Understanding liver cancer development in Europe: Novel mouse models for pre-clinical trials.
Today, liver cancer – also called hepatocellular carcinoma (HCC) – reflects the 3rd most common cause for cancer related death world-wide with approximately 800.000 deaths per year. In stray African or Asian countries HCC has become the most common cause for cancer-related death, mainly as a consequence of viral infections with Hepatitis B and C- viruses (HBV; HCV). As of today 550 million people are persistently infected with HBV or HCV and are at risk to develop liver cancer. Besides, chronic or acute intoxication (e.g. chronic alcohol or drug abuse, uptake of aflatoxin-b) is a known risk factor to cause HCC, but responsible only for a relatively small number of cases. Additionally to HBV or HCV induced HCC, which for sure represent the largest clinical health problem causing HCC, our life style – mainly in industrialized countries has become a major factor driving inflammatory liver disease – thereby strongly increasing the risk to develop liver cancer. Combination of high fat, high sugar diet and little exercise additionally worsen this problematic development. Indeed, it was shown that dietary and genetic obesity promotes non-alcoholic steatohepatitis (NASH; (pathologic hepatic lipid deposition and hepatitis) and tumorigenesis. Notably, in Europe and the USA HCC is increasing, reflecting the fastest increasing cancer type in the USA, and prospectively this trend will develop further in the USA, in Europe and other industrialized countries.
Importantly, HCC do not resemble a single entity but rather a diverse spectrum of cancer subtypes in humans. In many cases individual patients carry different liver cancer-subtypes, not only distinct in their morphology, their genetics and epigenetics but also different in their composition of inflammatory cells. Personalized therapeutic approaches will be needed in the future – depending on the tumor-type, the tumor-stage as well as the individual composition of distinct liver cancers in one and the same patient.
Due to the above outlined problems a systemic, therapeutic approach to treat liver cancer in humans is not available – underlining the urgent need for new targets that can be included basic research and clinical trials. Given the effort that has been invested in the past to understand and treat HCC – either induced by viruses, high fat diet or chronic alcohol consumption – clinical success has been extremely small. Although these regimens are successful approaches to prolong the life span of liver cancer patients – these drugs are rather palliative than curative. Up to now liver transplantation has been the most effective way to prolong the live-span of patients – but in 50% of the cases cancer is coming back.
In the light of the above modeling liver cancer in rodents appears to be very important. Stratification of HCC in mice and human is needed to identify the respective HCC subtypes and – hopefully – the individual efficient therapies for the stratified patient cohorts.
We recently have established several models to mimic virus or toxin-driven liver damage and cancer. This includes models of chronic liver inflammation (mimicking virus-induced liver inflammation), chronic liver damage or high fat diet induced liver cancer. Our mouse models were stratified in comparison to human specimens on histological, genetic, post-translational and transcriptional level. These experiments indicated that indeed mouse models exist that recapitulate to high degree human pathology on various levels and that these mouse models – reflecting particular HCC subtypes that could be used to treat the respective HCC subtypes in human.
Institute of Virology
TU Munich
Schneckenburgerstr. 8
81675 München
Helmholtz Zentrum München
German Research Center for Environmental Health (GmbH)
Institute of Virology
Ingolstädter Landstraße 1
85764 Neuherberg
Germany
Tel: +49 89 41 40 74 40
Fax: +49 89 41 40 74 44
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