Abstract
Simple SummaryLeptomeningeal metastasis (LM) is a terminal stage cancer manifestation to whole neuraxis via cerebrospinal fluid (CSF). Up to now, LM has no solid biomarkers for disease progression or treatment response. Extracellular vesicles (EVs) in biofluids have been recently studied to evaluate cancer diagnostics and prognostics. Here, we measured nanoparticles in human CSF from 472 patients with both Dynamic Light Scattering and Nanoparticle Tracking Analysis. We found that the size distribution and concentration of nanoparticles in LM-disseminating CSF were significantly different from those in non-LM CSF samples. Changes in EVs concentration showed a potential biomarker for the therapy response in patients undergoing intra-CSF chemotherapy. Our suggestion of combined biomarker of EVs concentration and onco-miR for LM chemotherapy could help physicians to perform this possible neurotoxic treatment with appropriate monitoring tools for the effectiveness.Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes for LM. We measured nanoparticles in 472 human cerebrospinal fluid (CSF) from patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations. NTA revealed that the concentration of CSF nanoparticles was significantly increased in LM compared to other groups (2.80 × 108 /mL vs. 1.49 × 108 /mL, p < 0.01). Changes in NTA-measured nanoparticles concentration after intra-CSF chemotherapy were further examined in 33 non-small cell lung cancer patients with LM. Overall survival was longer for patients with increased EV than the others (442 vs. 165 days, p < 0.001). Markers of extracellular vesicles (CD9/CD63/CD81) significantly decreased in the EV-decreased group. MicroRNA-21 expression decreased in this favorable prognostic group, whereas it increased in the EV-decreased group. In conclusion, the elevated concentration of extracellular vesicles in cerebrospinal fluid in patients with LM may be a predictive marker for survival duration. Moreover, EV changes combined with microRNA-21 might be a biomarker for monitoring the efficacy of intracranial chemotherapy of LM in non-small cell lung cancer patients.
Highlights
Cerebrospinal fluid (CSF) circulates in the central nervous system (CNS) and transports neurotransmitters, hormones, and other actively or passively secreted metabolites from brain cells [1].Analyzing CSF could detect CNS disease activities such as brain tumors [2,3,4]
The Leptomeningeal metastasis (LM) groups showed a significantly higher number of nonwhich were measured by Nanoparticle Tracking Analysis (NTA) as extracellular vesicles (EVs) (Supplementary Figure S4)
We particles abolished after proteinase K treatment, these non-vesicular particles were mainly at a size of did not identify those particles abolished after proteinase K treatment, these non-vesicular particles more than 200 nm, and they can be a result of leptomeningeal disease activity, at which cancer cells were mainly at a size of more than 200 nm, and they can be a result of leptomeningeal disease activity, destroy the surface membrane of brain and spinal cord
Summary
Cerebrospinal fluid (CSF) circulates in the central nervous system (CNS) and transports neurotransmitters, hormones, and other actively or passively secreted metabolites from brain cells [1]. Analyzing CSF could detect CNS disease activities such as brain tumors [2,3,4]. Recent studies have examined nanoparticles in human biofluids and their role in normal physiology and disease processes [5,6]. Extracellular vesicles (EVs) are one of the most abundant nanoparticles in biofluids, appearing to stably maintain internal metabolites [7,8]. Human CSF has been studied to be rich in nanoparticles, including EVs and extracellular RNAs [7,8,9]. A behavior of EVs in CNS tumor and metastases is not well known due to low level of these materials and a hardship to acquire
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