A Synthetic Polymer Scaffold Reveals the Self-Maintenance Strategies of Rat Glioma Stem Cells by Organization of the Advantageous Niche

Abstract

Cancer stem cells (CSCs) are believed to be maintained within a microenvironmental niche. Here we used polymer microarrays for the rapid and efficient identification of glioma CSC (GSC) niche mimicries and identified a urethane-based synthetic polymer, upon which two groups of niche components, namely extracellular matrices (ECMs) and iron are revealed. In cultures, side population (SP) cells, defined as GSCs in the rat C6 glioma cell line, are more efficiently sustained in the presence of their differentiated progenies expressing higher levels of ECMs and transferrin, while in xenografts, ECMs are supplied by the vascular endothelial cells (VECs), including SP cell-derived ones with distinctively greater ability to retain xenobiotics than host VECs. Iron is stored in tumor infiltrating host macrophages (Mus), whose protumoral activity is potently enhanced by SP cell-secreted soluble factor(s). Finally, coexpression of ECM-, iron-, and Mu-related genes is found to be predictive of glioma patients' outcome. Our polymer-based approach reveals the intrinsic capacities of GSCs, to adapt the environment to organize a selfadvantageous microenvironment niche, for their maintenance and expansion, which redefines the current concept of anti-CSC niche therapy and has the potential to accelerate cancer therapy development. STEM CELLS 2016;34:1151-1162 SIGNIFICANCE STATEMENTA specialized microenvironment called niche that maintains cancer stem cells (CSCs) has been studied as a promising target of cancer therapy. However, as recapitulating the niche by conventional approaches is challenging due to its biological and physical complexity, some important aspects of CSC biology might remain unelucidated. We here provide the first demonstration of the utility of synthetic polymer as a niche mimic for GSCs. Our approach also reveals an important finding, that is, self-organization of the GSC niche, which appends a new aspect to the current concept of CSC regulation and could help development therapeutic strategies for cancer eradication.

Requirement of ABC transporter inhibition and Hoechst 33342 dye deprivation for the assessment of side population-defined C6 glioma stem cell metabolism using fluorescent probes

“…Our previous cDNA microarray data for the expression of some ABC transporter genes (available in NCBI GEO repository #GSE72431) reveal that only ABCB1 gene is specifically upregulated in C6 glioma SP cells compared with MP cells approximately by 10.6-fold (SP:MP = 0.64:0.060), suggesting that the ability of SP cells to expel xenobiotics is mainly dependent on ABCB1 in C6 cells [25, 26]. In addition, it has been reported that ABCB1 is overexpressed in human glioma tissues and its expression level is strongly correlated with that of another glioma CSC marker CD133, suggesting the importance of ABCB1 in glioma CSCs [27].…”

Induction of protumoral CD11chigh macrophages by glioma cancer stem cells through GM‐CSF

“…To prove this possibility, mouse bone marrow-derived monocytes were cultured with SP-or MP-conditioned medium (SPor MP-CM). When monocytes were cultured in 10% FBS-DMEM alone, the number of monocytes was decreased by 4.85% after 4-day culture (Tabu et al 2016). The cell number was higher in the culture with SP-CM than that in MP-CM, and the effect of the CM was in a concentration-dependent manner, suggesting that CSCs promote the survival of bone marrow-derived monocytes via soluble factors more efficiently than non-CSCs ( Fig.…”

“…We and others have found that CSCs have a potential to create their own niche which helps maintain the CSC phenotype and promote tumor progression (Tabu et al . ; Ricci‐Vitiani et al . ; Korkaya et al .…”

“…Like tissue stem cells, CSCs are maintained in special microenvironment, called niche, which is considered to be composed of a large variety of components such as extracellular matrixes, blood vessels, stroma cells and immune cells (Sneddon & Werb 2007;Borovski et al 2011). We and others have found that CSCs have a potential to create their own niche which helps maintain the CSC phenotype and promote tumor progression (Tabu et al 2016;Ricci-Vitiani et al 2010;Korkaya et al 2011;Cheng et al 2013;Niibori-Nambu et al 2013;Yamashina et al 2014;Zhou et al 2015). For example, CSCs were observed to differentiate into vascular endothelial cells, pericytes, and produce extracellular matrices in glioblastoma (Ricci-Vitiani et al 2010;Cheng et al 2013;Niibori-Nambu et al 2013).…”

WITHDRAWN: Intranasal GM-CSF enhances efficacy of local ACNU delivery rendezvousing with TMZ plus irradiation in glioblastoma

“…Thus, therapeutic strategies against CSCs are essential for the accomplishment of cancer eradication [3]. Other researchers have found that CSCs have a potential to create their own niche, which helps maintain the CSC phenotype and promote tumor progression [4,5].…”