Epigenetics in high-grade astrocytomas - Opportunities for prevention and detection of brain tumors

Human high-grade astrocytomas (HGA) are the most prevalent incurable brain tumors. We found that the vast majority of HGA patients over-express a restricted receptor for an immune regulatory cytokine, interleukin 13 (IL-13). Interestingly, the HGA-associated restricted receptor protein IL-13Ralpha2 is expressed in the testes, and its gene is localized to chromosome X. These mirror the expression pattern and genomic localization of cancer/testes tumor antigens (CTA). Hypothetical considerations and now experimental evidence are beginning to point towards epigenetics, and DNA methylation alterations in particular, as being responsible for the appearance in cancer of CTA, including IL-13Ralpha2. In line with our interest in the X chromosome and oncogenesis, we have identified a new ubiquitous angiogenic factor in HGA, a vascular endothelial growth factor-D (VEGF-D). We have also demonstrated that the activating protein-1 (AP-1) family of transcription factors play a potentially critical role in the progression of gliomas by eliciting uncontrolled upregulation of VEGF-D and other compounds essential for cancer cell proliferation, tumorigenesis, and infiltration. The possibility exists that an unopposed constitutive increase in AP-1 activity in HGA is related to epigenetic silencing of the inhibitors of AP-1 activity. These phenomena offer potential targets for exploitation in either prevention or early detection of brain tumors. For example, anticancer vaccines against shared CTA could help in prevention of HGA development. Furthermore, drugs with anti-AP-1 activity could be effective in preventing formation/progression of HGA, or progression from less malignant lower grade gliomas to HGA. Also, circulating antibodies against CTA and factors that are AP-1 regulated may provide a useful tool in early detection of brain tumors or for monitoring their progression following initial treatment.