Nanoparticles in 472 Human Cerebrospinal Fluid: Changes in Extracellular Vesicle Concentration and miR-21 Expression as a Biomarker for Leptomeningeal Metastasis
Abstract Background Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggest that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help to diagnose or predict outcomes for LM. Methods We measured nanoparticles in 472 human CSF from controls and patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations. Results NTA revealed nanoparticles distributed at a median 193 nm in size, and 1.74 × 108 /ml in concentration, and those were significantly higher in LM compared to other groups (211 nm vs. 188 nm, p < 0.001 and 2.80 × 108 /ml vs. 1.49 × 108 /ml, p < 0.01, respectively). Changes in NTA-measured nanoparticles (EV from here) concentration after intra-CSF chemotherapy were further examined in non-small cell lung cancer patients with LM (n = 33). Overall survival was longer for patients with increased EV than the others (442 vs. 165 days, p < 0.001). Exosome surface markers (CD9/CD63/CD81) significantly decreased in the EV-decreased group (ratio 0.64, p < 0.0001). MicroRNA-21 expression decreased in this favorable prognostic group, whereas increased in the EV-decreased group (p = 0.003). Conclusions The elevated concentration of extracellular vesicles in cerebrospinal fluid in patients with LM can be a diagnostic marker. Moreover, EV changes combined with microRNA-21 might be a biomarker for monitoring intracranial chemotherapy of LM.