Abstract
Hedgehog pathway activity has been demonstrated in malignant glioma. However, its role in tumor growth has not been determined. Here we demonstrate that pharmacological inhibition of the Hedgehog pathway in established orthotopic malignant glioma xenografts confers a survival advantage. Pathway inhibition is measured in transplanted human tumor cells and not in host mouse brain. Correspondingly, survival benefit is observed only in tumors with an operational Hedgehog pathway. These data indicate that Hedgehog signaling regulates the growth of select malignant gliomas. We also demonstrate that Hedgehog pathway component and gene target expression segregate to CD133+ tumor initiating cells. Treated mice eventually succumb to disease, thus, targeting the Hedgehog pathway in CD133+ cells produces significant, but incomplete tumor regression. Therefore, our studies suggest that more complete tumor regression may require the inclusion of other therapeutic targets, including CD133− cells.
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Acknowledgements
We are grateful to Infinity Pharmaceuticals for supplying cyclopamine. Histological services were performed, in part, by the Vanderbilt Medical Center (VMC) Human Tissue Acquisition and Pathology Shared Resource (supported by the Vanderbilt Ingram Cancer Center, P30 CA68485). Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource (supported by the Vanderbilt Ingram Cancer Center, P30 CA68485, and the Vanderbilt Digestive Disease Research Center, DK058404). This work was supported by grants to MKC from the NINDS (K02 NS053614), the Burroughs Wellcome Fund and the Doris Duke Charitable Foundation (for human tissues) and VMC development funds (for animal studies).
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Sarangi, A., Valadez, J., Rush, S. et al. Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival. Oncogene 28, 3468–3476 (2009). https://doi.org/10.1038/onc.2009.208
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DOI: https://doi.org/10.1038/onc.2009.208
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