the key cancer phenotype , namely unconstrained cell proliferation ( hoshida et al . concept proposes that , in a physiological context , growth - promoting pathways are coupled with the activation of control mechanisms such as cellular senescence or apoptosis that limit their growth effects , producing a natural homeostasis of tissue mass . additionally , the existence of cancer stem cells ( csc ) is now being intensely investigated in liver and hcc , since proliferation of stem cells is a frequent and permanent process in this organ and since the accumulation of adverse molecular events , e.g. mutations , bears a high risk of csc generation ( mishra et al . such cancer stem cells , depending on their fate at the time point of carcinogenic conversion , could account for the development of hcc or cholangiocarcinoma ( ccc).thus , in cld upon initial chronic liver damage , various progression phases can be distinguished in which a complexity of cellular crosstalk occurs . tgf- has a pivotal role in orchestrating and regulating the corresponding phenotypes of cld ( fig .  1 ) . upon liver damage , tgf- production is initiated in non - parenchymal liver cells , e.g. granulocytes , macrophages ( especially kupffer cells ) and hsc ( nakatsukasa et al . 1990 ) , whereas fully differentiated epithelial cells do not express tgf-. interestingly , hepatocytes appear to absorb and store significant amounts of latent tgf- in the cytoplasm and this might be activated and available upon damage , thus contributing to the initiation of hsc activation and the wound - healing process ( roth et al . 1998 ) . of note , hepatocytes under culture conditions lose polarity and activate survival signalling pathways , thus gaining a fibroblastoid phenotype and the facility of autonomous tgf- production ( dooley et al . 2008).fig . 1pros and cons of transforming growth factor- ( tgf- ) signalling during the progression of chronic liver diseases . upon liver damage caused by many different aetiologies , active tgf- ligands show up in the liver and induce downstream signalling in all cell types investigated . tgf- is recognised as a major profibrogenic cytokine and , thus , tgf--directed therapies are being investigated for their capacity to interfere with fibrogenesis and combat disease progression . although many of these approaches have shown promising results in animal disease models for more than a decade , there is currently still no effective treatment for human disease on the market . this scheme attempts to explain the difficulties one faces when dealing with chronic liver diseases in human patients . in animal models , severe damage from fibrosis and inflammation can be achieved within weeks , whereas the establishment of end - stage liver disease in humans usually takes several decades to establish . during that life span , the liver undergoes many different phases , as shown along the central time line . strongly depending on the disease stage , tgf- and thus its targeting might have a good ( + ) or bad (  ) outcome in the organ . tgf- enhances damage to epithelial cells by inducing apoptosis and oxidative stress , triggers myofibroblast ( mfb ) activation and a wound - healing response , controls or inhibits liver regeneration by hepatocyte apoptosis and inhibition of proliferation , activates regulatory t cells ( treg ) and th17 differentiation to calm down inflammatory responses , causes fibrogenesis and liver scarring in chronic disease , inhibits the proliferation of premalignant cells , activates stroma fibroblasts in the neighbourhood of tumour cells , inhibits tumour - directed inflammatory responses , facilitates tumour angiogenesis and induces epithelial - mesenchymal transition ( emt ) of tumour cells . this multiplicity of outcomes in one organ during the different stages of one disease clearly reveals the difficulties that we have to face while directing therapeutic approaches towards tgf-. one must select the accurate therapeutic window , target the right cell type and interfere with the adverse downstream branches of the signalling pathway . to achieve this , a great deal of basic research is still required pros and cons of transforming growth factor- ( tgf- ) signalling during the progression of chronic liver diseases . upon liver damage caused by many different aetiologies , active tgf- ligands show up in the liver and induce downstream signalling in all cell types investigated . tgf- is recognised as a major profibrogenic cytokine and , thus , tgf--directed therapies are being investigated for their capacity to interfere with fibrogenesis and combat disease progression . although many of these approaches have shown promising results in animal disease models for more than a decade , there is currently still no effective treatment for human disease on the market . this scheme attempts to explain the difficulties one faces when dealing with chronic liver diseases in human patients . in animal models , severe damage from fibrosis and inflammation can be achieved within weeks , whereas the establishment of end - stage liver disease in humans usually takes several decades to establish . during that life span , the liver undergoes many different phases , as shown along the central time line . strongly depending on the disease stage , tgf- and thus its targeting might have a good ( + ) or bad (  ) outcome in the organ . tgf- enhances damage to epithelial cells by inducing apoptosis and oxidative stress , triggers myofibroblast ( mfb ) activation and a wound - healing response , controls or inhibits liver regeneration by hepatocyte apoptosis and inhibition of proliferation , activates regulatory t cells ( treg ) and th17 differentiation to calm down inflammatory responses , causes fibrogenesis and liver scarring in chronic disease , inhibits the proliferation of premalignant cells , activates stroma fibroblasts in the neighbourhood of tumour cells , inhibits tumour - directed inflammatory responses , facilitates tumour angiogenesis and induces epithelial - mesenchymal transition ( emt ) of tumour cells . this multiplicity of outcomes in one organ during the different stages of one disease clearly reveals the difficulties that we have to face while directing therapeutic approaches towards tgf-. one must select the accurate therapeutic window , target the right cell type and interfere with the adverse downstream branches of the signalling pathway . to achieve this , hscs are a primary target for active tgf- in cld . results of experiments in which tgf- is misexpressed in liver by using adenovirus or transgenic tgf- mice have revealed an important contribution of tgf- to hsc activation and fibrogenesis ( kanzler et al . 2003 ) . upon its activation and phenotypic transdifferentiation , the tgf- response in this cell type changes . whereas platelet - derived growth - factor - induced proliferation of quiescent hsc is antagonised by tgf- , transdifferentiated myofibroblasts demonstrate a growth stimulatory effect in response to tgf- ( dooley et al . 2000 ) . 1 ( nieto et al . 2001 ) and 2 ( inagaki et al . 1995 ) type ( i ) pro - collagen , tissue inhibitor of metalloproteinase-1 and 2 ( herbst et al . 1997 ) and plasminogen activator inhibitor ( pai)-1 ( knittel et al . 1996 ) have been identified as direct tgf- target genes in this cell type , whereas the transcriptional activation of myofibroblast markers -smooth muscle actin ( sma ) and connective tissue factor ( ctgf ) are induced in a tgf--independent manner . instead , tgf- signalling is required for -sma organisation and stress - fibre formation ( dooley et al . 2003 ; uemura et al . 2005).quiescent hsc respond to tgf- treatment by smad activation and display a functional negative feedback regulation via the induction of smad7 . in contrast , myofibroblasts are fully stimulated via autocrine tgf- signalling and display a strong intrinsic r - smad activation and , importantly , lack smad7 upregulation ( stopa et al . tahashi and co - workers ( 2002 ) have confirmed this finding with myofibroblasts isolated from chronically injured rat livers ; they conclude that the lack of smad7 induction as observed in myofibroblasts in cld could be one reason for excessive tgf- effects during the progression of liver fibrosis.several studies have identified smad3 as being the main mediator of the fibrogenic response of hsc , especially with respect to the induction of collagen expression ( schnabl et al . 2001 ; furukawa et al . 2003 ; inagaki et al . 2001a ; 2001b ; seyhan et al . p38/jun amino - terminal kinase ( jnk)/map kinase ( mapk)-mediated smad3 linker phosphorylation has been reported to be associated with hsc migration and disease progression ( yoshida et al . in addition to affecting the activin receptor - like kinase-5 ( alk5)-smad3 pathway , tgf- has been found to mediate its profibrogenic action via the activation of an alternative type i receptor pathway in hscs , i.e. the alk-1-induced smad1 pathway mediating id1 expression . ectopic overexpression of id1 enhances hsc activation , whereas its depletion blunts this tgf--induced response ( wiercinska et al . 