Role of NF-kappaB in Maintenance of Glioblastoma Stem Cells

 

Trainee:

Amanda Rinkenbaugh

rinkenbaugh

Research Mentor

Dr. Albert Baldwin, PhD

baldwin

Clinical Co-mentor

Dr. Ryan Miller, MD

miller ryan
Home Department Molecular & Cellular Pathology
Project Description Glioma is the most common primary brain malignancy. Typical therapies used against cancer (surgery, radiation, and chemotherapy) are generally ineffective with these tumors, leading to an incredibly high recurrence rate and a median survival of only 15 months from diagnosis for these patients. Cancer stem cells have been identified in a variety of cancer types, including glioma, and are of great interest for the development of new treatments. The cancer stem cell hypothesis suggests that there is a distinct population of stem and progenitor cells that drive tumor progression and growth when dysregulated. As these cells are capable of both self-renewal and differentiation, they can give rise to the heterogeneous group of cells typically seen in tumors. Studies have shown that xenograft tumor formation is greatly reduced when the cancer stem cell population is eliminated. Additionally, it is this same population of cancer stem cells that appears to be resistant to current cancer treatments. If this is the case, then therapies must be developed to specifically target and eliminate the cancer stem cells or to induce their differentiation such that they can be targeted by current treatments.

We plan to investigate how these pathways are functioning within glioma stem cells through the use of specific IKK and NF¬-кB inhibitors, using both human tumor explants and mouse models. Our preliminary studies indicate activation of the IKK/NF-кB pathways could have a critical role in the maintenance of these stem cells, and thus would be a prime target for new therapeutics. Our experiments on CD133+ glioma stem cells have shown induction of morphological changes following IKK inhibition. Gene expression analysis under the same conditions shows downregulation of stem cell markers such as nestin and LIF, with upregulation of GFAP, an astrocytic marker. Taken together, these changes suggest that the inhibitor induces stem cell differentiation. Ultimately, these results could be translated into new treatments for glioma patients. Additionally, we feel NF-кB activation may not be limited to glioma stem cells, but could be a more universal feature of cancer stem cells, thus allowing these new treatments to be more broadly utilized with cancer patients.