Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies

Abstract

Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations.

Keywords: CNS cancers; biomarkers; cerebrospinal fluid; microRNA.

Figure 1

Main types and locations of primary brain tumors: (1) Gliomas, (2) Supratentorial Ependymoma, (3) Infratentorial Ependymoma, (4) Astrocytomas, (5) Medulloblastomas, (6) Meningioma, (7) Craniopharyngioma, (8) Pituitary tumors, and (9) Schwamannomas.

Figure 2

Time line depicting the discoveries of body fluids’ miRNAs and their contribution to cancer detection. CSF: Cerebrospinal fluid. * [36,37,38]; ** Lung [39], Brest [40], Ovarian [41], Cervical [42], Prostate [43], Renal [44], Rectal [45], Gastric [46], Liver [47], Pancreatic [48], Oesophageal [49], Head and neck [50], Thyroid [51], Skin [52], laryngeal [53], Lymphomas [54], Leukaemia [55] and Brain cancer [56,57,58,59]; *** Serum [11,31], Plasma [14], CSF [12]; **** Glioma [2,60,61], PCNSL [29,61,62], Medulloblastoma [22,61], Brain metastasis [2,61].

Figure 3

Depiction of hypothetical origins and types of miRNAs in the CSF: Brain tumor-associated miRNAs in the CSF could be actively released by brain tumor cells to the CSF either enclosed in small membranous microvesicles (e.g., exosomes) or packaged with RNA-binding proteins, e.g., high-density lipoprotein (HDL) or Argonaute (Ago). A second possibility is that miRNAs are passively released in the CSF by dead/dying cancer cells where it remains stably complexed to Ago in the extracellular environment. In addition, freely circulating naked miRNAs (free of exosomes or microvesicles) might be actively secreted from brain tumor cells or passively released from apoptotic or necrotic cells. A third possibility is that a proportion of miRNAs are likely associated with detached brain cancer cells (C.C) that are circulating in the CSF.