ABSTRACT
Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
Subject(s)
Cerebellar Neoplasms/metabolism , Hedgehog Proteins/metabolism , Inhibitor of Apoptosis Proteins/deficiency , Medulloblastoma/metabolism , Repressor Proteins/deficiency , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Biphenyl Compounds/pharmacology , Blotting, Western , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cerebellar Neoplasms/drug therapy , Cerebellar Neoplasms/genetics , Chemoradiotherapy , Child , Hedgehog Proteins/antagonists & inhibitors , Humans , Imidazoles/pharmacology , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Inhibitor of Apoptosis Proteins/genetics , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Ki-67 Antigen/metabolism , Medulloblastoma/drug therapy , Medulloblastoma/genetics , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, Nude , Mice, SCID , Microscopy, Confocal , Naphthoquinones/pharmacology , Pyridines/pharmacology , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/genetics , Survivin , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Cerebellar granule neurons are the most abundant neurons in the brain, and a critical element of the circuitry that controls motor coordination and learning. In addition, granule neuron precursors (GNPs) are thought to represent cells of origin for medulloblastoma, the most common malignant brain tumor in children. Thus, understanding the signals that control the growth and differentiation of these cells has important implications for neurobiology and neurooncology. Our previous studies have shown that proliferation of GNPs is regulated by Sonic hedgehog (Shh), and that aberrant activation of the Shh pathway can lead to medulloblastoma. Moreover, we have demonstrated that Shh-dependent proliferation of GNPs and medulloblastoma cells can be blocked by basic fibroblast growth factor (bFGF). But while the mitogenic effects of Shh signaling have been confirmed in vivo, the inhibitory effects of bFGF have primarily been studied in culture. Here, we demonstrate that mice lacking FGF signaling in GNPs exhibit no discernable changes in GNP proliferation or differentiation. In contrast, activation of FGF signaling has a potent effect on tumor growth: treatment of medulloblastoma cells with bFGF prevents them from forming tumors following transplantation, and inoculation of tumor-bearing mice with bFGF markedly inhibits tumor growth in vivo. These results suggest that activators of FGF signaling may be useful for targeting medulloblastoma and other Shh-dependent tumors.
