Researchers identify a new way to reduce the spread of brain cancer
Scientists at Virginia Commonwealth University’s (VCU) Massey Cancer Center and Harold F. Young Neurosurgical Center with researchers at Old Dominion University have discovered a mechanism in glioblastoma (GBM) cells, the most common and aggressive form of brain cancer, that promotes the disease’s characteristic invasiveness. This finding could potentially lead to new therapies for this difficult-to-treat disease.
Reported in the Journal of Neurosurgery, the scientists showed that suppression of the Wilms tumor 1 protein (WT1) decreases the amount of CD97 gene expression in three glioblastoma cell lines and reduces the cancer’s ability to invade healthy brain tissue. WT1 is a protein that controls the development of several tissue types in humans through a process known as transcription, which is the first of a series of steps leading to gene expression. CD97 is a protein that has been shown in prior research to facilitate tumor cell invasiveness in other malignancies. This study revealed for the first time that CD97 is overexpressed in GBM cells.
“The invasive nature of brain tumors is what makes them difficult to treat,” says lead researcher William C. Broaddus, M.D., Ph.D., F. Norton Hord, Jr. Professor at the VCU School of Medicine and researcher at VCU Massey Cancer Center. “We think that some treatment approaches that limit blood supply to the tumor such as bevacizumab, or Avastin, may actually contribute to the disease’s invasive behavior. Therefore, if we are able to reduce invasiveness by targeting CD97, then we may increase the effectiveness of other treatments.”
In order to reduce WT1 gene expression in their laboratory experiments, the researchers used short interfering RNA (siRNA). siRNA can interfere with the expression of genes, and are often referred to as “silencing” RNA for this reason. The researchers directed the siRNA against WT1 in three different GBM cell lines, U251-MG, U1242-MG and GBM-6, and reduced invasiveness in all of them. In addition, they demonstrated that WT1 silencing increased the expression of seven genes that play a role in tumor suppression and decreased the expression of nine genes that play a role in tumor formation.
Moving forward, the researchers hope to replicate their findings in animal models and other complex experiments that more closely mimic the conditions in the human body. In these studies, the researchers will try to isolate the exact isoform(s) of CD97 that are expressed in GBM cells, as there are several different types of the CD97 protein.
“By demonstrating for the first time the role of CD97 in cellular invasiveness, and the ability to inhibit it by silencing the WT1 protein, we have potentially opened the door to a new treatment approach,” says Broaddus. “While we are encouraged by our findings, more research is needed in order to fully understand the biological mechanisms involved.”
Broaddus collaborated with Archana Chidambaram, Ph.D., from the VCU Departments of Anatomy and Neurobiology; Timothy E. Van Meter, Ph.D., from the VCU Departments of Anatomy, Neurobiology, Neurosurgery and Pediatric Hematology-Oncology and the Harold F. Young Neurosurgical Center; and Catherine I. Dumur, Ph.D., VCU Massey Cancer Center researcher from the Department of Pathology; and Helen L. Fillmore, Ph.D., who is affiliated with VCU’s Department of Neurosurgery and Harold F. Young Neurosurgical Center as well as with Old Dominion University’s Office of Research.
The full manuscript of this study is available at: http://thejns.org/doi/abs/10.3171/2011.11.JNS111455.