Achieving a better molecular understanding of the role played in the occurrence of cancer of so-called death receptors which make the progression of pancreatic cancer in particular especially aggressive and almost always fatal – this is the goal of scientists at the Institute for Experimental Tumor Research at Kiel University. The working group headed up by Professor Anna Trauzold and Professor Holger Kalthoff has been working for more than ten years now on these death receptors which can cause the controlled death of the cell, the programmed cell death, in almost all body cells and, in principle, also in cancer cells. This suicide program is typically triggered by receptors on the cell membrane. Cancer cells have developed a wide range of mechanisms, however, with which they can bypass this program. The body's own safety switch is, so to speak, switched off, and resistances are developed to chemotherapy or radiation. The research group in Kiel has recently been able to gain new insights into the mechanisms with which death receptors in cancer cells contribute towards accelerated malignant progressions of the disease: "We were able to show why death receptors paradoxically occur more frequently in many cancer cells and how the reprogramming of the death receptors in the cell is brought about," says Professor Trauzold, explaining the latest findings.
The receptors for programmed cell death are surface molecules on the membrane of cancer cells such as the molecule CD95 or the molecules of the TRAIL-R group. In cooperation with colleagues at the Clinic for General Surgery and Thorax Surgery at the University Clinic of Schleswig-Holstein, Campus Kiel, the research group has now been able to convincingly demonstrate that pancreatic cancer cells can reprogram the signals of these receptors. Instead of the desired cell death program, they then initiate an alternative cell-biological mechanism. The actual function of the cell's protective switch is deactivated, and instead there is the opposite effect of an aggressive proliferation of the disease. "In clinical cancer research, the receptors TRAIL-R1 and TRAIL-R2 are actually regarded as promising therapy approaches, because the associated neurotransmitter is, in principle, capable of killing off cancer cells while causing no damage to normal body cells," says Professor Kalthoff. In this context, however, he says that the effect of the defective safety switch is particularly fatal as a treatment with TRAIL ligands then develops a strong, opposite effect, and can lead to accelerated proliferation of the tumor. This is in line with the observation of the Kiel researchers that pancreatic cancer cells often produce this neurotransmitter themselves, thus stimulating themselves.
The precise distribution of the death receptors plays an important role in this reprogramming of the death receptors. Analyses by the scientists in Kiel have shown that these molecules are often not positioned on the cell membrane where they normally trigger the cell death. Instead they are in the nucleus of the cancer cell and occur there more frequently. The research group was already able to demonstrate this in 2014 in the prominent international scientific journal Gastroenterology. There they cause various alternatives processes to the cell death program whose result is increased growth and increased migration of the cancer cells. In a current publication in the scientific journal Cancer Cell in April of this year, the Kiel researchers in collaboration with the research group under Professor Henning Walczak from the University College in London have now shown that the TRAIL receptor receives support in its undesired activities from a long-known cancer gene: in many malignant tumors and in almost all pancreatic cancer cells there is a mutation of the so-called KRAS gene. This cooperates with the death receptor in such a way that the latter changes its program from the initiation of the cell death to growth and proliferation of cancer cells – even when the death receptor is on the "right" position on the cell membrane.
"Our results mean that even in conventional cancer treatments with chemotherapy or radiation, the role of the death receptors and their influence on the proliferation of cancer cells will have to be given greater consideration in the future," says Professor Trauzold. At the same time, the investigations of the Kiel research group suggest new possible approaches to overcome the resistance to therapy of cancer cells. Experiments with cell cultures show that a very high occurrence of death receptors on the cell surface ensures that even pancreatic cancer cells die off. Trauzold and Kalthoff see an urgent need for further research into the question as to how the receptors can be brought back to their position on the cell surface of cancer cells where they can be effectively activated, for example by inhibition of the undesired signal pathways.
Verena Haselmann, Alexandra Kurz, Uwe Bertsch, Sebastian Hübner, Monika Olempska–Müller, Jürgen Fritsch, Robert Häsler, Andreas Pickl, Hendrik Fritsche, Franka Annewanter, Christine Engler, Barbara Fleig, Alexander Bernt, Christian Röder, Hendrik Schmidt, Christoph Gelhaus, Charlotte Hauser, Jan–Hendrik Egberts, Carola Heneweer, Anna Maria Rohde, Christine Böger, Uwe Knippschild, Christoph Röcken, Dieter Adam, Henning Walczak, Stefan Schütze, Ottmar Janssen, F. Gregory Wulczyn, Harald Wajant, Holger Kalthoff, Anna Trauzold, Gastroenterology: Nuclear Death Receptor TRAIL-R2 Inhibits Maturation of Let-7 and Promotes Proliferation of Pancreatic and Other Tumor Cells
Silvia von Karstedt, Annalisa Conti, Max Nobis, Antonella Montinaro, Torsten Hartwig, Johannes Lemke, Karen Legler, Franka Annewanter, Andrew D. Campbell, Lucia Taraborrelli, Anne Grosse-Wilde, Johannes F. Coy, Mona A. El-Bahrawy, Frank Bergmann, Ronald Koschny, Jens Werner, Tom M. Ganten, Thomas Schweiger, Konrad Hoetzenecker, Istvan Kenessey, Balazs Hegedüs, Michael Bergmann, Charlotte Hauser, Jan-Hendrik Egberts, Thomas Becker, Christoph Röcken, Holger Kalthoff, Anna Trauzold, Kurt I. Anderson, Owen J. Sansom, Henning Walczak
Cancer Cell: Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis http://dx.doi.org/10.1016/j.ccell.2015.02.014
Website of the research group Experimental Tumor Research:
Research report of the Cancer Institute at University College London:
Prof. Dr. Anna Trauzold
Institute for Experimental Tumor Research