Feb. 3, 2013 The research team of Prof. Dr. Martin Röcken from the Department of Dermatology of the University Medical Center Tübingen has shown for the first time that the immune system is able to drive tumours and tumour cells into a form of permanent dormancy (1). The resulting growth arrest allows tumour control in the absence of cancer cell destruction. This permanent dormancy -- scientifically known as senescence (2, 3) -- may persist for the whole life of the organism. Thus, immunotherapy can prevent tumour development without destroying the cells (1, 4).
Prof. Martin Röcken, Director of the Department of Dermatology of the University Medical Center Tübingen, outlines the current state of tumour therapy as follows: "About 50 years ago the former President of the United States of America Richard Nixon declared the "War on cancer." Strong financial and logistic efforts were undertaken and thought to overcome this devastating disease in relatively short time. At this time, researchers and clinicians learned to use chemotherapeutics or natural killer cells to directly attack the tumour cells and to destroy cancers including their environment. This led to several very important, partly brilliant achievements in the understanding of tumour development and to improved cancer diagnostics. What's more, the treatment of several different cancers was markedly improved by new and innovative operation techniques, radiation, chemo- and immunotherapy. However, the main goal, ie. the decisive victory on cancer, remained absent." "[For some time]," Prof. Röcken explains further, "doubts were raised about the strategy of the "War on cancer" which exclusively focussed on cancer destruction, as for example published in an essay in the journal The Lancet and other recent publications (5, 6, 7)."
Importantly, the work of the Röcken group revealed that immune responses also drive tumours of human origin into senescence. The human body apparently defends itself from cancer by inducing the senescence program in tumour cells thereby inhibiting tumour growth (1).
In this line, two well known signalling molecules of cancer therapy and immunology of infectious diseases move again in the center of attention: the interferons and tumor necrosis factor. Repeatedly, a bulk of researchers and clinicians tried to use these molecules and other techniques to destroy the tumour cells and their supplying blood vessels, and so did the scientists from Tübingen. Surprisingly, however, the Röcken group found that a combination of both signalling molecules, interferon and tumor necrosis factor, stopped the tumour growth in vivo without any signs of tumour or tissue destruction.
In animal experiments, the efficacy of immunotherapy-induced senescence proved to be much better than any other therapy based on "cancer destruction" (4). Most importantly, the common action of both signalling molecules, interferon and tumor necrosis factor, also stopped the growth of human tumours (1).
In the course of a natural immune response, the research team even detected senescence induction in regressing malignant tumours of cancer patients . Seven years ago, it was shown in principle that cancer cells can be shifted towards permanent dormancy or senescence (2, 3). Those theoretical insights were now successfully transferred into a therapeutic approach, here an immunotherapeutic regimen (1, 4).
The new therapeutic option will enable clinicians to approach their goal of a life-prolonging, mainly adverse effect-free cancer therapy. "It is very likely that we can't win the "War on cancer" by exclusive military means.," Prof. Röcken resumes. "Instead, it will be an important milestone to restore the bodies´ immune control of malignant tumours."
1. Braumüller et al. M. T-helper-1-cell cytokines drive cancer into senescence. Nature, in press (2013).
2. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720-724 (2005).
3. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660-665 (2005).
4. Müller-Hermelink, N. et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13, 507-518 (2008).
5. Sporn, MB. The war on cancer. The Lancet 347, 1377-1381 (1996).
6. Gatenby, RA. A change of strategy in the war on cancer. Nature 459, 508-509 (2009).
7. Röcken, M. Early tumor dissemination, but late metastasis: insights into tumor dormancy. J. Clin. Invest. 120, 1800-1803 (2010).
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- Heidi Braumüller, Thomas Wieder, Ellen Brenner, Sonja Aßmann, Matthias Hahn, Mohammed Alkhaled, Karin Schilbach, Frank Essmann, Manfred Kneilling, Christoph Griessinger, Felicia Ranta, Susanne Ullrich, Ralph Mocikat, Kilian Braungart, Tarun Mehra, Birgit Fehrenbacher, Julia Berdel, Heike Niessner, Friedegund Meier, Maries van den Broek, Hans-Ulrich Häring, Rupert Handgretinger, Leticia Quintanilla-Martinez, Falko Fend, Marina Pesic, Jürgen Bauer, Lars Zender, Martin Schaller, Klaus Schulze-Osthoff, Martin Röcken. T-helper-1-cell cytokines drive cancer into senescence. Nature, 2013; DOI: 10.1038/nature11824
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