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James L Sowers¹, Kenneth M Johnson, Charles Conrad

¹Department of Pharmacology and Toxicology, The University of Texas Medical Branch (UTMB), Galveston, TX, USA.

Advances in Experimental Medicine and Biology

|May 14, 2014

Abstract:

Malignant brain tumors are among the most lethal of human tumors, with limited treatment options currently available. A complex array of recurrent genetic and epigenetic changes has been observed in gliomas that collectively result in derangements of common cell signaling pathways controlling cell survival, proliferation, and invasion. One important determinant of gene expression is DNA methylation status, and emerging studies have revealed the importance of a recently identified demethylation pathway involving 5-hydroxymethylcytosine (5hmC). Diminished levels of the modified base 5hmC is a uniform finding in glioma cell lines and patient samples, suggesting a common defect in epigenetic reprogramming. Within the tumor microenvironment, infiltrating immune cells increase oxidative DNA damage, likely promoting both genetic and epigenetic changes that occur during glioma evolution. In this environment, glioma cells are selected that utilize multiple metabolic changes, including changes in the metabolism of the amino acids glutamate, tryptophan, and arginine. Whereas altered metabolism can promote the destruction of normal tissues, glioma cells exploit these changes to promote tumor cell survival and to suppress adaptive immune responses. Further understanding of these metabolic changes could reveal new strategies that would selectively disadvantage tumor cells and redirect host antitumor responses toward eradication of these lethal tumors.

Insights

Malignant brain tumors like gliomas show reduced 5-hydroxymethylcytosine (5hmC) levels, indicating epigenetic reprogramming defects. Metabolic changes in glioma cells promote survival and immune suppression, offering potential therapeutic targets.

Area of Science:

Neuro-oncology
Epigenetics
Cancer Metabolism

Background:

Malignant brain tumors, particularly gliomas, are highly lethal with few treatment options.
Gliomas exhibit complex genetic and epigenetic alterations impacting cell signaling pathways.
DNA methylation and the 5-hydroxymethylcytosine (5hmC) pathway are crucial epigenetic regulators.

Purpose of the Study:

To investigate the role of 5-hydroxymethylcytosine (5hmC) levels in glioma.
To explore metabolic alterations in glioma cells within the tumor microenvironment.
To identify potential therapeutic strategies targeting glioma metabolism and immune response.

Main Methods:

Analysis of 5-hydroxymethylcytosine (5hmC) levels in glioma cell lines and patient samples.
Investigation of metabolic pathways, including amino acid metabolism (glutamate, tryptophan, arginine) in glioma.
Examination of the tumor microenvironment's influence on glioma evolution and immune response.

Main Results:

Diminished 5-hydroxymethylcytosine (5hmC) levels are consistently observed in gliomas, suggesting epigenetic reprogramming defects.
Glioma cells adapt by altering metabolism of key amino acids to enhance survival and evade immune surveillance.
The tumor microenvironment contributes to genetic and epigenetic changes during glioma progression.

Conclusions:

Reduced 5-hydroxymethylcytosine (5hmC) is a hallmark of gliomas, pointing to epigenetic dysregulation.
Targeting glioma-specific metabolic pathways may offer novel therapeutic avenues.
Understanding metabolic adaptations is key to developing strategies to overcome immune suppression and eradicate gliomas.

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