Brain tumors are among the most devastating cancers that present unique challenges to therapy and pose major health problems around the world. Despite recent advances in surgery, radiation and chemotherapy, a cure for brain tumor is still wanting. The location, aggressive growth, multi-drug resistance and fast recurrence are some of the unique challenges in combating brain tumors. Brain tumor stem cells (BTSC) are a small population of tumor cells that maintain self-renewal, transplantation and metastasis properties and remain as novel therapeutic targets in the treatment of brain tumor. Nuclear hormone receptors are a family of ligand-dependent transcription factors that regulate cell growth, differentiation and homeostasis. We and others have shown earlier that nuclear hormone receptors modulate growth and differentiation of stem cells and tumor cells. In this study we investigated how BTSC can be targeted through nuclear receptors for the treatment of brain tumors. We first isolated and expanded CD133+ BTSC from T98G human glioma as tumorspheres in culture. Using real-time RT-PCR, we analyzed the expression levels of 45 nuclear receptors in BTSC and compared them with that in T98G glioma cells. We found that the expression of 6 nuclear receptors (HNF4α, TLX, PNR, RORα, RORγ, PXR) increased more than 200 fold, 17 nuclear receptors increased more than 10 fold, and 2 nuclear receptors (DAX1, CARα) decreased more than 10 fold in BTSC than T98G cells. Moreover, treatment with specific agonists for highly altered nuclear hormone receptors resulted in differential anti-proliferative responses in brain tumor and BTSC in culture. These findings highlight the fact that the nuclear hormone receptors with altered expression and activation profile in BTSC can be used as novel therapeutic targets in the treatment of brain tumors.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA