Brain Tumor Markers

Tumors may vary in location, growth rate, and are typically categorized according to the cell of origin (1,2). There are also distinct differences between adult and childhood brain tumors.

Oncogenes

Tumor suppressors p53  and PTEN  (Figure 1) are associated with many types of cancer and can therefore be found in many brain tumor types (3). Mutations in these known oncogenes contribute to aberrant growth through the downstream effects on cell cycle transition, proliferation, and apoptosis.

Figure 1. Immunohistochemistry of paraffin-embedded human prostate cancer tissue slide using 22034-1-AP (PTEN antibody) at a dilution of 1:200 (under 40x lens).

Upregulation

Patterns in gene expression are often used as markers as many tissue markers are expressed in healthy cells and tumor cells alike, but at different levels. Overexpression of growth factor receptors such as PDGFRa     and EGFR indicate tumor cells rather than normal brain tissue, and are associated with tumor progression and clonal expansion (4, 5). Increased expression of cell adhesion molecule L1CAM    has also been identified in a number of different cancers, indicating a role for this protein beyond cell migration (6). 

Tumor types

The many different types of brain tumors are differentiated with a range of techniques, including histopathology. Tumors derived from glial cells are known as gliomas and can be further subcategorized as astrocytomas, oligodendrogliomas, and ependymomas depending on the cell type of origin. These different subtypes can be identified in part by cell-type-specific markers – for example, astrocytomas have GFAP (Figure 2) expression. Heterogeneous tumors that comprise multiple cell types may also be identified this way. The WHO classification of tumors of the central nervous system is the commonly used method for defining tumor types.

Figure 2. Immunofluorescent analysis of ( 4% PFA) fixed mouse brain tissue using 16825-1-AP (GFAP antibody) at dilution of 1:200 and Alexa Fluor 488-Conjugated AffiniPure Goat Anti-Rabbit IgG (H+L).

The most common type of adult brain tumor is glioblastoma (GBM), a grade 4 astrocytoma that contains a number of different types of cells, including differentiated astrocytic cells and neural stem cell-like cells. Whole exome sequencing of GBM (7) revealed common mutations that can characterize tumor subtypes. This enabled the categorization of GBMs into four distinct molecular subtypes, proneural, neural, classical, and mesenchymal, which are characterized by differing mutations in a variety of genes.

One example is mutations in the metabolic enzyme IDH (Figure 3), which change the function of the protein and appear to have an effect on prognosis in patients (8) but also is explored as a potential therapeutic target.

Figure 3. Immunohistochemical of paraffin-embedded human gliomas using 12332-1-AP (IDH1 antibody) at dilution of 1:50 (under 10x lens).

Brain tumors derived from cells other than glial cells are less common but include meningeal tumors, lymphomas, and tumors of the cranial and paraspinal nerves. Similarly to gliomas, they also express cell-specific markers; for example, neuroblastoma tissue will express Synaptophysin.

Cancer stem cells

The cellular heterogeneity of brain tumors is added to by the presence of cancer stem cells in tumors, identified from patient biopsies. These multipotent and self-renewing cells are thought to be the reason why many tumors are resistant to chemotherapy and return after treatment. These cancer stem cells are identified by their expression of common markers of neural stem cells such as Nestin   and Olig2, which mark neural and glial cell lineage respectively and are not found in fully differentiated mature cells. Neurodevelopmental transcription factors like FOXG1    and Sox2   are shown to haveincreased expression in brain tumor cancer stem cells, causing a proliferative phenotype (9).

Figure 4. Immunofluorescent analysis of (4% PFA) fixed mouse brain tissue using 11064-1-AP (SOX2 antibody) at a dilution of 1:50 and Alexa Fluor 488-Conjugated AffiniPure Goat Anti-Rabbit IgG (H+L).

The huge number of brain tumor types requires a spectrum of markers to successfully identify and study mechanisms in vivo and in vitro.

Relevant brain tumor markers

References

1. Louis, D. N. et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007).
2. Louis, D. N. et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 131, 803–820 (2016).
3. Checler, F. & Alves da Costa, C. p53 in neurodegenerative diseases and brain cancers. Pharmacol. Ther. 142, 99–113 (2014).
4. Gialeli, C. et al. PDGF/PDGFR signaling and targeting in cancer growth and progression: Focus on tumor microenvironment and cancer-associated fibroblasts. Curr. Pharm. Des. 20, 2843–8 (2014).
5. Lu, F. et al. Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma. Cancer Cell 29, 669–683 (2016).
6. Altevogt, P., Doberstein, K. & Fogel, M. L1CAM in human cancer. Int. J. Cancer 138, 1565–1576 (2016).
7. Parsons, D. W. et al. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 1807–1812 (2008).
8. Cohen, A. L., Holmen, S. L. & Colman, H. IDH1 and IDH2 mutations in gliomas. Curr. Neurol. Neurosci. Rep. 13, 345 (2013).
9. Bulstrode, H. et al. Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators. Genes Dev. 31, 757–773 (2017).