Heikenwälder
Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Heikenwälder
Completed research project
| Title / Titel | Molecular and cellular dissection of hepatocellular carcinogenesis in mice with chronic hepatitis | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | The link between inflammation and carcinogenesis in general and more specifically in liver has been acknowledged for a long time (1, 2). Hepatocellular carcinoma (HCC) is the most common liver cancer. It is associated with chronic liver damage as seen in Hepatitis B/C virus infection, chronic drug use and alcohol abuse as well as autoimmune diseases and typically accompanied by chronic hepatitis. Interestingly, only 30-40% of all patients with chronic hepatitis develop HCC and the molecular, genetic and cellular events that drive chronic hepatitis induced liver carcinogenesis remain elusive. Due to the lack of mouse models with chronic hepatitis induced HCC research has focused either on (a) animal studies using carcinogenic substances to induce liver cancer or (b) on patient samples. (a) In the past, scientists have used carcinogenic substances such as diethylnitrosamine (DEN) to induce liver cancer in mice (1, 4). The pathogenesis of HCC in these mouse models differs from that in humans and thus may not be directly comparable to chronic hepatitis induced human HCC. However, DEN-induced HCC might have a genetic signature similar to that of human HCCs with poor prognosis (5). (b) Alternatively, research in humans has centred on patient liver samples, with sometimes limited ability to dissect cellular and molecular events of chronic hepatitis induced HCC. Recent work with liver samples from patients with chronic hepatitis associated HCC has demonstrated that proinflammatory cytokines, Lymphotoxin (LT) and are specifically upregulated on hepatocytes and oval cells (3). In addition, a recent study has provided evidence that LT receptor and LT are actively involved in hepatitis C virus replication (6). In order to establish a mouse model for chronic hepatitis induced HCC we have decided to ectopically express LT and in hepatocytes (AlbLT mice). We could show that these mice develop laboratory evidence and histological signs of insidiously developing chronic hepatitis at 6 to 9 months of age persisting through life time (7). Indeed, 17/54 AlbLT mice mice aged 300 days developed hepatocellular carcinoma (Heikenwalder et al., in preparation). In the proposed Ph.D. project, Monika Wolf will aim at studying the molecular and cellular prerequisites of HCC development through chronic inflammation. |
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| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Foundation Roche Research Foundation |
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| Duration of Project / Projektdauer | Apr 2008 to Sep 2009 |