Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli.

Yuki Shirakawa,Kou Yonemaru,Ayumi Kanemaru,Takuichiro Hide,Shunsuke Miyake,Michiko Yamaoka,Naoki Shinojima,Kunimasa Ohta,Akari Kuwano,Hideyuki Saito,Naofumi Ito,Yuki Ito,Akitake Mukasa,Hirofumi Jono,Shota Uchino

doi:10.3390/cells10112970

Abstract

Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

Highlights

IntroductionDespite the existence of several treatments, such as chemo-radio therapy and surgical resection, the median survival of patients is about 1 year [2], and several standard therapeutic strategies have not improved over the past three decades
Several studies recently revealed that the incorporation of lactic acid bacteria induced stem cell properties in human dermal fibroblast (HDF) cells, and ribosomes represented an actual component for the induction of stem cell characters [13,17]
These studies suggested that ribosome incorporation induced stem cell characters in eukaryotic cells including human cells, the biological and clinical significance of ribosome incorporation was totally unclear

Summary

Introduction

Despite the existence of several treatments, such as chemo-radio therapy and surgical resection, the median survival of patients is about 1 year [2], and several standard therapeutic strategies have not improved over the past three decades. GBM frequently shows characteristics of chemo-radio resistance and recurrence after resection [3]. Part of the reason for chemoradio resistance and recurrence is the presence of a small population of stem cell character cells called GBM stem-like cells (GSCs) [3,4,5]. Since GSCs play important roles in angiogenesis, self-renewal, unlimited proliferation maintains tumor tissue of GBM, and low mitotic activity, those characteristics protect GSCs from therapeutic approaches directed against actively dividing cells [5,6].

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