Molecular and Protein Pathways in Glioblastoma Multiforme

Cancer Glioblastoma
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Different factors contribute to the formation of glioblastoma multiforme,
these include cell proliferation, de-differentiation, invasiveness and motility

Glioblastoma multiforme (GBM) is the most aggressive and malignant type of brain tumor that has a very short survival rate.[1] The cells involved in producing the Glioblastoma are involved in either one or multiple gene mutations that have compromised the normal cellular function of glia cells. Therefore, the cancer shares in common similar characteristics of other tumors such as excessive, motility, invasiveness, proliferation, and differentiation that are brought about by the specific mutation of some genes. Although there are many proteins that induce the cancer, different proteins either individually or cooperatively produce the Glioblastoma multiforme cancer, which points to the delicate balance of expressed proteins and how simply the balance can be compromised. In addition, to single protein mutations that may result in cancer, viruses such as Human papillomavirus are also involved in oncoprotein pathways that lead to gliomas. [2] Therefore, viruses or other environmental agents may also lead to the over expression or down regulation of essential proteins, which can have detrimental effects. Here, we investigate the different proteins that may lead to the progression of cancer and different the environmental causes such as viruses and carcinogenic agents that compromise the normal functioning of the proteins and later lead to tumor formation.

Glioblastoma multiforme presents in different sub-types with unique genetic and protein expressions. The four sub-types for the primary GBM include Classical, Proneural, Mesenchymal, and Neural. [2] Within each of the subtypes, there are characteristic genes or proteins that become mutated or overexpressed which lead to tumors.

Molecular and Protein Pathways

Molecular Pathway
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Glioma precursor cells present different methods
through which they can become mutated and lead to GBM.
Additionally, there are multiple proteins involved in each
step increasing the complexity of the pathways

It is difficult to assign a gene or a protein only one function in the classification of invasiveness, motility, de-differentiation, and proliferation of cells that lead to GBM. This is because proteins are often involved in multiple pathways cooperate together to produce a result. Some of the most prominent genes and proteins that result in the GBM include, IDH1 and IDH2, P53, P21, PAI1, TCTP, NF1 PTEN, CDHNZA, MiR-328, and PDGFRSA

Proliferation

Proliferation is another term used to describe cell growth. With respect to cancer cells and Glioblastoma Multiforme, the excessive and uncontrolled dividing of the cancerous cells result in tumors. The division is a result of shorted cell cycle in which, it goes through the M, G1, G2 and S phase at an accelerated rate and produces more daughter cells. Often the GBM tumor has necrosis at the center and increased proliferation surrounding the dead cells leads to its survival. The excessive proliferation presents difficulty in curing the disease and is caused by a number of different genes that become mutated.

IHD1
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The mutation of the IDH1 protein leads to a structural
difference in the protein and in the active site of the enzyme.
Thereby, producing different products 2-hydroxyglutarate instead
of alpha-ketoglutarate, which leads to excessive proliferation
of cells

Isocitrate dehydrogenase (IDH)

The mutation of IDH1 and IDH2 gene is common in most gliomas namely in low-grade primary and high-grade secondary gliomas [3], the mutation of this gene leads to the alteration of the enzymes function, it results in the excessive production of 2-hydroxyglutarate. [3] Instead of the normal conversion of Isocitrate to alpha-ketoglutarate through enzymatic activity, the mutation of the gene R132H results in the mutated IDH1 that produces 2-hydroxyglutarate. This oncometabolite is created due to the conversion of an arginine residue in the 132 position, which is the active site of the enzyme is mutated and replaced by a histidine. [4] This molecule is recognized as an onco-metabolite that results in the progression of the tumor. This leads to the production of excess amount of reactive oxygen species and alteration of NADPH metabolism collectively contributing to cancer development. [4] Additionally, leukoencephalopathy is developed elevating the risk of cancer. [4]

Translationally Controlled Tumor Protein (TCTP)

The multiform protein, translationally controlled tumor protein (TCTP) plays an important role in the functioning of cells with respect to cell apoptosis, immune responses, tumorigenicity, and proliferation. [5] The protein functions in a way that extends the life of cells, it prevents cell death through binding with calcium and the N-terminal end of the protein associates and inhibits p53 and other apoptotic factors within the cell. This molecular association leads to the inhibition of factors that promote apoptosis.
Research done by Gu et al. demonstrate that the abnormal expression of the molecule leads to increased proliferation of glial cell in vitro and in vivo. [5] Through immunoblotting, immunohistochemical staining and real time PCR it was determined that there is a significant increase in the expression of TCTP within cancerous high-grade gliomas. [5] Additionally, the molecule acts through association with Wnt/β-catenin and TCF signaling pathways. This pathway while important in embryonic development is also involved in adult tumor genesis. [5] Therefore, the protein of interest TCTP, binds the TCF-4, which increases the TCF-4 affinity for the β-catenin and enhancing its role in cell proliferation. [5] Overall, it has been demonstrated that TCTP is significantly overexpressed in high-grade gliomas and that it leads to poor survival rate among the patients with GBM. Since it promotes excessive cell proliferation through association with other proteins mentioned above.

