Targeting cancer stem cells through L1CAM suppresses glioma growth

Malignant gliomas are lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, LICAM, in glioma stem cells as LICAM regulates brain development and is expressed in gliomas. LICAM' and CD133' cells cosegregated in gliomas, and levels of LICAM were higher in CD133' glioma cells than normal neural progenitors. Targeting LICAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133' glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for LICAM regulation of cell survival as LICAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and upregulated the p21wAF1/c1P1 tumor suppressor in CD133' glioma cells. To determine if targeting LICAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted LICAM in glioma cells before injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of LICAM expression in vivo suppressed tumor growth and increased the survival of tumorbearing animals. Together, these data show that LICAM is required for maintaining the growth and survival of CD133' glioma cells both in vitro and in vivo, and LICAM may represent a cancer stem cell-specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.