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Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival

Oncogene volume 28, pages 3468–3476 (2009)Cite this article

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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References

  • Ahn S, Joyner AL . (2005). in vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437: 894–897.

    Article  CAS  Google Scholar 

  • Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760.

    Article  CAS  Google Scholar 

  • Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W et al. (2007). Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25: 2524–2533.

    Article  CAS  Google Scholar 

  • Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M et al. (2009). Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457: 608–611.

    Article  CAS  Google Scholar 

  • Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN et al. (2002). Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297: 1559–1561.

    Article  CAS  Google Scholar 

  • Chen JK, Taipale J, Cooper MK, Beachy PA . (2002a). Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 16: 2743–2748.

    Article  CAS  Google Scholar 

  • Chen JK, Taipale J, Young KE, Maiti T, Beachy PA . (2002b). Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99: 14071–14076.

    Article  CAS  Google Scholar 

  • Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL et al. (2006). Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66: 9339–9344.

    Article  CAS  Google Scholar 

  • Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A . (2007). HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17: 165–172.

    Article  CAS  Google Scholar 

  • Ehtesham M, Sarangi A, Valadez JG, Chanthaphaychith S, Becher MW, Abel TW et al. (2007). Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 26: 5752–5761.

    Article  CAS  Google Scholar 

  • Fomchenko EI, Holland EC . (2006). Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res 12: 5288–5297.

    Article  CAS  Google Scholar 

  • Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H et al. (2002). Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 1: 10.

    Article  Google Scholar 

  • Gutmann DH, Maher EA, Van Dyke T . (2006). Mouse Models of Human Cancers Consortium Workshop on Nervous System Tumors. Cancer Res 66: 10–13.

    Article  CAS  Google Scholar 

  • Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A et al. (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431: 707–712.

    Article  CAS  Google Scholar 

  • Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A . (2007). Tumor growth need not be driven by rare cancer stem cells. Science 317: 337.

    Article  CAS  Google Scholar 

  • Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC et al. (2002). The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61: 215–225; discussion 226–229.

    Article  Google Scholar 

  • Kleihues P, Soylemezoglu F, Schauble B, Scheithauer BW, Burger PC . (1995). Histopathology, classification, and grading of gliomas. Glia 15: 211–221.

    Article  CAS  Google Scholar 

  • Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9: 391–403.

    Article  CAS  Google Scholar 

  • Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA et al. (2007). Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53: 503–517.

    Article  CAS  Google Scholar 

  • Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR et al. (2006). Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5: 67.

    Article  Google Scholar 

  • Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA et al. (2008). Identification of A2B5+CD133- tumor-initiating cells in adult human gliomas. Neurosurgery 62: 505–514; discussion 514–515.

    Article  Google Scholar 

  • Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G et al. (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444: 761–765.

    Article  CAS  Google Scholar 

  • Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ . (2008). Efficient tumour formation by single human melanoma cells. Nature 456: 593–598.

    Article  CAS  Google Scholar 

  • Rohatgi R, Scott MP . (2007). Patching the gaps in Hedgehog signalling. Nat Cell Biol 9: 1005–1009.

    Article  CAS  Google Scholar 

  • Rubin LL, de Sauvage FJ . (2006). Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5: 1026–1033.

    Article  CAS  Google Scholar 

  • Sanchez P, Ruiz i Altaba A . (2005). In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev 122: 223–230.

    Article  CAS  Google Scholar 

  • Shu Q, Wong KK, Su JM, Adesina AM, Yu LT, Tsang YT et al. (2008). Direct orthotopic transplantation of fresh surgical specimen preserves CD133+ tumor cells in clinically relevant mouse models of medulloblastoma and glioma. Stem Cells 26: 1414–1424.

    Article  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumour initiating cells. Nature 432: 396–401.

    Article  CAS  Google Scholar 

  • Suggitt M, Bibby MC . (2005). 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clin Cancer Res 11: 971–981.

    CAS  PubMed  Google Scholar 

  • Trowbridge JJ, Scott MP, Bhatia M . (2006). Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci USA 103: 14134–14139.

    Article  CAS  Google Scholar 

  • Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV et al. (2000). Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97: 14720–14725.

    Article  CAS  Google Scholar 

  • Weinstein IB, Joe A . (2008). Oncogene addiction. Cancer Res 68: 3077–3080; discussion 3080.

    Article  CAS  Google Scholar 

  • Xu Q, Yuan X, Liu G, Black KL, Yu JS . (2008). Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 26: 3018–3026.

    Article  CAS  Google Scholar 

  • Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP et al. (2008). A paracrine requirement for hedgehog signalling in cancer. Nature 455: 406–410.

    Article  CAS  Google Scholar 

  • Zhang XM, Ramalho-Santos M, McMahon AP . (2001). Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 105: 781–792.

    Article  CAS  Google Scholar 

  • Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT et al. (2009). Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457: 603–607.

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Neurology, Vanderbilt Medical Center, Nashville, TN, USA

    A Sarangi, J G Valadez & M K Cooper

  2. Vanderbilt Neuroscience Graduate Program, Vanderbilt Medical Center, Nashville, TN, USA

    A Sarangi & M K Cooper

  3. Department of Pediatrics, Vanderbilt Medical Center, Nashville, TN, USA

    S Rush

  4. Department of Pathology, Vanderbilt Medical Center, Nashville, TN, USA

    T W Abel

  5. Vanderbilt Ingram Cancer Center, Vanderbilt Medical Center, Nashville, TN, USA

    R C Thompson

  6. Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA

    R C Thompson

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  1. A Sarangi
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  2. J G Valadez
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Correspondence to M K Cooper.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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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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