Induction of protumoral CD11c^high macrophages by glioma cancer stem cells through GM‐CSF

Abstract

Cancer stem cells (CSCs) are maintained under special microenvironment called niche, and elucidation and targeting of the CSC niche will be a feasible strategy for cancer eradication. Tumor-associated macrophages (TAMs) are known to be involved in cancer progression and thus can be a component of CSC niche. Although TAMs are known to play multiple roles in tumor progression, involvement of CSCs in TAM development fully remains to be elucidated. Using rat C6 glioma side population (SP) cells as a model of glioma CSCs, we here show that CSCs induce the TAM development by promoting survival and differentiation of bone marrow-derived monocytes. CSC-induced macrophages can be separated into two distinct subsets of cells, CD11c low and CD11c high cells. Interestingly, only the CD11c high subset of cells have protumoral activity, as shown by intracranial transplantation into immune-deficient mice together with CSCs. These CD11c high macrophages were observed in the tumor formed by co-transplantation with CSCs. Furthermore, CSCs produced GM-CSF and anti-GM-CSF antibody inhibited CSC-induced TAM development. In conclusion, CSCs have the ability to selfcreate their own niche involving TAMs through CSC-derived GM-CSF, which can thus be a therapeutic target in view of CSC niche disruption.

Absence of host NF-κB p50 induces murine glioblastoma tumor regression, increases survival, and decreases T-cell induction of tumor-associated macrophage M2 polarization

“…When normalized to tumor size using bioluminescence, we observe a 4-fold increase in the density of Ly6C int MHCII hi TIMs, and no change in the density of Ly6C lo MHCII hi TIMs, in p50−/− mice (not shown). In a rat glioma model, CDllc hi macrophages potentiated orthotopic tumor growth [32]. Consistent with reduced tumor growth, CDllc expression was decreased in the predominant Ly6C int MHCII hi TIM subset, but was unchanged in the other three Ly6C;MHCII populations in p50−/− hosts (Fig.…”

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

“…Specifically, we postulate that the delay in disease onset we have noted is a result of a diminished activation state of CNS macrophages that are involved in reactivating pathogenic T cells that have trafficked into the CNS during the day +4 through day +8 interval. + cells in EAE has not been reported, but in other contexts cells with this phenotype have been reported to serve either an inflammatory or regulatory function (29)(30)(31). We found these cells exhibited a proinflammatory phenotype in both control and tolerized cohorts as evidenced by their production of TNF-a (via intracellular staining; data not shown).…”

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].…”