Not only the number of migrating cancer cells determines the risk for metastasis but also their characteristics, scientists from the German Cancer Research Center (DKFZ) have now reported in Nature Communications. For circulating cancer cells to be able to invade tissues and settle at other sites in the body, they have to exhibit a specific polarity. This discovery might in future help to better predict individual risk for metastasis and find appropriate therapies that can reduce it.
Metastatic tumors, the dreaded "daughter tumors", form when cancer cells break away from a tumor and migrate via the lymph and the bloodstream in order to finally settle at some distant site in the body. However, the quantity of circulating cancer cells in the body is not the only factor that determines a patient's risk of developing metastatic sites. "Some patients display high quantities of circulating tumor cells and have no or only a few metastatic sites while in others who suffer from many metastases, hardly any migrating tumor cells can be found," said Mathias Heikenwälder from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.
The team led by Heikenwälder has therefore taken a closer look at the properties of migrating cancer cells. In human cancer cells as well as in patients with different types of cancer, and also in mice, they observed that a portion of the circulating cancer cells exhibit a specific polarity. "Under the microscope, this looks as if the cells had a kind of nose," Heikenwälder described. Two cytoskeletal proteins called ezrin and merlin play a key role in the formation of this nose. Furthermore, the scientists also found that the number of freely circulating tumor cells exhibiting this special polarity correlates with the risk of developing metastasis, both in human tumor cell lines and in mice.
"This polarity seems to help the free cancer cells return from the blood vessels into body tissue," explains Anna Lorentzen, who is the first author of the publication. With the polarized end, i.e., with the nose, the cells attach to the endothelial layer lining the interior of the vessels. Subsequently, the pole is shifted to the side facing the attachment site and the tumor cell migrates through the endothelial layer into the tissue.
As a cross-check, the researchers used a cell-biological trick to block polarization of the circulating cells. Both in culture and in mice, the manipulated cells were no longer able to attach efficiently to endothelial cells.
With this discovery, the DKFZ researchers have not only found a new mechanism promoting the formation of metastatic sites. "We also have found a link that might in future be used to better predict and even reduce the risk for metastasis in cancer patients," Heikenwälder stressed.
Anna Lorentzen, Paul F. Becker, Jan Kosla, Massimo Saini, Kathrin Weidele, Paolo Ronchi, Corinna Klein, Monika J. Wolf, Felix Geist, Bastian Seubert, Marc Ringelhan, Daniela Mihic-Probst, Knud Esser, Marko Roblek, Felix Kuehne, Quentin Mu?ller, Kathleen Schuck, Sebastian Lange, Daniel Hartmann, Saskia Spaich, Olaf Groß, Jochen Utikal, Sebastian Haferkamp, Martin R. Sprick, Amruta Damle-Vartak, Nachiket Vartak, Alexander Hapfelmeier, Norbert Hu?ser, Ulrike Protzer, Andreas Trumpp, Dieter Saur, Christoph A. Klein, Bernhard Polzer, Lubor Borsig and Mathias Heikenwalder: Single cell polarity in liquid phase facilitates tumour metastasis. Nature Communications, 2018, DOI: 10.1038/s41467-018-03139-6
A picture is available for Download: https://www.dkfz.de/de/presse/pressemitteilungen/2018/bilder/ezrin.jpg
Picture Caption: A human melanoma cell exhibits polarity which helps attaching to the endothelial layer of the blood vessel (ezrin stained in orange)
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The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
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