2006 ) . furthermore , non - smad tgf- signalling via ras , raf-1 , mitogen - activated protein kinase kinase and mapk p42 and p44 signalling has been reported , although the outcome of these pathways on hsc activation and fibrogenesis has not been extensively studied ( reimann et al . hepatocytes the first investigations of tgf- effects on hepatocytes were performed in cultured cells and indicated that tgf- counteracted the stimulatory action on dna synthesis by various growth factors such as hepatocyte growth factor ( hgf ) , epidermal growth factor ( egf ) or insulin ( hayashi and carr 1985 ; nakamura et al . this tgf--induced growth arrest in hepatocytes was at least in part mediated via the interaction of smad proteins with sp1 transcription factors , which induce the expression of the cyclin - dependent kinase ( cdk ) inhibitor p21 ( moustakas and kardassis 1998 ) . ( 1986 ) showed that tgf- mrna increases in a late stage of the regenerating liver after phx . they further reported that , in the regenerating as in the normal liver , tgf- mrna is present in non - parenchymal cells but not in hepatocytes and the authors therefore suggested that tgf- was a component of a paracrine regulatory loop controlling hepatocyte replication ( fausto et al . subsequently , this cytostatic effect could also be shown in cultured hepatocytes from hepatectomised rat livers ( strain et al . 1987).in addition to being anti - mitogenic , tgf- ( and activin ) has been found to induce hepatocyte apoptosis ( schwall et al . the adaptor protein daxx , which is associated with the fas receptor that mediates the activation of jnk and programmed cell death induced by fas , was suggested to provide the connection between tgf- receptors and the apoptotic machinery ( perlman et al . tgf--induced apoptosis was shown to be mediated via smad - mediated induction of death - associated protein ( dap ) kinase ( jang et al . 2002 ) . furthermore , tgf- has been shown to induce hepatocyte apoptosis via enhanced expression of the pro - apoptotic protein bim ( ramesh et al . 2008).tgf- has been found , as for many other epithelial cell types , to have a biphasic role in hcc . initially , in the primary tumour , tgf- has tumour - suppressive effects . in agreement with this notion , the reduced availability of tgf- type ii receptor ( trii ) by the ectopic expression of soluble trii in hepatocytes ( kanzler et al . 2001 ) or by using heterozygous mice with reduced trii expression ( i m et al . 2001 ) results in enhanced susceptibility to hcc , confirming the tumour - suppressor function of the tgf- signalling pathway . ectopic expression of mutated ha - ras but not c - myc , has been found to abrogate the cytostatic effect of tgf- on hepatocytes ( houck et al . hcc cells might become selectively resistant to the cytostatic effects of tgf- ( braun et al . 1990 ) and not lose all responses to tgf- , such as epithelial - to - mesenchymal transition ( emt ) . these hepatocytes display a high degree of differentiation and undergo cell cycle arrest in the g1 phase following exposure to tgf-. they maintain epithelial polarisation , despite the expression of oncogenic ha - ras ; however , upon tgf- stimulation , they convert into a migratory cell type with fibroblastoid morphology and proliferation is no longer inhibited by tgf-. without oncogenic ras , in a preneoplastic setting , tgf- might activate the epidermal growth factor receptor ( egfr ) and induce c - src phosphorylation leading to akt activation and cell survival . the blocking of egfr signalling then amplifies the apoptotic response to tgf- , whereas tgf--mediated emt in hepatocytes is unaffected ( murillo et al . 2005 ) . this indicates that the activation of egfr is required for impairing cytostatic tgf- activity but is dispensable for the emt process.using monolayer and sandwich culture systems , we have shown that hepatocytes can exist in differentiated and dedifferentiated states that are reversible and can be switched by manipulating the responsible key factors of the signalling network . for example , focal adhesion kinase - mediated akt and extracellular signal - regulated kinase 1/2 signalling interferes with the cytostatic effects of tgf- , thus facilitating fibroblastoid transdifferentiation ( emt ) . abrogating survival signalling resensitises hepatocytes to tgf--induced apoptosis ( godoy et al . in addition , immortalised , highly differentiated hepatocytes , when treated with tgf- , maintain their epithelial morphology and undergo dramatic alterations in adhesion , leading to detachment , re - adhesion and spreading . these alterations in adhesive behaviour are caused by sequential changes in the expression of 51 integrin and its ligand fibronectin ( biname et al . 