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Page 6 of 16 Bookland et al. J Cancer Metastasis Treat 2019;5:33 I http://dx.doi.org/10.20517/2394-4722.2018.110

and one case of an ependymoma. Ventricular CSF samples and serum samples were acquired and levels of
MHPG, HVA, and 5-hydroxyindoleacetic acid were measured. The authors found that MHPG levels were
significantly higher (19.4%) in astrocytoma patients versus medulloblastoma patients. However, none of the
[55]
measured monoamine metabolites significantly varied from age-matched controls in this small study .
Like tumor metabolite CSF biomarkers, most protein biomarkers investigated in CSF are part of well-
defined aberrant tumor cell signaling pathways. One of the most well studied family of proteins influencing
proliferation and differentiation in pediatric brain tumors is the insulin-like growth factor (IGF) family
of mitogens, binding proteins, and receptors. The IGF mitogens are primarily synthesized in the liver and
circulate in conjunction with any of 7 IGF binding proteins (IGFBP) to promote CNS development, among
other functions. They have been implicated in the proliferation and formation of medulloblastomas and
ependymomas in in vitro and murine models [56,57] , and IGF-1 levels have been shown to correlate with an
[58]
individual’s propensity for developing cancer .
In a study of 35 CSF samples from pediatric patients, mostly medulloblastoma patients, IGFBP-3 levels
were found to be significantly elevated in the CSF of medulloblastoma patients compared to control or
ependymoma patients. This finding was comparable to mRNA levels for IGFBP-3 in the tumors themselves.
The study did have several limitations that tempered the confidence that could be assigned to the results. The
levels of IGFBP were overall highly correlated with total CSF protein levels, as has been the case with other
CSF-based protein biomarkers for brain tumors [59,60] , suggesting that IGFBP may just be an indicator of BBB
disruption, rather than a specifically oncologic biomarker. The authors did attempt to normalize IGFBP-3
levels to total CSF protein levels, and the significance of the finding remained. Another issue with the study
was that correlation with tumor treatment could not be assessed, as follow-up CSF samples in all patients
were taken within 2 weeks of surgical resection, potentially contaminating the samples with tumor cell
[61]
slough and physiologic changes related to general anesthesia and surgery . Even so, this study suggests that
the IGF signaling pathway may be leveraged in the future to identify and track disease in pediatric patients
with medulloblastoma.

[62]
Another paper by Desiderio et al. examined changes in the CSF proteome of 14 pediatric brain tumor
patients and 5 controls from the time of surgical resection and at 6 days post-surgery via top down liquid
chromatography-mass spectrometry. The authors found a non-significant trend towards decreased LVV-h7
[62]
and VV-h7 hemorphins in the CSF of pediatric patients with brain tumors. In Desiderio et al. ’s cohort,
the LVV-h7 and VV-h7 protein suppression reversed in the same patients if they underwent a gross total
resection of their tumor and had no metastatic tumor burden. These findings have yet to be verified in a
[62]
follow-up study, and the results included CSF samples within the window of surgical contamination .
A similar whole-CSF proteome approach was utilized by Saratsis et al. to search for biomarkers predictive
[63]
of diffuse intrinsic pontine gliomas. In this study, 55% of patients with diffuse intrinsic pontine gliomas
demonstrated elevated levels of cyclophilin A in their CSF, while no patients with alternate supratentorial
gliomas or control patients had meaningfully detectable levels of the same protein. Those patients with
elevated cyclophilin A levels also showed a greater tendency towards radiographic evidence of necrosis and
rapid tumor progression, suggesting that cyclophilin A may be indicative of more aggressive forms of diffuse
intrinsic pontine glioma .
[63]
Lastly, a study of 33 pediatric medulloblastoma patients and 25 age matched controls in a multi-centered
study of prostaglandin D2 synthase (PGD2S), a highly abundant glycoprotein found in CSF, found a 6-fold
reduction in PGD2S levels in medulloblastoma patients compared to controls. This was a highly significant
finding (P < 0.00001). The authors theorized that this may be related to a host response to the tumor, as it
has been described in other brain tumor patients and in some demyelinating diseases. PGD2S CSF levels