Abstract
Gli signaling is critical for central nervous system development and is implicated in tumorigenesis. To monitor Gli signaling in gliomas in vivo, we created platelet-derived growth factor-induced gliomas in a Gli-luciferase reporter mouse. We find that Gli activation is found in gliomas and correlates with grade. In addition, we find that sonic hedgehog (SHH) is expressed in these tumors and also correlates with grade. We identify microvascular proliferation and pseudopalisades, elements that define high-grade gliomas as SHH-producing microenvironments. We describe two populations of SHH-producing stromal cells that reside in perivascular niche (PVN), namely low-cycling astrocytes and endothelial cells. Using the Ptc-LacZ knock-in mouse as a second Gli responsive reporter, we show beta-galactosidase activity in the PVN and in some tumors diffusely throughout the tumor. Lastly, we observe that SHH is similarly expressed in human gliomas and note that an intact tumor microenvironment or neurosphere conditions in vitro are required for Gli activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / metabolism
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Astrocytes / pathology
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Down-Regulation
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Genes, Reporter
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glioma / genetics
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Glioma / metabolism*
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Glioma / pathology
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Hedgehog Proteins / biosynthesis
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Hedgehog Proteins / genetics
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Humans
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Kruppel-Like Transcription Factors / metabolism*
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Mice
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Mice, Transgenic
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Oligodendroglioma / genetics
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Oligodendroglioma / metabolism
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Oligodendroglioma / pathology
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Platelet-Derived Growth Factor / biosynthesis
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism*
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Transcription Factors / metabolism*
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Zinc Finger Protein GLI1
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beta-Galactosidase / metabolism
Substances
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GLI1 protein, human
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Gli1 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Platelet-Derived Growth Factor
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SHH protein, human
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Shh protein, mouse
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Transcription Factors
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Zinc Finger Protein GLI1
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beta-Galactosidase