Histological Characterization of the Tumorigenic "Peri-Necrotic Niche" Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma.

Aya Ishii,Keiyo Takubo,Hirokazu Sadahiro,Hiroo Kawano,Tokuhiro Kimura,Michiyasu Suzuki,Eiji Ikeda,Anita B Hjelmeland

doi:10.1371/journal.pone.0147366

Aya Ishii, Keiyo Takubo + Show 6 more

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https://doi.org/10.1371/journal.pone.0147366

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Abstract

BackgroundCharacterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically.MethodsMulti-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay.ResultsA small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity.ConclusionsThese data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.

Highlights

Astrocytic tumors are the most common tumors arising in the central nervous system
A small subpopulation of hypoxia-inducible factor (HIF)-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas
Peri-Necrotic Niche in Glioblastoma condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. These data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and may be a therapeutic target to control the behavior of glioblastomas

Summary

Introduction

According to the WHO classification system [1], infiltrating astrocytic tumors are classified into diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). A glioblastoma tissue is composed of various regions from well-vascularized areas to severely hypoxic necrotic areas. This microenvironmental heterogeneity has various effects on the properties of tumor cells and influences the pathophysiology of the tumor. Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. We examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically

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Conclusion