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bearing brain tumors of different histology and grades. By was further validated with Western blot analysis and
performing retrospective analyses on 60 samples derived immunohistochemical assays using CSF and brain tissue as
from astrocytomas WHO grade II, III, and IV, schwannomas, well as in blood samples from DIPG. Immunohistochemical
metastastic brain tumors, inflammatory samples, and non- staining showed selective upregulation of secreted but not
neoplastic controls, the group identified 103 potential tumor- cytosolic CypA and DDAH1 in patients with DIPG. Their
specific markers of which 20 were high-grade astrocytoma- study indicated that detection of secreted CypA and DDAH1
specific. SPARCL1, FGF14, VEGF-B, tau, b2M, bdefensin in CSF and serum has potential clinical application, with
and Attractin were found as an upregulated marker in the implications for assessing treatment response and detecting
CSF of patients with malignant astrocytoma and mediates tumor recurrence in patients with DIPG.
glioma cell migration. Sampath et al. assessed whether
[47]
[48]
vascular endothelial growth factor (VEGF) could be Primary central nervous system lymphoma (PCNSL) is
measured in the CSF of patients with cerebral neoplasms another highly aggressive tumor that can lead to quick
and used as a marker of particular brain cancer tumors. death if not diagnosed in time. The diagnosis of PCNSL can
They investigated CSF samples from 27 patients with high- present a diagnostic challenge. It relies on histopathology
grade astrocytomas, 39 patients with nonastrocytic CNS of brain biopsies to the same extent as most brain tumors,
neoplasms, and 14 patients with no known CNS neoplasm. while less invasive tests to detect early tumor pathogens
In their study, VEGF was detectable in 89% of samples with sufficient diagnostic accuracy are not available yet.
with malignant astrocytoma and not normal CSF samples. Proteomic analysis of CSF has revealed various proteins
The levels of VEGF were significantly higher in high-grade that are differentially expressed in CNS lymphoma. [52-54]
astrocytomas than in nonastrocytic tumors indicating that Among these, antithrombin III (ATIII), a serine protease
detection of VEGF in CSF could be a potential marker for inhibitor that is associated with neovascularization in CNS
differentiating astrocytic from nonastrocytic tumors. lymphoma, has been prospectively validated. ATIII
[26]
expression was reported by Roy et al. to be elevated in
[55]
Another group applied mass spectrometry based technology the CSF of patients with CNS lymphoma compared to those
to identify possible CSF peptide markers of GBM. patients with control. ATIII levels higher than 1.2 g/mL
[49]
Out of 2,000 detected CSF peptides four peptides which made the detection of CNS lymphoma possible with >70%
significantly distinguished GBM from controls were sensitivity and 99% specificity. Elevated antithrombin
[26]
identified. They were specific C-terminal fragments of III levels significantly correlated with shorter survival rates
alpha-1-antichymotrypsin, osteopontin, and transthyretin and less response to chemotherapy. However and on the
as well as N-terminal residue of albumin. Interestingly the contrary a recent study from Finland, by Kuusisto et al.
[56]
identified four molecules are constituents of normal CSF, but declared that ATIII is not a suitable biomarker for diagnosis
this group are the first to report their significant elevation in of PCNSL and increased concentrations of ATIII in CSF
CSF of GBM patients. To detect biomarkers in high-grade might be due to leakage of the blood-brain barrier. [57]
astrocytomas, Ohnishi et al. analysed the differential
[50]
expression of proteins in the CSF from two cases each of CXCL13 protein that is known to mediate chemotaxis of
diffuse astrocytoma (grade II), and glioblastoma (grade CNS lymphoma cells was detected within biopsy specimens
IV) using agarose 2-D gel electrophoresis. The authors from PCNSL patients raising the possibility that this
[58]
found that the expression of gelsolin protein is decreased chemokine may contribute to CNS tropism. Rubenstein et
[55]
with histological grade. To examine whether gelsolin is a al. investigated the concentration of CXCL13 in CSF of
useful indicator of tumor aggressiveness the group further CNS lymphoma patients and control cohorts in a multicenter
analysed the gelsolin expression in 41FFPE astrocytomas. study involving 220 patients. Their result demonstrated
Gelsolin expression was found to be significantly lower in that elevated CXCL13 concentration in CSF is a highly
high-grade than in low-grade astrocytomas. Moreover the specific marker for the detection of CNS lymphoma and
overall survival of patients in the low-gelsolin expression can be helpful as an adjunctive diagnostic test and response
was significantly poorer than in the high expression group to treatment assessment. Following their steps in studying
highlighting the usefulness of gelsolin as a potential chemokine in PCNSL, Sasagawa et al. investigated CSF
[59]
prognostic factor in astrocytoma. from 19 patients with CNS lymphoma (15 and 26 non-
lymphoma patients with various brain tumors) and reported
Diffuse intrinsic pontine glioma (DIPG) is not surgically that CSF IL-10 is a superior biomarker for initial screening
resectable, resulting in a paucity of tissue available for for patients with CNS lymphoma.
molecular studies and, currently, there are no effective
treatments. Saratsis et al. investigated 15 CSF specimens Medulloblastoma (MB) is the most common malignant
[51]
from patients with DIPG for proteomic analysis. Protein brain tumor in children. It includes various subtypes with
profiling was generated by mass spectrometry. CSF group 3 and 4 subtypes being clinically distinct with regard
proteomic analysis revealed selective upregulation of to metastasis and prognosis, which may also manifest in
Cyclophillin A (CypA) and dimethylarginase 1 (DDAH1) a difference in their proteomic spectra. With the aim to
in DIPG, compared with controls. Protein expression identify putative biomarkers for MB in CSF, Rajagopal et

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