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Inflammation stimulates the mobility of cancer cells

No. 11b | 19/03/2014 | by Sok/Munich

Joint press release of the German Consortium for Translational Cancer Research and the Ludwig Maximilian University of Munich
Scientists have known for some time that inflammations can promote the development of cancer and the migration of cancer cells through the body. The mechanisms that connect these events, however, have long remained unclear. Scientists from the Munich and Frankfurt partner sites in the German Consortium for Translational Cancer Research (DKTK) have now uncovered a feedback mechanism that explains how chronic inflammation contributes to the development of cancer.

Picture: Rene Jackstadt, Pathologisches Institut der LMU

Malignant tumors spread through the body through a migration of cancer cells. For this to happen, tumor cells growing in one location have to undergo changes that permit them to migrate and invade other tissues. Growing evidence suggests that this transformation can be triggered by inflammation. A chemical messenger in the body called interleukin 6 (IL-6) plays an important role in this process. Both immune cells and tumor cells release IL-6, which goes on to bind to a receptor molecule called interleukin-6 (IL-6R) on the surface of cells. “We have now been able to show that even a short exposure to IL–6 can lead to lasting changes in cancer cells that enhance their mobility and thus contribute to metastasis,” said study head Professor Heiko Hermeking, a researcher at the Institute of Pathology of the University of Munich (LMU).

The scientists studied colon cancer cells in cell cultures to show that IL-6 acts through a feedback loop that depends on a microRNA (an extremely short RNA molecule) called microRNA-34a (miR-34a). Normally miR-34a triggers a protective mechanism that prevents carcinogenesis and metastasis. “The activation of IL-6R cancels this protection,” Hermeking says. “The reason is interference from another factor, called STAT3 factor, which becomes activated and prevents the production of miR-34a by suppressing its gene. We also discovered that if miR-34a is produced, it directly inhibits the IL-6 receptor itself. Without it, in cases where the microRNA is repressed, the cell produces more of the receptor.” This creates a feedback loop that can either suppress or activate cancer-promoting genes, depending on whether miR-34a or IL-6 has the predominant role.

Since inflammations cause our cells to secrete higher amounts of IL-6, the newly discovered pathway may explain how chronic inflammations contribute to the onset of metastasis. “We have now been able to prove this connection for the first time in vivo in the mouse model,” said Hermeking. “We studied mice whose cells are unable to produce the short RNA miRNA-34a in collaboration with Professor Florian Greten of the Georg Speyer Haus at the DKTK partner site in Frankfurt. We discovered that these mutant mice develop inflammation-induced tumors and that they grow invasively. To demonstrate that this feedback loop is also activated in other types of cancer in humans, we studied human breast and prostate cancer cells. Furthermore, an analysis of tumor cells from numerous colorectal cancer patients revealed a link between the activation of the feedback loop and metastasis.”

The discovery of the feedback mechanism offers new potential targets for therapeutic intervention. “STAT3 und IL-6 are already targeted in tumor therapy,” Hermeking says. “The new study suggests that the small RNA, miRNA-34a, may provide another particular therapy target, for example in treating metastasizing colorectal cancer. We think that diagnostic or prognostic applications may also be possible.”

The research projects were supported by German Cancer Aid (Deutsche Krebshilfe) and the German Consortium for Translational Cancer Research (DKTK).

Matjaz Rokavec, Meryem Gülfem Öner, Huihui Li, Rene Jackstadt, Jiang Longchang, Dmitri Lodygin, Markus Kaller, David Horst, Paul K. Ziegler, Sarah Schwitalla, Julia Slotta-Huspenina, Franz G. Bader, Florian R. Greten, Heiko Hermeking. IL-6R/STAT3/miR-34a feedback controls EMT, invasion and metastasis of colorectal cancer. Journal of Clinical Investigation 2014, DOI: 10.1172/JCI73531.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.


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