Liver cancer (hepatocellular carcinoma) is one of the most common malignancies worldwide. In the majority of cases hepatocellular carcinoma develops after liver damage due to chronic Hepatitis B- or C virus infections. Researchers at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and Hanover Medical School have now revealed how an intact immune system is able to recognize and eliminate premalignant liver cells at an early stage. Cells which are at a high risk for malignant transformation – e.g. as a result of chemical stress or radiation – often exit from their normal life cycle and enter a state of arrest, known as “senescence”. Together with co-workers from other research institutions the HZI scientists discovered that such senescent cells make themselves visible for the immune system, e.g. by secreting factors which can attract immune cells. As a result, senescent cells are continuously cleared by the immune system, a mechanism which was designated as “senescence surveillance”. The researchers found that a continuous immune surveillance of senescent hepatocytes is important to suppress the development of liver cancer and they propose that a mechanism, similar to the one shown in liver, may play a key role in tumor suppression in other organs as well. The results of the study have now been published in an advance online release by the renowned scientific journal “Nature”.
Liver tissue section with a senescent liver cell directly in the center of the image. The cell is surrounded by small cells, attacking immune cells that have recognized and will eliminate the senescent cell (Hämatoxylin-Eosin-stained section).
At the end of their life cycle or if their genetic information gets damaged, cells either undergo a program of controlled cell death or, alternatively, enter a kind of “hibernation”, the so-called cellular senescence program. This arrest prevents defective cells from uncontrolled proliferation and thus avoids the formation of tumors. Professor Lars Zender, head of the HZI research group Chronic Infections and Cancer and his team were able to demonstrate that the immune system plays a crucial role in the continuous surveillance of these resting cells. “By this means it prevented that the damaged cells can acquire further alterations which may result in the development of aggressive tumors”, explains Lars Zender.
To analyze how the senescence program and the immune system interact to prevent tumor development Lars Zender and his team used a genetic method to induce the senescence program in liver cells of laboratory mice. “It was impressive to see, how efficient the immune system recognizes and eliminates modified cells”, says Zender. After a few weeks the modified, senescent cells were eliminated.
In immunodeficient mice which are missing so called T-helper cells, researchers were able to observe that senescent liver cells were not cleared but rather progressed into liver carcinomas. “This clearly shows how important the surveillance of senescent cells is – a task carried out by the immune system, and specifically coordinated by T-helper cells”, says Zender.
This newly identified mechanism may also help to explain why HIV-positive patients have an increased risk of developing liver cancer. To investigate this phenomenon, researchers determined the number of senescent cells in the livers of patients with chronic Hepatitis C virus infection who were also HIV-positive. The results were compared to the numbers of senescent cells in livers of Hepatitis C virus infected patients without concomitant HIV infection. “As expected, in the group of Hepatitis C/HIV co-infected patients the number of senescent cells were strongly increased”, says Zender. “In HIV patients, the activity of T-helper cells is impaired and, as a consequence, - senescent liver cells probably cannot be eliminated effectively.”
The authors of the study hope that the newly discovered mechanism will enable new strategies for cancer prevention and therapy.
Senescence surveillance of premalignant hepatocytes limits liver cancer development. Tae-Won Kang, Tetyana Yevsa, Norman Woller, Lisa Hoenicke, Torsten Wuestefeld, Daniel Dauch, Anja Hohmeyer, Marcus Gereke, Ramona Rudalska, Anna Potapova, Markus Iken, Mihael Vucur, Siegfried Weiss, Mathias Heikenwalder, Sadaf Khan, Jesus Gil, Dunja Bruder, Michael Manns, Peter Schirmacher, Frank Tacke, Michael Ott, Tom Luedde, Thomas Longerich, Stefan Kubicka and Lars Zender. Nature, Advanced Online Publication, DOI: 10.1038/nature10599