Obviously, structural and functional abnormalities pertinent to alcoholic cirrhotic transformation such as profound alterations of extracellular matrix composition, growth factor and cytokine milieu, disturbed angiogenesis, impaired immune function and reduced capacity of cirrhotic tissue to handle oxidative and/or toxic insults result in an environment that favours dedifferentiation and malignant growth.

Certain histological features typically seen in established HCC are already present, albeit to a lesser extent, in alcoholic cirrhosis and thereby support the assumption that some pathogenic hallmarks leading to cirrhosis precede those causing HCC [6]. Enzyme-altered foci and preneoplastic nodules are typically observed premalignant lesions which can also be induced in experimental rodent models of HCC [18]. Interestingly, Mallory body (MB) formation is high in HCC, and the incidence of HCC is significantly higher in cirrhosis with MBs than without leading to the hypothesis that MBs reflect an initial phenotypical alteration in the carcinogenic transformation of hepatocytes [19]. In addition, oval cells—pluripotent liver progenitor cells—are present in premalignant liver tissues HCC and adjacent tissues and evolve in response to long-term alcohol exposure [20].

HCC evolution is closely linked to chronic liver injury from various causes requiring cell/tissue regeneration for replacement of hepatocyte decay, but rarely develops in healthy liver during physiological aging. One possible explanation for this tight correlation is that HCC development requires increased cell proliferation, leading to the stepwise accumulation of genetic hits allowing for dysplastic and eventually malignant transformation. The most common and unifying condition associated with hepatocarcinogenesis is cirrhosis which takes long to develop (20–40 years). As mentioned above, cirrhosis induces alterations of the microenvironment including altered cytokine secretion from activated hepatic stellate cells and portal fibroblasts, as well as proinflammatory stimuli from invading immune cells. Regarding the latter, molecular signals derived from proinflammatory tumour-necrosis factor α (TNFα) are considered pivotal in ALD [13]. Excessive alcohol consumption can lead to an increased portosystemic uptake of lipopolysaccharides/endotoxins from gram-negative gut bacteria which contribute to necroinflammation and fibrosis progression via various molecular mechanisms including TNFα and the CD14/toll-like receptor-4 complex to produce ROS via NADPH oxidase [21–23]. In fact, elevated TNFα levels and other proinflammatory cytokines are prominent features of ALD, resulting in hepatocyte proliferation or apoptotic/necrotic death, recruitment of inflammatory cells and tissue remodelling. Molecular responses are triggered upon binding of TNFα to its cellular receptors on hepatocytes and other liver cells leading to activation of adaptor protein 1 (AP-1; c-jun/c-fos), crosstalk with epidermal growth factor signalling and subsequently enhanced cell proliferation and potentially to apoptosis via caspase activation [24]. Beyond that, TNFα activates sphingomyelinase to increase intracellular ceramide which inhibits the mitochondrial electron transport chain. Consequently increased production of ROS promotes lipid peroxidation and apoptosis independently of caspases. However, increased oxidative stress also contributes to the activation of transcription nuclear factor κB which is instrumental for the initiation of cell survival mechanisms involving the upregulation of antiapoptotic proteins such as Bcl-2, manganese superoxide dismutase and nitric oxide synthase that can all protect mitochondrial integrity and function. Indeed, constitutive upregulation of nuclear factor κB expression has been convincingly demonstrated both in human and experimental ALD [25, 26] and is a typical feature in human HCC [27]. Hence, TNFα may dose-dependently activate cellular survival mechanisms or precipitate apoptosis and/or necrosis. This may provide an explanation why hepatocytes challenged by inflammatory insults below the threshold of cell death may acquire proliferative advantages and become susceptible to dedifferentiation triggered by carcinogens such as (alcohol-derived) acetaldehyde.