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al. investigated the CSF proteome from 33 children with number of other potential CSF protein biomarkers for CNS
[60]
MB and compared it against the CSF proteome from 25 age- cancers have been reported in the literature such as Insulin-
matched controls using two-dimensional gel electrophoresis. like growth factor binding protein 2 (IGFBP2), Insulin-like
In their study levels of prostaglandin D2 synthase (PGD2S) growth factor binding protein 3 (IGFBP3), Polysialic-
[66]
were found to be six-fold significantly decreased in the CSF neural cell adhesion molecule (PSANCAM), Total
[63]
of tumor samples most likely representing a host response Tau (t-Tau), Tumor necrosis factor (TNF) alpha and
[68]
[67]
to the presence of the tumor. Usually biomarkers are CSF , S-100, Neuron-specific (NSE), neuron growth
[61]
[69]
[70]
often thought to be elevated in a disease state compared factor, HCG. Apolipoprotein A-II, MIC-1/GDF15,
[72]
[71]
[73]
to normal levels however candidate negative diagnostic Elevated expression of such markers in the CSF was found
marker such as PGD2S could be useful for detecting MB to be relatively specific for brain cancer [74,75] however
as well as recurrence of the disease. On the other hand it sensitivities and specificities have widely varied. [26]
has to be said that while negative biomarkers are potentially
useful, their relationship to tumor biology is less direct and MICRORNAS
more highly complex in comparison to proteins that are
over-expressed in tumor associated samples. Desiderio MicroRNAs (miRNA) are short, non translated fragments
[40]
et al. investigated CSF from 14 children with posterior of RNA that bind to 3’ untranslated regions of messenger
[62]
fossa tumors (6 Pilocytic astrocytoma, 5 Medulloblastoma, RNA and repress protein translation in several molecular
[26]
3 Ependymoma and 5 nontumoral control). In their study the pathways. The discovery of miRNAs role in controlling
CSF proteomics demonstrated the potential biomarker role essential regulators of key pathways implicated in
of the hemoglobin subunit beta fragments (peptides LVV- development of CNS tumors make them a powerful tool for
and VV-hemorphin-7) in posterior cranial fossa pediatric detection of cancer, risk assessment and prognosis. During
brain tumors. Both LVV- and VV-h7 were detectable in the past decades, great efforts have been made in conducting
control-CSFs but absent in the patient CSFs collected research evaluating the diagnostic value of miRNAs in
[76]
before surgery (i.e. in presence of tumor). Interestingly CNS cancer’s tissue. However, a major drawback of
both LVV- and VV-h7 were also absent in the CSF collected the tissue-based approach centers on the need for invasive
6 days after the resection tumor in patients with tumor surgical procedures in sample collection. MiRNAs have
relapse. Their data suggest that analysis in post-surgery been found to stably coexist in several body fluids including
CSF could be used to predict patient prognosis. However, CSF which can be collected with minimal invasiveness and
[26]
it will be interesting to evaluate the cancer specificity of permit following the disease over time. In this context
LVV- and VV-h7 in relation to other forms of CNS pediatric several reports have described that deregulated miRNAs in
tumors. Finally levels of polysialic-neural cell adhesion CSF are closely associated with the clinical course of CNS
molecule (PSANCAM), considered a marker of developing malignant tumors. [2,77-82]
neuron, were found to be significantly higher in CSF from
[77]
MB patients that are refractory to treatment or those who For example Baraniskin et al. found that combined
relapsed, than patients in remission. [63] expression analyses of miR-21 and miR-15b were able to
distinguish patients with glioma from controls with various
Atypical teratoid/rhabdoid (AT/RT) tumor is a rare, highly neurologic disorders, including patients with carcinomatous
malignant tumor of the CNS most commonly found in brain metastases and primary CNS lymphoma with
children less than 5 years of age. Osteopontin (OPN) a bone accuracy of 90% sensitivity and 100% specificity. While
matrix glycoprotein levels were found to be significantly Teplyuk et al. reported that combined analysis of a
[2]
elevated in patients with AT/RT. Clinical studies identified group of seven CSF miRNAs enabled the discrimination
OPN as a potential diagnostic marker in ovarian, breast, between GBM and metastatic brain cancers with more than
colon, prostate, and lung cancers. Using enzyme-linked 90% accuracy. miRNA-21 and miR-10b expression levels
[64]
immunosorbent assay and immunohistochemical analysis, were significantly increased only in brain tumor lesions
Kao et al. investigated plasma, CSF, and brain tissue (in patients with GBM or brain metastases) compared to
[65]
specimens from 39 patients MB, 16; AT/RT, 8; epilepsy, 6; nonneoplastic conditions while members of the miR-200
hydrocephalus, 9) and found that patients with AT/RT have family were found solely in CSF of patients with brain
higher plasma and CSF OPN levels in comparison with metastases, indicating that CSF miRNAs could be used to
patients with MB, hydrocephalus, or epilepsy. Interestingly discriminate between glioblastoma and metastatic brain
significant correlation between OPN levels and the risk tumors, an important consideration for cancer treatment.
[2]
of tumor relapse in patients with AT/RT was identified GBM is the deadliest glioma with median survival of
while OPN levels in the CSF were found to decrease with only 14 months despite the recent advances in intensive
treatment. therapeutic strategies. Due to their anatomic location
[80]
and infiltrative nature, these tumors are not amenable to
Other biochemical markers surgical resection or even to biopsy in some cases. The
Malignant brain tumors may show an increased fraction of paucity of biomarkers represents a sizable gap in improving
anaerobic LDH concentrations (LD4 and LD5) in CSF. A the clinical management of these patients. Analysis of CSF
[52]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 18, 2016 ¦ 181