TCTP
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The co-expression of TCTP and β-catenin
strongly suggest the cooperative nature of the two
molecules and indicate their role in GBM and
mortality

De-differentiation

Cell differentiation and dedifferentiation of neurons and astrocytes are methods in which neural stem cells and progenitor cell produce gliomas. The process in which a cell becomes more specialized is called differentiation. However, the loss or mutation of genes involved in cell survival and division can result in the reversal of this step, in which a differentiated cell reverts to becoming a multipotent cell and through unbalanced protein activity proliferates to become a high-grade glioma cancer. As mentioned before, protein involved in GBM formation are often involved with not one but multiple attributes that contribute to tumor formation. Therefore, it is difficult to isolate a protein or gene based on its function and label it as a protein that is involved in only one aspect of the cancer cell formation. Instead, genes work in linking pathway that encompass the tumor formation.

Nuclear factor IA (NFIA) and p53

TP53
The video explains the role of TP53 gene
in regulation of the cell cycle and apoptosis and the
protein pathways it is involved in differentiation

The nuclear factor IA (NFIA) has a functional role in glioma pathogenesis in that it is a glial fate determinant. [6] Through its transcriptional repression of p53 and, p21 and plasminogen activator 1 (PAI 1) [6], it increases cell growth, migration, and regulates cell differentiation. The molecule is a protein transcription factor that binds DNA and acts an activator or repressor of the mentioned genes [7]. Additionally, the gene plays an important role in development of the neural stem cells through specifying glial identity and regulating astrocyte differentiation. [6] Additionally, the knockdown or silencing of the gene leads to myeloid differentiation. [8]

Furthermore, TP53 gene that produces the p53 protein is highly involved in primary high-grade GBMs. The mutation of this gene prevents the normal functioning of the protein, which is involved in genetic and cellular stability. Through its regulation of the cell cycle and prevention of de-differentiating cells and promotion of apoptosis, it prevents the formation of tumors. [9] Nevertheless, the gene of interest may become mutated or alternatively the protein is inhibited through its interaction with other proteins, such was the case with its interaction with the NFIA transcription factor. Since the protein not only leads to apoptosis of cell, but also controls the cell cycle. In case of de-differentiating cells, the protein interferes, resets the cell cycle, and promotes DNA repair through its association with p21 and other proteins. [9] However, the mutation of the gene or inhibition thereof, prevents normal functioning and induces GBM cells.

Metastasis
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The image presents sagittal,
horizontal, and coronal section view
of the brain infected with GBM, the artifact
in the image not only presents the main
tumor but also the surrounding
demonstrate the metastatic nature of
the tumor

Metastasis

Malignant tumors have the capability to metastasize and spread to other organs or another part of an already infected organ. Cell metastasis occurs through the invasion of cancerous cell to the through the [http://en.wikipedia.org/wiki/Basal_membrane#Membrane_polarity basal membrane and then re entry of the cells at another location where it forms a secondary tumor also known as a metastasized tumor. [9]

miR-328

A feature that makes the GBM malignant is the infiltrative nature of the cancer. The affected cell, present features that allow them to become infiltrative and invasive through the up or down regulation of proteins. [11] One particular protein that is highly expressed in invading glioma cells is the microRNA 328. [11] Delic et al. report that through luciferase assays and T-cell factor reporter assays that the molecule was excessively up regulated in the invasive glial cells. The molecule acts through the inhibition of SFRP1 and the activation of the wild type gene to produce the infiltrative glioma phenotype. [11] Furthermore, while the miRNA itself can be a diagnostic tool identify glioma progression at an early stage, it has an unfavorable outcome for those who are affected by the disease.

Viral Pathways

HVV-6
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The image demonstrates the co-localization of tumor cells and HHV-6
virus infected cells, illustrating the role of HHV-6 in promotion of GBM

Viruses as well as other pathogens in the environment contribute to the tumor growth and the occurrence of Glioblastoma. Viruses such as cytomegalovirus (CMV), Human herpesvirus 6 (HHV-6), and Simian vacuolating virus 40 (SV40) are known to contribute to tumor growth and result in GBM. Nevertheless, the molecular pathways that the mentioned viruses compromise is still under investigation. Through different experiments, researchers have been able to support these hypotheses.

HVV-6

The Human Herpesvirus-6 has been associated with many diseases involving the central nervous system and glial tropism. [12] While there still remains to be direct evidence to support the direct correlation of HVV-6 and GBM there is strong evidence to support the likelihood of its involvement with GBM. Chi et al. have demonstrated that there is a slightly significant amount of HHV-6 in cells of glioma patients. They were successful isolating the strain in glioma tumors and suggested that the infection of cells with HHV-6 results in the production of excess interleukin factors, IL-6, IL-8 and TGF-β. [13] The excessive production of these immunological factors in the glia cells produce cysts that carry these material, which are hypothesized to promote tumor growth and lead to GBM. [13]

CMV

Cytomegalovirus is another type of virus that promotes the formation of GBM. It has been thoroughly studied and strong evidence is present regarding how its role in glioblastomas. Price et al. investigate this virus through cell and mice models. Neuronal stem cells from the sub ventricular zone in mut3 mice where infected and the formation of glioblastoma neurospheres were observed. [14] The murine form of the CMV was utilized in infecting the host and individual cells in vitro as a result of this infection measured increases in phosphorylated STAT3 (p-STAT3) was observed. [14] The STAT3 molecule is a molecule that upon phosphorylation increases cell proliferation. Therefore, with the addition of the CMV that promotes the phosphorylation of the STAT3 to p-STAT3 the affected cell demonstrate excessive proliferation. [14] Therefore, it was concluded that the CMV through the p-STAT3 pathway leads to GBM.

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