Hepatocellular carcinoma (HCC) reflects the most common primary liver cancer as well as the 2nd most common cause of cancer related death in humans worldwide. In most cases HCC is caused by chronic liver damage that is either induced by chronic viral infections (e.g. Hepatitis B or C viruses), by chronic alcohol consumption or by changes in our lifestyle (e.g. high fat, high sugar diet and sedentary life style). So far treatment options and treatment success for patients diagnosed with HCC are small, with surgical interventions being the most successful ones. Consequently, a lot of energy has been invested in the generation of various mouse models for HCC in the last 15 years to mimic human pathology, setting the ground for pre-clinical trials in animals and being the starting point for subsequent clinical trials in human patients.
Due to the unique regenerative capacity the liver has become an unbelievable playground with several different mechanisms that can cause liver cancer. This led to a plethora of mouse models that – in part – turned out to be useful to understand the mechanisms possibly involved in liver cancer development. Still, research with these models indicated that the outcome of liver tumors or HCC is not the only measurement that should be taken into account when identifying the molecular and cellular mechanisms of liver cancer development. It is even more important to identify the character of HCC on transcriptional, genetic, epi-genetic and histological model and to compare it with the human pathology. As it turns out that “the HCC” does not exist in human patients but rather a group of subtypes with different etiologies (e.g. viral, dietary), molecular and cellular mechanism, distinct types of inflammation and most likely also demanding different treatment strategies, a through phenotyping of HCC mouse models will be most important for the identification of mouse models with predictive value for human therapy. Importantly, aetiologies causing HCC in industrialized countries is slowly changing: Alterations in our lifestyle over the last decades, including high caloric intake (e.g. through high fructose and high fat diet) combined with a sedentary lifestyle have augmented the worldwide incidence of overweight and metabolic syndrome, characterized by abdominal obesity, insulin resistance and Type-2 diabetes, hypertonia and dyslipidemia. This trend is not only observed in industrialized countries in the US or Europe but also gradually now in developed as well as developing countries. At the moment it is believed that approximately 90 million Americans and 40 million Europeans suffer from a fatty liver (also called Non-alcoholic fatty liver disease (NAFLD)). Consequently, the price we will have to pay – from a global point of view – for our consequent aim to achieve progressive industrialisation and enhanced economic development in the 3rd world as well as developing countries is the adaptation to the ‘Western’ unhealthy diet and its concomitant lifestyle. It should also be mentioned that particularly this development – in the long run – will lead to a huge problem as developing and developed countries will contribute greatly to the number of people suffering from the metabolic syndrome and fatty liver disease. It is estimated that more than 100 million people will suffer from fatty liver disease, the metabolic syndrome and its consequences from China and India alone.
From a European point of view, a further increase of the metabolic syndrome as well as fatty liver disease is to be expected – underlining the need of therapeutic options to efficiently treat these patients in the next 20 years. We know today that overweight and metabolic syndrome lead to diseases of several kinds, including coronary heart diseases, Type-2 diabetes but also cancer (e.g. liver cancer, colorectal cancer). Epidemiological data clearly indicate that overweight and metabolic syndrome are reaching pandemic dimensions in industrialised countries – and can be seen to a high degree in the US and in Europe. As mentioned above, it is prospected that newly developing countries – as a consequence of industrialization and adaptation of their lifestyle – will also experience a steep increase in overweight and metabolic syndrome-triggered diseases. In the past 10 years, the rate of obesity has doubled in adults and tripled in children in the US. A similar trend has also been observed in Europe, and this trend will accelerate and steepen.
