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CD133+ cells from medulloblastoma and PNET cell lines are more resistant to cyclopamine inhibition of the sonic hedgehog signaling pathway than CD133− cells

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Tumor Biology

Abstract

CD133 has recently been used as a reliable marker for brain tumor stem cells isolation. Sonic hedgehog (SHH) is implicated in medulloblastoma and central primitive neuroectodermal tumor (cPNET) formation. It has recently been suggested a role for the EWS/FLI1 fusion protein—typical of pPNET—in the upregulation of GLI1 and PTCH1 genes. Cyclopamine inhibits the SHH pathway in medulloblastoma cell lines, but its effect on cPNET and pPNET cell lines has not been well established yet. Our purpose was to study the effect of cyclopamine on medulloblastoma and PNET cell lines and to analyze whether CD133 expression might be able to modify this effect. We analyzed gene expression, cell viability, apoptosis, and tumorigenic capability before and after cyclopamine treatment in CD133 high-expressing and CD133 low-expressing cell lines. All medulloblastoma and PNET cell lines displayed an inhibitory effect on the expression of SHH pathway genes, on viability, and on tumorigenic potential after treatment. Nevertheless, CD133 expression made the cells more resistant to cyclopamine inhibition. These results open new doors to the understanding of CD133+ cancer stem cells as residual cells that might be responsible for treatment resistance.

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Abbreviations

BTSC:

brain tumor stem cell

CNS:

central nervous system

cPNET:

central primitive neuroectodermal tumor

EGL:

external granular layer

GCP:

granule cell precursor

NSC:

neural stem cell

pPNET:

peripheral primitive neuroectodermal tumor

SHH:

sonic hedgehog

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Acknowledgments

M. Enguita-Germán and P. Schiapparelli thank the Asociación de Amigos de la Universidad de Navarra and the Departamento de Educación del Gobierno de Navarra for the fellowships received. J.S. Castresana thanks the Asociación Española de Pediatría for the VIII Premio Nutribén de Investigación Pediátrica and the Sociedad Española de Hematología y Oncología Pediátricas, Madrid. This research was supported in part by grants from the Departmento de Salud del Gobierno de Navarra (9/07), Caja Navarra (08/13912) and Fundación Universitaria de Navarra, Pamplona and Fondo de Investigación Sanitaria (PI081849), Madrid.

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Authors and Affiliations

  1. Brain Tumor Biology Unit, University of Navarra School of Sciences, Pamplona, Spain

    Mónica Enguita-Germán, Paula Schiapparelli & Javier S. Castresana

  2. Research Unit, La Paz University Hospital, Madrid, Spain

    Juan A. Rey

  3. Unidad de Biología de Tumores Cerebrales, CIFA, Universidad de Navarra, Irunlarrea 1, 31008, Pamplona, Spain

    Javier S. Castresana

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  1. Mónica Enguita-Germán
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  2. Paula Schiapparelli
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Correspondence to Javier S. Castresana.

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Enguita-Germán, M., Schiapparelli, P., Rey, J.A. et al. CD133+ cells from medulloblastoma and PNET cell lines are more resistant to cyclopamine inhibition of the sonic hedgehog signaling pathway than CD133− cells. Tumor Biol. 31, 381–390 (2010). https://doi.org/10.1007/s13277-010-0046-4

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