BMP Signaling in High Grade Gliomas

Abstract

Improved therapies for high grade gliomas (HGG) are urgently needed, as the median survival for grade IV gliomas is just 15 months after treatment with surgery, chemotherapy and radiation. Recently, bone morphogenetic protein (BMP) signaling has been shown to play a tumor suppressing role on the glioma stem cell (GSC) population. However, the effects of BMP signaling on the differentiated population comprising the bulk of the tumor remains incompletely understood. In addition, studies examining the expression of BMP signaling molecules in HGG have shown contrasting results. To further our knowledge of the role of BMP signaling in HGG we used a combination of genetic analyses and a novel murine model of HGG to generate transformed astrocytes with oncogenic Kras, deletion of p53 and deletion of Bmpr1a. As a result of our studies, we have shown that BMP signaling is not largely altered or lost in human Glioblastomas. In addition we found that BMP signaling is present and active in the majority of HGG cells, indicating that BMP signaling is active in the differentiated, astrocytic tumor cells. Finally, using transformed murine and human oncogenic astrocytes, we determined that BMP signaling is tumor promoting in differentiated tumor cells through increased proliferation, invasion and migration. Our results indicate that BMP signaling is context dependent in HGG and as a result we suggest BMP inhibition as a novel therapeutic agent in the treatment of both adult and pediatric HGG.