Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033-0850, USA
Address for correspondence: Waldemar Debinski, M.D., Ph.D., Section of Neurosurgery/H110, Department of Surgery, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850. Voice: 717-531-4541; fax: 717-531-5906.
wdebinski{at}psu.edu
Ann. N.Y. Acad. Sci. 983: 232-242 (2003).
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-13R
2 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-13R
2. 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.