2008 ) . ctgf is potently induced by tgf- and both factors are thought to play an important role and to cooperate in fibrogenesis and emt ( wang et al . 2011 ; gressner and gressner 2008).the results described in the preceding paragraph and from others ( kaimori et al . 2007 ; zeisberg et al . 2007 ) show that tgf- , e.g. via the induction of the transcriptional repressor snail , induces adult mouse hepatocytes to undergo phenotypic and functional changes typical of emt . whether , however , hepatocyte emt occurs in vivo during fibrogenesis is currently under discussion . ( 2007 ) have performed lineage - tracing experiments with albcre - r26rstoplacz double - transgenic mice and demonstrated that hepatocytes undergoing emt substantially contribute to the population of fibroblast - specific protein-1 ( fsp1)-positive fibroblasts in carbon tetrachloride ( ccl4)-induced liver fibrosis . moreover , rowe et al . ( 2011 ) have demonstrated that hepatocytes up - regulate the expression of snail in vivo during tissue remodelling . hepatocyte - specific ablation of snail demonstrates that this transcription factor plays a key role in liver fibrosis progression in vivo by triggering multiple aspects of fibrogenesis , including growth factor expression , extracellular matrix ( ecm ) synthesis and chronic inflammatory responses ( rowe et al . ( 2010 ) have strongly challenged the concept that hepatocytes in vivo acquire a mesenchymal phenotype through emt to produce ecm in liver fibrosis . when triple - transgenic mice expressing rosa26 stop -galactosidase , albumin cre and collagen 1(i ) green fluorescent protein ( gfp ) and in which hepatocyte - derived cells are permanently labelled by -galactosidase and type i collagen - expressing cells are labelled by gfp are subjected to the induction of liver fibrosis by repeated ccl4 injections , no cells with double - positivity for gfp and -galactosidase can be found , although all -galactosidase - positive cells exhibit abundant cytoplasm and the typical morphology of hepatocytes and express none of the mesenchymal markers including -sma , fsp1 , desmin and vimentin . the authors conclude that type i collagen - producing cells do not originate from hepatocytes and that hepatocytes in vivo neither acquire mesenchymal marker expression nor exhibit a morphological change that is distinguishable from normal hepatocytes ( taura et al . wells and coworkers present even more convincing results that , in alfp - cre 3 rosa26-yellow fluorescent protein ( yfp ) mice , neither hepatocytes , nor cholangiocytes ( or their bipotential progenitors ) display evidence for in vivo colocalisation of yfp with mesenchymal markers s100a4 , vimentin , -sma or procollagen 1 2 in three animal models of chronic liver disease ( bile duct ligation , ccl4 and 3,5-diethoxycarbonyl-1,4-dihydrocollidine ( chu et al . 2011).reconciling these apparently contradictory findings will require further investigations . nevertheless , if transgenic mice with upregulated smad7 expression only in their hepatocytes are challenged with chronic exposure to ccl4 , they demonstrate significantly diminished liver damage and fibrosis when compared with controls ( dooley et al . 2008 ) , indicating that tgf- signalling in hepatocytes in vivo is required for fibrogenesis progression , as it is in hsc . other cell types of the liver much less intensely investigated are the effects of tgf- on other cell types of the liver , e.g. bdec , immune cells and liver sinusoidal endothelial cells , although a major influence can be expected in liver physiology and during cld . similar to hepatocytes , tgf- might provide cytostatic and tumorigenic effects towards bdec , in particular during carcinogenic progression in cholangiocarcinoma . from many studies in other tissues , an inhibitory role of inflammation is expected , especially in its role as a differentiation factor for regulatory t cells ( tregs ; becker et al . finally , the impact of tgf- as a pro - angiogenic factor has been well - described ( ten dijke and arthur 2007 ) and will be relevant in the branched sinusoid network of the liver in the settings of regeneration , cirrhosis and carcinogenesis . various strategies have been pursued to accomplish the inhibition of tgf- signalling in fibrosis ( fig . 