Medulloblastoma (MB) is the most common malignant brain tumor in children. In addition to a poor 5-year survival rate, survivors are often challenged with severe complications from present intensive therapies. Therefore, the development of more effective and better tolerated treatment regimens is essential, and understanding the molecular aspects of MB tumorigenesis is a crucial step in this process.
With increasing focus on characterizing the tumor microenvironments (TMEs) of various cancers, novel opportunities for therapeutic intervention are being revealed. For MB, a new study by Gong et al. reports exciting findings involving tumor-associated astrocytes (TAAs), which are the critical cell type found in the TMEs associated with both primary and relapsed MBs (1). The authors found that complement component C3 is activated (producing the proinflammatory C3a fragment) in MB tissue and that the C3a receptor (C3aR) is expressed on TAAs. C3a binding to C3aR triggers IL-6 and TNF-α expression via the p38 MAPK pathway in the TAAs, and the released TNF-α stimulated MB cell proliferation. Importantly, both in vitro and in vivo assays were then used to show that application of a p38 MAPK pathway inhibitor or specific antagonists of C3aR or the TNF-α receptor (TNF-αR) was sufficient to block this proliferative effect, indicating a C3-p38 MAPK-TNF-α-dependent event. Thus, Gong et al. have demonstrated not only the role of complement pathway activation in astrocyte-mediated MB progression, but also that C3aR and TNF-αR antagonists could prove to be consequential agents for MB treatment.
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- J Neuroinflammation. 2022 Jun 20;19(1):159. doi: 10.1186/s12974-022-02516-9.