In order to colonize other organs and grow into metastases, tumor cells that detach from the parent tumor need to manipulate their new microenvironment and create a 'metastatic niche'. Scientists from the German Cancer Research Center and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine* have now discovered that some cancer cells stimulate connective tissue cells in their environment to release transmitters that promote metastasis. This discovery plays a key role in better understanding how these dangerous metastases arise.
If cancer cells detach from a tumor and move around the body, they are entering enemy territory. Many detached cancer cells do actually die before they manage to colonize other tissues and form metastases, because the body's immune system is geared toward protecting healthy tissue from intruders of all kinds. Moreover, these migrant cancer cells can only survive if they manage to manipulate the cells in their new environment to create a metastatic niche that helps the migrant cancer cells survive.
Thordur Oskarsson and his team at the German Cancer Research Center (DKFZ) and at the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) are investigating how this metastatic niche arises. The scientists have now discovered both in cell cultures and in mice that some particularly aggressive breast cancer cells induce a situation similar to inflammation in lung tissue. This ultimately ensures that they can colonize the tissue and grow into metastases.
Specifically, the detached tumor cells release two inflammatory signaling molecules, known as interleukins, which stimulate fibroblasts in the lung to release two further inflammatory signaling molecules into the microenvironment: CXCL9 and CXCL10. In turn, these attach to a receptor molecule that several aggressive migrant cancer cells carry on their surface, marking a decisive step in the process of growing into a metastasis. These aggressive breast cancer cells thus benefit directly from the inflammation and from the signaling molecules CXCL9 and CXCL10.
"Interestingly, the very tumor cells that stimulate the fibroblasts to produce CXCL9 and CXCL10 also have the relevant receptor for these cytokines and thus benefit from the process," explained Maren Pein, lead author of the study. "That underlines how crucial the cellular communication between the detached cancer cells and the fibroblasts in their new microenvironment is for metastasis."
Furthermore, the scientists prevented metastasis in the lung in an experimental setting by treating mice with an inhibitor that blocked the receptor molecule on the cancer cells.
Tumor tissue samples from patients show that this cellular interaction probably plays a role in breast cancer patients too: Thus cancer cells that carry the relevant surface receptor and can therefore harness the interaction with fibroblasts to form metastases are also found in patients with metastatic breast cancer.
Oskarsson emphasized that it was still too early to identify a new treatment approach from these findings. "Our work is initially designed to help understand the underlying mechanisms that are necessary for metastases to actually arise," he explained. "But we obviously hope that this better understanding will lead to us being able to prevent metastases some time in the future."
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*The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) is a partnership between DKFZ and the Dietmar Hopp Foundation
Maren Pein, Jacob Insua-Rodríguez, Tsunaki Hongu, Angela Riedel, Jasmin Meier, Lena Wiedmann, Kristin Decker, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sütterlin, Andreas Schneeweiss, Andreas Trumpp and Thordur Oskarsson: Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs Nature Communications 2002, DOI: 10.1038/s41467-020-15188-x
A photo to accompany the press release is available for download at: https://www.dkfz.de/de/presse/pressemitteilungen/2020/bilder/Lungenmetastase.jpg
Photo caption: Lung metastasis in a breast cancer patient: the arrows indicate fibroblasts (brown) that communicate with metastatic cancer cells. Cell nuclei are stained blue.
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The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. At DKFZ, more than 1,300 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.
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Jointly with partners from Heidelberg University Hospital, DKFZ runs the National Center for Tumor Diseases (NCT) located in Heidelberg and Dresden, and, also in Heidelberg, the Hopp Children's Cancer Center (KiTZ). In the German Cancer Consortium (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 at the NCT and DKTK sites is an important contribution to the endeavor of translating promising approaches from cancer research into the clinic in order to improve 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.
Journal
Nature Communications