Premium
Epigenetics in High‐Grade Astrocytomas
Author(s) -
DEBINSKI WALDEMAR,
GIBO DENISE,
MINTZ AKIVA
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb05978.x
Subject(s) - epigenetics , carcinogenesis , dna methylation , cancer research , biology , tumor progression , glioma , gene silencing , downregulation and upregulation , cytokine , immune system , angiogenesis , cancer , methylation , vascular endothelial growth factor , transcription factor , medicine , immunology , gene , gene expression , genetics , vegf receptors
A bstract : Human high‐grade astrocytomas (HGA) are the most prevalent incurable brain tumors. We found that the vast majority of HGA patients overexpress a restricted receptor for an immune regulatory cytokine, interleukin 13 (IL‐13). Interestingly, the HGA‐associated restricted receptor protein IL‐13Rα2 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‐13Rα2. 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.