Tumor metastasis is the primary cause of mortality in cancer patients and remains the major challenge for cancer therapy. Researchers from the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) in Vienna have now revealed a novel mechanism by which immune cells can spontaneously reject metastatic tumors. Their findings provide a proof-of-principle that it might be possible to develop a "pill" that awakens the immune system to kill cancer metastases.
The immune system is not only responsible for controlling infections, but also for recognizing and destroying cancer cells. Cancer immunotherapy has therefore become one of the breakthroughs in tumor treatment. Austrian scientists, in collaboration with researches in Australia and Germany, have now shown that a molecule called Cbl-b acts as a molecular brake for Natural Killer (NK) cells to reject cancer. Deletion or targeted inactivation of Cbl-b efficiently enhanced the anti-tumor function of NK cells. As a result the progression of metastases in melanoma and breast cancer was significantly inhibited.
Receptor inhibition unleashes NK cells to kill tumor cells
The researchers also identified a molecular path by which Cbl-b blocks NK cell activity towards metastatic tumors. In collaboration with researchers at the Lead Discovery Centre of the Max Planck Society in Germany, they developed an inhibitor molecule directed against the receptors that are regulated by Cbl-b in NK cells, the so called TAM-receptors. "Cbl-b/TAM constitutes an inhibitory pathway for NK cell activation. Blocking TAM receptors via different routes of administration, including giving it as an oral 'pill', markedly reduced metastatic spreading in our model systems," says Magdalena Paolino, first author of the study. Last author Josef Penninger explains: "Metastases are the main reason why cancer patients die. Our results hold promise that it might be possible to develop Cbl-b or TAM inhibitors that empowers the innate immune system to kill cancer metastases. This would be indeed opening the Holy Grail for cancer therapy. However, more research needs to be conducted to advance our findings and to test for possible side-effects."
Solving a mystery in metastases control
Along the way, the researchers also solved a more than 50 year old puzzle in cancer treatment. It has been known for decades that warfarin, the most widely used anticoagulant worldwide, reduces tumor metastasis in model systems. However, the underlying mechanisms remained unclear. "Our findings provide a molecular explanation for this old paradoxon, revealing that warfarin has anti-metastatic effects through inhibiting the novel identified Cbl-b/TAM receptor pathway in NK cells. This also offers the possibility to re-assess the use of vitamin K antagonists such as warfarin in cancer therapy," concludes Magdalena Paolino.
Era of Immunotherapy
Every day, multiple cells in our body become transformed and develop the potential to become cancer cells. However, such tumor cells display unusual antigens that are either inappropriate for the cell type or its environment, and can thus be recognized by the body's immune system. Modern medicine therefore aims to stimulate the patient's immune system to attack the tumor cells. In light of recent findings and future promises, cancer immunotherapy has even been chosen as scientific breakthrough of the year 2013 by the journal Science. The findings made by IMBA scientists now provide evidence that one can find key molecular brakes in innate immune cells that, when modified, allow such cells to seek out and destroy metastatic tumors.
- Magdalena Paolino, Axel Choidas, Stephanie Wallner, Blanka Pranjic, Iris Uribesalgo, Stefanie Loeser, Amanda M. Jamieson, Wallace Y. Langdon, Fumiyo Ikeda, Juan Pablo Fededa, Shane J. Cronin, Roberto Nitsch, Carsten Schultz-Fademrecht, Jan Eickhoff, Sascha Menninger, Anke Unger, Robert Torka, Thomas Gruber, Reinhard Hinterleitner, Gottfried Baier, Dominik Wolf, Axel Ullrich, Bert M. Klebl, Josef M. Penninger. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature, 2014; DOI: 10.1038/nature12998
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