The liver – which is the most important metabolic organ – is strongly affected by a chronic state of overweight and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD), which is the most frequent liver disease worldwide, is a clinical manifestation of overweight and metabolic syndrome. NAFLD is a chronic disease that can last several decades, characterised by predominant macrovesicular steatosis of the liver and that can easily become more. Although the prevalence of NAFLD is increasing globally, epidemiology and demographic characteristics of NAFLD vary worldwide. It is becoming increasingly clear that a number of pathways are involved in the pathogenesis of NASH, and its progression to advanced stages of liver disease. These pathways may be diverse in different cohorts of patients with NASH. Understanding of which pathways play a role in the development of NASH will be critical before launching treatment modalities. A significant number of NAFLD patients develop non-alcoholic steatohepatitis (NASH), fibrosis and consequently hepatocellular carcinoma (HCC). In recent years, obesity leading to metabolic syndrome, steatosis and steatohepatitis has attracted increased attention due to an increased HCC incidence in the US and Europe. In line, the most common etiology for HCC in industrialised countries has recently switched from chronic viral infections (e.g. Hepatitis B and Hepatitis C virus) to obesity, making HCC the most rapidly increasing type of cancer in the US, with a similar trend observed in Europe.
Today, we lack a detailed understanding how chronic steatosis develops into NASH and what factors control its transition from NASH to HCC. At the same time no therapeutics exist to efficiently treat NASH, and treatment options for the therapy of late stage HCC are limited and only prolong the life span of patients between 3 to 6 months. In laboratory mice, NASH can be induced by several different diets such as methionine/choline-deficient diet (MCD) or choline-deficient diet (CD) but not by high fat diet (HFD) alone. However, C57BL/6 mice fed with MCD or CD do not develop obesity or metabolic syndrome and the diet has to be discontinued after a few months due to weight loss (up to 40%) or occasional cachexia. Thus, these approaches do not recapitulate NASH and its consequences (e.g. transition to HCC) in humans and appropriate mouse models for genetically and mechanistically dissecting NAFLD induced NASH and NASH triggered HCC development have been thus far lacking. Deficiency in the essential nutrient choline was described in NAFLD patients to exacerbate NAFLD and NASH. Moreover, humans with inadequate choline uptake were shown to have defects in hepatic lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction and ER stress. Based on the clinical observations of choline deficiency to exacerbate NAFDL and NASH patients, we have recently combined choline deficiency with a high fat diet (CD-HFD) as a chronic diet for laboratory mice, which may lead to metabolic syndrome, steatosis, liver damage and NASH, thus delivering the ‘second hit’ that promotes dietary-induced liver carcinogenesis – similar to the human situation. This approach enabled us to establish a chronic mouse model of NASH and metabolic syndrome, triggering subsequent HCC in a wild-type C57BL/6 mouse, in the absence of chemical carcinogens or genetic mutations predisposing to NASH or HCC development (Wolf et al., Cancer Cell, 2014). CD-HFD treated mice display obesity, overweight, insulin resistance, liver damage and fibrosis and hepatic mitochondrial damage, dyslipidemia and NASH as observed in human patients. HCC developed 12 months post CD-HFD start and resembled histologically, genetically and morphologically human HCC. The foreseeable development of NASH into a pandemic disease in Europe will force health authorities to act. It will need strong political efforts to change the thinking of our idea about living, about nutrition as well as about preventive measures each individual person can take to lead a more healthy life. Moreover, research has to be strongly supported to find – besides a European wide political strategy of prevention – therapeutic measures to prevent, to early diagnose and to treat NASH as well as subsequent diseases of NASH. The monetary effort for such political, educational and research programs is justified and will surely be just a small proportion to what will be needed in 20 years from now. The clock is ticking and unfortunately it appears as if European political decision makers rather want to wait until the problem is evident.
Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, RingelhanM, Simonavicius N, Egger M, Wohlleber D, Lorentzen A, Einer C, Schulz S, Clavel T, Protzer U, Thiele C, Zischka H, Moch H, Tschöp M, Tumanov AV, Haller D, Unger K, Karin M, Kopf M, Knolle P, Weber A, Heikenwalder M. “Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes”. Cancer Cell. 2014 Oct 13;26(4):549-64. doi: 10.1016/j.ccell.2014.09.003
Prof. Dr. Mathias Heikenwalder
Institute of Virology, Technische Universität München,
Schneckenburgerstr. 8, 81675 München
Institute of Virology, Helmholtz Zentrum München,
German Research Center for Environmental Health (GmbH),
Ingolstädter Landstraße 1, 85764
Tel: +49 89 4140 7440
Fax: +49 89 4140 7444