Effect of the combination of retinoic acid and rapamycin on cerebellar granule cell and medulloblastoma proliferation

2077 Background: Cerebellar granule cell precursors (CGCPs) are neuroblasts that proliferate in early postnatal life and may become transformed, giving rise to medulloblastoma. The proliferation of CGCPs is driven by mitogenic signals including Sonic Hedgehog (SHH), and growth factors that activate the protein mTOR. Dysregulation of these intercellular signals can promote medulloblastoma formation. We propose that microenvironmental signals that down-regulate the response of CGCPs to mitogens may inhibit medulloblastoma growth. Retinoic acid (RA) is an endogenous signaling molecule with potent anti-neoplastic effects. We investigated whether SHH, mTOR, and RA signaling pathways interact to regulate CGCP and medulloblastoma proliferation. Methods: We measured proliferation in cultured CGCP explants and the CGCP-derived murine medulloblastoma cell line PZp53 using quantitative phosphohistone-H3 immunocytochemistry. We examined the effects of adding to culture medium SHH, the mTOR inhibitor rapamycin, and al...