Two at One Stroke – How Cells Protect Themselves from Cancer – New Findings of MDC and Charité Researchers

Researchers have known for some time that – paradoxically – oncogenes themselves can activate these cell protection programs in an early developmental stage of the disease. This may explain why some tumors take decades to develop until the outbreak of the disease. The Myc oncogene triggers apoptosis (programmed cell death), inducing damaged cells to commit suicide in order to protect the organism as a whole. By means of chemotherapy, physicians activate this protection program to treat cancer.

The second protection program – not as well understood as apoptosis – is senescence (biological aging). This program is triggered by another oncogene, the ras gene. Senescence stops the cell cycle, and the cell can no longer divide. But in contrast to apoptosis the cell continues to live and is still metabolically active. Professor Schmitt, physician at Charité University Hospital and research group leader at the MDC, was able to show on an animal model for lymphoma that senescence can block the development of early-stage malignant tumors.

Myc oncogene triggers cascade to activate both protection programs
Now, for the first time, Dr. Reimann, Dr. Soyoung Lee, Dr. Christoph Loddenkemper, Dr. Jan R. Dörr, Dr. Vedrana Tabor and Professor Schmitt have provided evidence that the Myc oncogene plays a key role in the activation of both protection programs – without the presence of the ras oncogene. "What is remarkable about this finding is that an oncogene can first trigger apoptosis and interact with the tumor stroma – the tissue that surrounds the tumor which also contains healthy cells – and with the immune system and then is able to switch on signals which lead to tumor senescence," Professor Schmitt said, summarizing how the interaction works.

"Fundamental significance"
According to the researchers‘ findings, the cascade occurs as follows: First the Myc oncogene triggers apoptosis in the lymphoma cells. The dying, apoptotic cells attract macrophages of the immune system, which devour and dispose of the dead lymphoma cells. The thus activated macrophages in turn secrete messenger molecules (cytokines), including the cytokine TGF-beta. It can block the growth of cancer cells in the early stage of a tumor disease. The MDC and Charité researchers discovered that the cytokines in the tumor cells that had escaped apoptosis switch on the senescence program and suppress the cancer cells.

"Our findings promise to have fundamental significance for elucidating the pathogenesis not only of lymphoma cancers, but of cancer in general. Our results indicate that senescence triggered by the immune system’s messenger molecules may be a further important active principle, apart from apoptosis induced by chemotherapy."

At present the researchers in Professor Schmitt’s group are focusing intensively on chemotherapy-mediated senescence. "If by inducing senescence we could obtain a sustained suppression of the cancer cells we can no longer destroy, this would mean exciting new possibilities for therapy," Professor Schmitt said.

*Tumor Stroma-Derived TGF-? Limits Myc-Driven Lymphomagenesis via Suv39h1-Dependent Senescence

Maurice Reimann1,6, Soyoung Lee1,2,6, Christoph Loddenkemper3,6, Jan R. Dörr1,6, Vedrana Tabor2,6, Peter Aichele4, Harald Stein3, Bernd Dörken1,2, Thomas Jenuwein5, and Clemens A. Schmitt1,2

1Charité – Universitätsmedizin Berlin/Molekulares Krebsforschungszentrum der Charité – MKFZ, Berlin, Germany
2Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
3Charité – Universitätsmedizin Berlin/Department of Pathology, Campus Benjamin Franklin, Berlin, Germany
4University Hospital Freiburg, Department of Immunology, 79104 Freiburg, Germany
5Research Institute of Molecular Pathology, Vienna, Austria (present address: Max-Planck-Institute of Immunology, Freiburg, Germany)
6These authors contributed equally to this work
Correspondence: clemens.schmitt@charite.de. Fon +49-30-450 553 687; Fax +49-30-450 553 986

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10, 13125 Berlin, Germany
Phone: +49 (0) 30 94 06 – 38 96
Fax: +49 (0) 30 94 06 – 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/
(idw, 03/2010)

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