HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.
Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.
Clement
Virginie
V
Department of Genetic Medicine and Development, University of Geneva Medical School, 8242 CMU, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland.
Sanchez
Pilar
P
de Tribolet
Nicolas
N
Radovanovic
Ivan
I
Ruiz i Altaba
Ariel
A
D000818:Animals; D001932:Brain Neoplasms / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000503:physiopathology*; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1