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Page 10 of 16 Bookland et al. J Cancer Metastasis Treat 2019;5:33 I http://dx.doi.org/10.20517/2394-4722.2018.110

A larger study of 106 pediatric patients with brain tumors, including gliomas, medulloblastomas, and
ependymomas, studied the relationship between serum levels of the pro-angiogenic growth factors and
pediatric brain tumors. In this study, serum vascular endothelial growth factor (VEGF) and basic fibroblast
growth factor (bFGF) levels were measured at presentation and following surgical resection or debulking of
the tumor. While the authors of the study found no statistically significant changes in bFGF levels between
groups, serum VEGF was 16.4% higher (P = 0.05) in pediatric brain tumor patients compared to controls.
Interestingly, subset analysis of only the glioma patients showed that serum VEGF levels were 16.4% lower
[89]
(P < 0.05) than controls . This is a curious result given glioblastoma and other high-grade glial tumors are
[90]
known to overexpress VEGF . The authors also found no statistically significant difference in serum VEGF
[89]
or bFGF levels in any of the post-surgical patients, regardless of the degree of tumor resection achieved .
These results are, in the end, difficult to reconcile; and this may reflect the extremely diverse collection of
pediatric brain tumors included.

[91]
Behrends et al. in a study of 40 pediatric cancer patients, including 10 brain tumor patients, employed
a less conventional method to identify humoral targets for biomarker development. In contrast to other
biomarker development projects that rely on a priori knowledge of cell signaling proteins known to be
abnormal in the disease process of interest, Behrend’s group used SEREX technology to identify potential
humoral targets, in some cases finding cancer antigens with no described function. The group utilized
autologous sera and serially screened these sera against autologous cDNA expression libraries in 4 pediatric
medulloblastoma patients. From this, the group identified 15 antigens. Humoral responses to these 15
antigens were then tested in the 40 pediatric cancer patients, as well as in 40 pediatric controls. Antibodies
were found to 5 of the 15 antigens exclusively in pediatric cancer patients. The authors noted, though, that
the humoral responses to these antigens was not uniform. Only 2-3 out of 5 medulloblastomas had detectable
antibodies to any one antigen, and the humoral responses varied over time depending on response of the
tumor to therapy. The authors also point out that humoral responses may change, as well, due to mutations
[91]
in some tumors that support immune evasion . Taken in balance, SEREX screening for humoral biomarker
targets is an innovative technique for identifying novel pediatric brain tumor biomarkers, but clinical
application is likely to be limited by the marked variability in humoral response across patients.

Limitations to serum biomarkers in pediatric brain tumor patients
While familiar and easily accessible, serum sources for biomarkers do have significant drawbacks. As a
peripheral biofluid, the milieu of serum proteins and genetic material is affected by every organ system in
the human body. Even large amounts of oncologic biomarkers can easily be diluted out by normal serum
[35]
components . Additionally, it is difficult to know what sources - host or tumor - are driving the targeted
biomarker concentration levels. Studies have shown that even epigenetic factors, such as a change in diet,
[38]
can significantly alter measured levels of some serum biomarkers for adult cancers . As with CSF, the
location and biology of pediatric brain tumors also seems to play a part in serum levels of some presumptive
biomarkers, with certain tumor-related proteins being undetectable outside of the BBB [61,63] .

Urine
Urine is a filtrate of serum via the glomeruli, and it represents a particularly easy and well-studied biofluid to
obtain from children. Excreted oncologic biomarkers such as metanephrine and VMA have been employed
clinically for decades as routine components in the work-up of several catecholamine producing solid
[92]
tumors, including pheochromocytomas and neuroblastomas in both children and adults .
[93]
A paper by Pricola Fehnel et al. in 2016 examined the use of urinary bFGF, MMP13 and TIMP3 levels as
biomarkers for juvenile pilocytic astrocytomas. The study followed 21 astroctyoma, 17 medulloblastoma,
and 21 control pediatric patients with serial urine samples pre-tumor treatment and post-tumor treatment.
The authors also examined bFGF and TIMP3 levels in primary juvenile pilocytic astrocytoma cell line
conditioned media. They found a significant elevation in bFGF and TIMP3 urine concentrations among the