2 ) , first in animal studies and then with the objective of being translated into humans ( see next paragraph ) . these include ( 1 ) sequence - specific anti - sense oligonucleotides that inhibit tgf- mrna expression , ( 2 ) isoform - selective neutralising antibodies , soluble trii fragments or synthetic peptides that interfere with ligand binding to the endogenous receptor complex , ( 3 ) overexpression of the natural tgf- signalling inhibitor smad7 or cytokines such as interferon- ( ifn- ) that induce smad7 expression , ( 4 ) neutralising antibodies to integrins that interfere with the activation of latent tgf- and ( 5 ) low - molecular - weight inhibitors antagonising the intracellular kinase activity of tgf- receptors ( iyer et al . 2005 ; pennison and pasche 2007 ; yingling et al . 2004 ; dooley et al . 2003 ; petersen et al . 2008 ; weng et al . 2007 ; hawinkels and ten dijke 2011 ) . such anti - tgf- approaches have been established and successfully used for the treatment of experimental fibrogenesis . for example , a synthetic peptide that blocks the interaction of tgf- with its receptor has been established to be effective in protection against ccl4-induced liver fibrosis ( ezquerro et al . further , dominant - negative or soluble triis have been applied to suppress fibrosis in mice and rats upon dimethylnitrosamine- , ccl4- or bile duct ligation - mediated liver damage ( qi et al . 2002 ) . in part , the inhibitory effect of soluble trii is achieved by interference with oxidative stress , including the generation of ros ( cui et al . similarly , tgf--binding proteins , such as decorin and antagonistic cytokines , such as bone morphogenetic protein-7 , hepatocyte growth factor , interleukin-10 or ifn- were as efficient as camostat mesilate , a protease inhibitor that possibly abrogates the proteolytic activation of tgf- ( breitkopf et al . 2005 ) . moreover , adenovirus - mediated overexpression of smad7 in the liver potently blunted bile duct ligation - induced liver fibrosis and achieved efficient inhibition of intracellular tgf- signalling . bile duct ligation induced profibrogenic effects in cultured hscs and in vivo were inhibited ( dooley et al . 2003 ) . a similar approach with adenovirus - mediated overexpression of smad7 successfully interfered with bleomycin - induced lung fibrosis in mice ( tgf- signals via heteromeric transmembrane complexes of type i and type ii receptors ( tr ) that are endowed with intrinsic serine / threonine kinase activity ( alk activin receptor - like kinase ) . upon type - ii - mediated phosphorylation of the type i receptor , the activated type i receptor initiates intracellular signalling by phosphorylating receptor regulated ( r)-smad2 and smad3 . activated r - smads form heteromeric complexes with smad4 and these complexes accumulate in the nucleus where they mediate transcriptional responses . inhibitory smad7 antagonises tgf-/smad signalling by competing with r - smads for receptor interaction and by recruiting e3 ubiquitin ligases to the activated receptor complex and mediating its degradation . this pathway has been targeted by anti - sense molecules that inhibit tgf- mrna expression , by neutralising antibodies against tgf- or tgf- receptors that interfere with ligand - receptor interactions , by antibodies that interfere with the activation of latent tgf- and by soluble extracellular domains of the type ii receptor that sequester ligand binding to endogenous receptors and small atp mimetics of tgf- receptor kinases . antagonising pathways , such as interferon- ( ifn- ) , tumour necrosis factor- ( tnf- ) and epidermal growth factor ( egf ) , can inhibit tgf-/smad - induced responses by stimulating smad7 expression tgf- signal transduction pathway and targets for therapeutic intervention . tgf- signals via heteromeric transmembrane complexes of type i and type ii receptors ( tr ) that are endowed with intrinsic serine / threonine kinase activity ( alk activin receptor - like kinase ) . upon type - ii - mediated phosphorylation of the type i receptor , the activated type i receptor initiates intracellular signalling by phosphorylating receptor regulated ( r)-smad2 and smad3 . activated r - smads form heteromeric complexes with smad4 and these complexes accumulate in the nucleus where they mediate transcriptional responses . inhibitory smad7 antagonises tgf-/smad signalling by competing with r - smads for receptor interaction and by recruiting e3 ubiquitin ligases to the activated receptor complex and mediating its degradation . this pathway has been targeted by anti - sense molecules that inhibit tgf- mrna expression , by neutralising antibodies against tgf- or tgf- receptors that interfere with ligand - receptor interactions , by antibodies that interfere with the activation of latent tgf- and by soluble extracellular domains of the type ii receptor that sequester ligand binding to endogenous receptors and small atp mimetics of tgf- receptor kinases . antagonising pathways , such as interferon- ( ifn- ) , tumour necrosis factor- ( tnf- ) and epidermal growth factor ( egf ) , can inhibit tgf-/smad - induced responses by stimulating smad7 expression as mentioned above , experimental evidence exists showing that smad3 is the predominant mediator of fibrogenic tgf- downstream signalling . therefore , strategies to interfere specifically with smad3 are promising . in line with this assumption , the targeted disruption of smad3 confers resistance to the development of dimethylnitrosamine - induced hepatic fibrosis in mice ( latella et al . 