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aberrations as a sign of malignancy, can also give additional brain tumors. Germ cell tumors retain the molecular
diagnostic information to CSF analysis, but still has a low characteristics of their primordial lineage as they maintain
sensitivity Table 2. PCR can also establish cancer diagnosis the expression of embryonic proteins, such as beta human
when cytology is inconclusive, but the genetic alteration of chorionic gonadotropin (bHCG) and alpha-fetoprotein
the neoplasia must be known for it to be amplified with this (AFP). bHCG is a 36 kDa glycoprotein normally secreted
[41]
technique, and this is generally not the case. [26] by placental tissues while AFP is a 70 kDa glycoprotein
normally secreted by the foetus primarily in the yolk sac,
PROTEOMIC ANALYSIS OF CSF gastrointestinal tract, and liver. AFP is elevated in wide
range of cancers, including colon adenocarcinoma, liver
Proteomic profiling has become an active area of research and gastric cancers while bHCG and AFP were found to
for the biomarker discovery and the identification of new be markedly elevated in the CSF of intracranial malignant
targets for therapeutic strategies. Recent studies have germ cell tumor patients. Both markers are currently
[42]
shown that specific proteomic patterns can differentiate utilized clinically as diagnostic and accurate indicators of
subtypes or grades of human brain tumors. [27-30] Modern response to therapy. Assessment of AFP and total bHCG in
technological advancements in protein quantification which both serum and CSF is mandatory in order to distinguish
provide rapid screening, low sample consumption, and between germinoma and NGGCT non-germinoma germ
accurate protein identification, have enhanced the precision cell tumors. CSF AFP > 1000 ng/mL at diagnosis, or age
of proteomic analyses and are anticipated to accelerate < 6 years, intracranial malignant germ cell tumor patients
brain tumor biomarker discovery. [31] are stratified as high risk and are treated more intensively.
Moreover, the verification of bHCG and AFP levels prior
Research work on traditional sampling sources for to surgical resection provides a reference point that can be
proteomic profiling, such as blood [31,32] and tissue lysates, used to assess recurrence during follow-up however their
[33]
have yielded asubstantial amount of information on absence does not rule out a germ cell tumor. Additional
potential brain cancer biomarkers. However, the majority of CSF protein markers such as placental alkaline phosphatase
these markers exhibited limited value in a clinical setting, (PLAP) and lactate dehydrogenase isoenzymes have
justifying the need for the exploration of more clinically been shown to be clinically useful in the diagnosis and
relevant sampling sources. One such a promising source monitoring of pediatric intracranial germinomas, however
for protein biomarker discovery is the CSF where protein such markers are less specific. Elevated levels of s-kit, the
[43]
presences might result from either secretion/leaking by soluble form of the c-kit receptor, a transmembrane tyrosine
tumor tissues or abnormal blood brain barrier function. [8] kinase receptor, was found to be a reliable marker for germ
cell tumor diagnosis that can differentiate germ cell tumors
CSF proteomic analysis for detection of brain from other CNS cancers. Miyanohara et al. also reported
[44]
cancer markers that s-kit expression is able to detect recurrence of germ cell
In the search for accurate biomarkers a number of reports tumors and subarachnoid dissemination.
have emerged over the past decade describing the analysis of
different brain cancer proteome using CSF. For example the Gliomas are the most common primary brain tumors in
CSF level of carcinoembryonic antigen (CEA), is a protein adults. Glioblastoma multiforme (GBM) is the deadliest
tumor marker that is commonly increased in several human glioma with a median survival of only 14 months despite
[45]
malignances, was found recently to play an important the recent advances in intensive therapeutic strategies.
role in differential diagnosis of primary and metastatic Hence more effort was applied to study whether specific
brain tumors [34,35] and useful auxiliary marker in diagnosis CSF proteomic profile can be generated to evaluate gliomas
of meningeal carcinomas. [36-38] In a study by Khwaja et prognosis. Fang Shen et al. conducted a review of the
[8]
al., the authors reported that proteomic analysis of CSF literature on the proteomic screening for glioma-related
[39]
can discriminate malignant and non-malignant disease of protein biomarkers in CSF. They were able to identify 19
the CNS and identified carbonic anhydrase protein (known differentially expressed proteins, the majority exhibited
to be overexpressed in many malignancies including high- increased concentrations (B2M, CA2, CA12, CALD1,
grade gliomas) as a prognostic marker of brain cancer. DDAH1, MYCN, PPIA, SPP1, VEGFB, ALB, MAPT,
SERPINA3, SPARCL1) while (GSN) was downregulated
The most significant example of how analysis of CSF in the glioma CSF. Further functional assessments revealed
proteins has impacted the clinical management of CNS several important protein networks (e.g., IL6/STAT-3) and
cancer is in the case of intracranial malignant germ cell four novel focus proteins (IL-6, galanin (GAL), HSPA5
tumors. Germ cell tumors are heterogeneous group of and WNT4) and the authors reported that these proteins
[40]
gonadal or extragonadal tumors that thought to arise from might be involved in glioma pathogenesis. On the same
the aberrant migration and differentiation of primordial theme, Khwaja et al. used two proteomic techniques,
[46]
germ cells during embryogenesis. Extragonadal germ cell two-dimensional gel electrophoresis and cleavable Isotope-
tumors can occur intracranial in the pineal and suprasellar Coded Affinity Tag to compare CSF proteomes in order to
regions and comprise approximately 3% of all pediatric identify tumor- and grade-specific biomarkers in patients

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 18, 2016 ¦ 179