Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas.
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.
Becher
Oren J
OJ
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Hambardzumyan
Dolores
D
Fomchenko
Elena I
EI
Momota
Hiroyuki
H
Mainwaring
Lori
L
Bleau
Anne-Marie
AM
Katz
Amanda M
AM
Edgar
Mark
M
Kenney
Anna M
AM
Cordon-Cardo
Carlos
C
Blasberg
Ron G
RG
Holland
Eric C
EC
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D017930:Genes, Reporter; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D001616:beta-Galactosidase / Q000378:metabolism
C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D010982:Platelet-Derived Growth Factor; C509239:SHH protein, human; C465570:Shh protein, mouse; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D001616:beta-Galactosidase