2002 ) . however , small molecule inhibitors announced as specific for smad3 ( jinnin et al . 2006 ) have not yet yielded breakthrough results and seem to need further improvement . with regard to interference with cancer , recent studies in g. giannelli s lab ( giannelli et al . 2011 ) have shown that the inhibition of tgf- signalling results in multiple synergistic downstream effects that probably improve the clinical outcome in hcc . further , the small molecule inhibitor ly2109761 , which targets tri / alk5 and trii induces a complete abrogation of smad - dependent and -independent signalling in human colon carcinoma cells harbouring activated k - ras , resulting in reduced tumour cell invasion and liver metastasis ( zhang et al . contrary to the stimulating beneficial outcome of anti - tgf- treatment in animal disease models ( breitkopf et al . for example , metelimumab , a monoclonal antibody against tgf-1 , has been used to treat systemic sclerosis . other studies involving the use of lerdelimumab , a monoclonal antibody against tgf-2 , to treat eye scarring ( mead et al . 2003 ) , or gc1008 , a pan - antibody against tgf-1 - 3 for lung fibrosis are still ongoing . intriguingly , an antisense strategy against tgf-2 has been successful in the treatment of glioma and is currently being tested in other malignant tumours such as pancreatic carcinoma , colon carcinoma and melanoma ( schlingensiepen et al . a major reason that most of these promising results from animal disease models have not yet robustly been translated into clinical use is probably the multiplicity of the possible biological - context - dependent functions of tgf-. in the time course of cld progression , various phases occur , such as initiation , regeneration , perpetuation , fibrogenesis , tumorigenesis and metastasis . depending on the specific disease stage , , it triggers the transdifferentiation of hsc to myofibroblasts and thus mediates a wound - healing response . during regeneration and hepatocyte proliferation , tgf- has an important tissue - mass - limiting cytostatic effect and controls inflammation by generating tregs . during perpetuation and fibrogenesis in chronic disease stages , the overwhelming scar - forming wound - healing reaction is adverse for the liver . in the pre - malignant stage , , the negative outcome of tgf- on inflammation might inhibit the immune response against arising tumour cells . in carcinogenesis , when tgf--cytostatic effects are lost and the signalling branch is redirected to emt , tgf- may favour cancer progression and metastasis . furthermore , the pro - angiogenic action of tgf- towards endothelial cells may also be important for tumour progression ( meyer et al . thus , an important consideration for tgf--directed treatment of fibroproliferative diseases , such as cld , is to select the right time point and cell type for targeted intervention ( fig .  1 ) . moreover , an additional challenge is that the selective inhibition of some but not all tgf--induced cellular responses might be beneficial .
transforming growth factor- ( tgf- ) is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma . 
 liver - damage - induced levels of active tgf- enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound - healing response , including myofibroblast generation and extracellular matrix deposition . 
 being recognised as a major profibrogenic cytokine , the targeting of the tgf- signalling pathway has been explored with respect to the inhibition of liver disease progression . whereas interference with tgf- signalling in various short - term animal models has provided promising results , liver disease progression in humans is a process of decades with different phases in which tgf- or its targeting might have both beneficial and adverse outcomes . 
 based on recent literature , we summarise the cell - type - directed double - edged role of tgf- in various liver disease stages . 
 we emphasise that , in order to achieve therapeutic effects , we need to target tgf- signalling in the right cell type at the right time .