| Summary: | Even though paediatric brain tumour survivors are more likely to be diagnosed with a neurodevelopmental or major psychiatric disorder later in life (Hsu et al., 2023), how tumour cells communicate with and alter the development of cortical neurones is poorly understood. One potential mechanism may be intercellular signalling mediated by the secretion of extracellular vesicles (EVs) by cancerous cells within the brain. EVs are small lipid vesicles that can contain proteins, lipids and RNA and have been shown to mediate intercellular signalling between peripheral cancer cells and neuronal models, promoting neurite outgrowth (Amit et al., 2020; Kovacs et al., 2020; Lucido et al., 2019; Madeo et al., 2018). However, it is unknown whether EVs derived from paediatric medulloblastoma cells have a similar effect on mouse primary cortical neurones.
To answer this question, EVs were isolated from two medulloblastoma cell lines (which were derived from a primary tumour and a recurrent tumour from the same patient) using size exclusion chromatography. Medulloblastoma was chosen for this study as it is a highly prevalent and highly survivable paediatric brain cancer. The EVs were then applied to mouse primary cortical neurones (C57BL/6J) after characterising the EVs using nanoparticle tracking analysis (NTA). The morphology of these neurones was then analysed at several time points using immunocytochemistry.
After 24 hours, EVs from both medulloblastoma cell lines accelerated the rate of neuritogenesis in the cortical neurones when compared to the vehicle treated group (One-way ANOVA, p < 0.05). EVs from the recurrent cell line increased axon length in the mouse primary cortical neurones after 24 hours (Kruskal-Wallis test, p < 0.01). The recurrent cell line released more EVs than the primary cell line, but this was not statistically significant (One-way ANOVA, p > 0.05). Importantly, the EV and protein fractions isolated from fresh medulloblastoma cell culture medium did not affect the growth or morphology of the cortical neurones (Kruskal-Wallis test, p > 0.05), suggesting that these findings were not due to any bovine-derived contaminants in the medium.
The results presented show that EVs released from medulloblastoma cell lines can increase the proportion of mouse primary cortical neurones that had at least one neurite and also increase axon length. However, more work is needed to identify the mechanisms behind this and to establish whether this intercellular communication can contribute towards the established relationship between paediatric brain cancer and neurodevelopmental disorders.
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