The PGI-KLF4 pathway regulates self-renewal of glioma stem cells residing in the mesenchymal niches in human gliomas

Abstract

Gliomas display cellular hierarchies with self-renewing tumorigenic glioma stem cells (GSCs) at the apex. The GSC niches function as a regulator of GSC maintenance, however, the exact components of GSC niches that mediate this process are still far from fully defined. Here, we showed that glioma cells with aberrant mesenchymal phenotypes constitute a mesenchymal niche for GSCs. Using patient-derived specimens, we demonstrated that the paracrine PGI signaling, initiated by mesenchymal glioma cells, induces the self-renewal and tumorigenic potentials of GSCs through induction of KLF4. Treatment of intracranial orthotopic xenografts with shPGI or shKLF4 leads to less lethal potency. Our data therefore suggest that blockade of the PGI-KLF4 pathway may provide a therapeutic strategy against GSC niches.

Transcriptional repression of FOXO1 by KLF4 contributes to glioma progression

“…KLF4 also plays crucial roles in maintenance of neural stem cells, and KLF4 deficiency causes impaired neurogenesis in adult mouse brain [30, 31]. KLF4 induced by PGI initiated by mesenchymal glioma cells, induces the self-renewal and tumorigenic potentials of glioma stem cells [32]. These reports and our findings suggest the potential role of KLF4 in glioma.…”

Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

“…Previous study has demonstrated that SOX2, by marking and regulating the functions of skin tumor-initiating cells and CSCs, establishes a continuum between tumor initiation and progression in primary skin tumors [22]. Zhu et al indicated that the paracrine PGI signaling induced the self-renewal and tumorigenic potentials of GSCs through induction of KLF4; treatment of intracranial orthotopic xenografts with shPGI or shKLF4 leads to less lethal potency [38]. Therefore their data suggested that blockade of the PGI-KLF4 pathway might provide a therapeutic strategy against GSC niches.…”

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

“…These findings highlighted the importance of BMI1 in GSCs. Zhu et al (2014) showed that the PGI-KLF4 pathway regulates self-renewal of GSCs in human gliomas, suggesting blockade of the PGI-KLF4 pathway may provide a therapeutic strategy against GSCs. These studies reinforce the importance of deep understanding of GSC markers.…”