25 September 2019

Scientists have revealed the molecular mechanism which enables lymphoma to form metastases in the central nervous system (CNS).

Using a mouse model, researchers at the German Cancer Research Centre (DKFZ) in Heidelberg demonstrated that chronic inflammatory processes in ageing brains lead to lymphoma cells entering the brain tissue and staying there instead of being released back into the blood.

The team also identified key molecules involved in this mechanism in tissue samples from patients with CNS lymphomas. They now hope to start to develop new therapies to help prevent the formation of secondary CNS lymphomas.

CNS lymphomas are a rare and very aggressive. To date, it has been unclear how lymphoma cells enter the brain and remain there.

Prof Mathias Heikenwälder of DKFZ and colleagues from the Helmholtz Centre Munich and TU Munich worked to examine inflammatory processes in the brain. They bred genetically modified mice in which NF-κB, an important factor in connection with chronic inflammation in the brain, is permanently active in the CNS.

“Very early on, these animals develop inflammation in the brain. We also find such inflammatory reactions in brains from lymphoma patients whose tissues we've examined,” said Prof Heikenwälder.

When the researchers injected lymphoma cells into the genetically modified mice, they developed metastatic lymphomas in the CNS. This did not happen in mice without chronic NF-κB activation. 

“Using a special microscopy technique, we observed that the lymphoma cells enter the brain from the blood vessels in normal mice, too,” said Prof Heikenwälder. “However, in these animals, they do not remain in the brain; instead, they go back into the peripheral blood vessels. In the genetically modified rodents, the lymphoma cells that have entered the brain remain there. So we wanted to know what keeps them there.”

The team found that in healthy brains without inflammation, the signalling molecule CXCL12 ensures both white blood cells and lymphoma cells leave the brain tissue and go back into the blood vessels. However, the signalling molecule CCL19, which is stimulated by NF-κB, is an “important antagonist” of the CXCL12.

“The two messenger substances [CXCL12 and CCL19] fight so to speak over where the lymphoma cells go,” said Prof Heikenwälder. “In the event of inflammation with increased NF-κB activity, there is also more CCL19, which means it gains the upper hand and keeps the lymphoma cells in the brain.”

Prof Heikenwälder said the research had not only ascertained for the first time how secondary CNS lymphomas arise, but has also identified inflammatory processes as potential risk factors for CNS lymphomas.

“Now we can think about whether and how inflammation in the brains of lymphoma patients can be treated to prevent the development of secondary CNS lymphomas,” he added.

Source: O'Connor, T., Zhou, X., Kosla, J., Adili, A., Garcia Beccaria, M., Kotsiliti, E., Pfister, D., Johlke, A.L., Sinha, A., Sankowski, R., Schick, M., Lewis, R., Dokalis, N., Seubert, B., Höchst, B., Inverso, D., Heide, D., Zhang, W., Weihrich, P., Manske, K., Wohlleber, D., Anton, M., Hoellein, A., Seleznik, G., Bremer, J., Bleul, S., Augustin, H.G., Scherer, F., Koedel, U., Weber, A., Protzer, U., Förster, R., Wirth, T., Aguzzi, A., Meissner, F., Prinz, M., Baumann, B., Höpken, U.E., Knolle, P.A., von Baumgarten, L., Keller U., Heikenwälder, M. (2019) “Age-related gliosis promotes central nervous system lymphoma through CCL19-mediated tumor cell retention”, Cancer Cell, doi: 10.1016/j.ccell.2019.08.001


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