Page 62 - Read Online

Bookland et al. J Cancer Metastasis Treat 2019;5:33 I http://dx.doi.org/10.20517/2394-4722.2018.110 Page 5 of 16

Table 1. Summary of commonly implicated miRNA alterations in pediatric brain tumors
MiRNA Tumor types Regulation Potential actions Ref.
MiR-15B Glioma Upregulated Modulates multi-drug resistance and cell migration [16,47]
MiR-21 Glioma Upregulated Targets PTEN, PDCD4, Bcl2 and other tumor [42,47,48]
Medulloblastoma Upregulated suppressor genes.
Ependymoma Upregulated
MiR-23A Glioma Upregulated May regulate cell migration and apoptosis. [44]
MiR-34A Ependymoma Upregulated Regulates apoptosis through SiRT1 [42]
MiR-124A Medulloblastoma Downregulated Modulates glycolysis and cell cycle through CDK6 [43,49]
MiR-125B Glioma Upregulated SHH pathway modulation and apoptosis [16,47-49]
Medulloblastoma Downregulated
MiR-128A Medulloblastoma Upregulated Tumor growth and apoptosis via MYC and Bcl2 [43]
MiR-146B Glioma Upregulated Suppresses stemness and migration [44]
MiR-518B Glioma Upregulated Tumor suppressor acting through PDGFRB [50]
Ependymoma Downregulated

molecules are secreted into the extracellular spaces, predominantly in microvesicles, apoptotic bodies,
and exosomes. Within these vesicles, the miRNA are protected from degradation by endogenous RNases,
making them an unusually stable transcript compared to other forms of RNA. Furthermore, research has
shown that extracellular vesicles from tumor patients tend to be particularly enriched with tumor-related
miRNA [44,45] , and these extracellular vesicles can induced oncogenic protein expression changes in adjacent,
normal cells .
[46]
A myriad of miRNA have been detected in the CSF of adult brain tumor patients, most prominently miR-21,
miR-15b, miR-125b, and miR-223 [16,44,48,49] . These markers individually or in combination with other miRNA
have demonstrated high levels of specificity and sensitivity for gliomas and medulloblastomas [47,49] . However,
there are no published articles at the time of this review analyzing the miRNA in the CSF of pediatric
glioma, embryonal, or ependymal tumor patients in isolation from adult populations. The composition and
clinical applicability of miRNA in the CSF of pediatric brain tumor patients remains a significant knowledge
gap, at present, in the field of pediatric neuro-oncology.

Tumor metabolites and proteins
Aberrations in tumor metabolism and cell signaling pathways relative to normal tissues tends to lead to an
accumulation of well-characterized small molecules that can be used to predict the presence of a malignancy;
[51]
and in certain instances, even predict the molecular signature of that malignancy . Dyscrasias have been
identified in all of the major metabolic cycles employed by cancer cells, including glucose metabolism, the
pentose phosphate pathway, amino acid metabolism, and fatty acid metabolism, as well as many proliferative
signaling pathways, such as the PI3K/AKT and WNT/β-catenin pathways [8,16] . Lactate, isocitrate, citrate, and
D-2-hydroxyglutarate are metabolites known to accumulate in gliomas utilizing aerobic glycolysis as their
dominant ATP source . D-2-hydroxyglutarate, in particular, has been shown to be elevated in the CSF of
[52]
patients with IDH1 mutant gliomas, and its detection in the CSF may be a surrogate for this prognostically
[53]
important mutation .
As with CSF-based miRNA, very little research has been done examining the use of CSF metabolites
to diagnose, track, and molecularly subtype pediatric brain tumors. What work has been done revolves
around monoamine metabolism in pediatric brain tumors. In 1987, Bostrom and Mirkin looked at
the concentrations of homovanillic acid (HVA), hydroxymethoxyphenylethyleneglycol (MHPG), and
vanillylmandelic acid in the CSF of adult and pediatric patients with leukemia, glial, neuroectodermal, or
retinoblastoma tumor histories. In their study, MHPG and VMA were significantly elevated among patients
with primary CNS tumors or neuroblastoma cranial metastases, suggesting that these metabolites increased
[54]
in response to disruption of the BBB or mass effect within the CNS . This work was followed in 2014 by
a study by Varela et al. of 22 pediatric patients with posterior fossa astrocytomas, medulloblastomas,
[55]