Table 1.
Characteristics and functions of GASCs.
| Nomenclature Used | Sources | Method of Identification | Characteristics of Cultured GASCs | Major Characteristics or Functions of GASCs Identified | References |
|---|---|---|---|---|---|
| GS-MSCs | Orthotopic xenografting of human gCSCs in mice | - Primary cultures | - Spindle-shape morphology - Markers: Sca-1+, CD9+ CD45−, CD11b−, CD31−, NG2− - Differentiation into adipocytes, osteoblasts and chondrocytes - Non-tumorigenic behavior |
Location of GASCs: - Predominantly located around blood vessels. |
[7] |
| GASCs | Peritumoral region from GBs | - Primary cultures - IF analysis: (FSP1/S100A4+) |
- Adherence to plastic with spindle-shape morphology - Markers: α-SMA+, PDGFRβ+, FSP1/S100A4+, CD105+, CD73+, CD90+, CD31−, CD14−, GFAP−, CD34−, CD45− - GASCs underwent osteogenesis, but not adipogenesis - Non-tumorigenic behavior - Diploid cells |
Tumor-supporting function: - GASCs have tumor-promoting effects on glioma cell lines in vitro and in vivo. - GASCs increase angiogenesis in the orthotopic U87MG glioma model. Heterogeneity of GASCs: - Two subtypes of GASCs identified in surgical margins of GB patients: GASC-B promoted the development of tumors and endothelium, whereas GASC-A did not. Invasion function: GASC-secreted CXCL14 may drive glycolysis and cell invasion in glioma via the UCA1/miR-182/PFKFB2 axis. Prognostic role: CXCL14 is overexpressed in GASCs and predicts clinical outcome. |
[21,22,23,24,25] |
| MSLCs/GS-MSLCs/tMSLCs | Human glioma specimens | - Primary cultures - IF analysis (CD105+/CD31− or CD105+/NG2−) |
- Adherence to plastic with spindle-shape morphology - Markers: CD105+, CD73+, CD90+, CD45−, CD31−, NG2− - Differentiation into adipocytes, osteoblasts and chondrocytes - Non-tumorigenic behavior |
Invasion function: - GASCs contribute to the abundance of HA in TME through HAS2 induction, thereby increasing the invasiveness of GB cells. - GASCs are involved in force-mediated proinvasive ECM remodeling through CCL2/JAK1/MLC2 signaling in GB, like CAFs in carcinoma. - GASCs promote the invasion of GB cells through the secretion of C5a into the TME, further increasing ZEB1 expression in GB cells via the C5aR1/p38 MAPK signaling pathway. Prognostic role: - The isolation of GASCs from the specimen of primary GB is negatively associated with patient survival. |
[9,10,12,13,15,16] |
| BT-MSCs | - GL261 murine glioma model - Human GB specimens |
- Primary cultures |
Murine model: - Fibroblastoid morphology - Markers: Lin-Sca1+/CD9+/CD44+/CD166+/− - Multilineage differentiation capacity - Tumorigenic behavior Human model: - Markers: CD44+, CD9+, CD166+ |
Tumor-supporting function: - The infiltration of GASCs is correlated with tumor progression. - GASCs increased the proliferation rate of GL261 cells in vitro. |
[8] |
| CAF-like cells | Human GB specimens | - IF analysis: (α-SMA+/GFAP- or TE-7+/GFAP-) |
- Markers: α-SMA+, TE-7+, GFAP− |
Location of GASCs: - Predominantly localized around abnormal blood vessels. |
[17] |
| GA-hMSCs | Human glioma specimens | - Primary cultures - IF analysis: (CD105+/CD31− or CD105+/PDGFRβ+) - Flow cytometry analysis: triple-positive (CD105+/CD73+/CD90+) cells |
- Adherence to plastic with spindle-shape morphology - Markers: CD105+, CD73+, CD90+, CD45−, CD34− - Did not harbor mutations common to GB - Differentiation into adipocytes, osteoblasts and chondrocytes (NB: some specimens differentiated into only two mesenchymal phenotypes) - Non-tumorigenic behavior |
Tumor-supporting function: - Increase the proliferation and self-renewal of GSCs in vitro and enhance GSC tumorigenicity and mesenchymal features in vivo. - These effects are mediated by the secretion of soluble growth-promoting factors, such as IL-6, and by the exosomal delivery of specific oncogenic miRNAs, such as miR-1587. Prognostic role: - The percentage of GASCs is inversely correlated with OS. |
[2,3,4] |
| MSLCs | Human glioma specimens | - Primary cultures | - Adherence to plastic with spindle-shape morphology - Markers: CD73+, CD105+, CD90+ or CD90− - Differentiation into osteoblasts and, to some extent, adipocytes and chondrocytes |
Heterogeneity of GASCs: - Two different subsets of GASCs, differing in their expression of the CD90 surface marker, were discovered after cell sorting. - The CD90− GASCs produce more VEGF and PGE2 than their CD90+ counterparts. |
[11] |
| tMSCs | Human glioma specimens | - Primary cultures | - Adherence to plastic with spindle-shape morphology - Markers: CD44+, CD105+, CD166+, CD45−, CD34− |
Heterogeneity of GASCs: - GASCs derived from LGGs and HGGs have different proteome profiles. - Molecules associated with mesenchymal cells (vimentin and transglin), and tumor aggressiveness with potential secretory behavior (e.g., cathepsin B) were among those for which differential gene expression was detected. |
[14] |
| GbMSCs | Human glioma specimens | - Primary cultures | - Adherence to plastic with spindle-shape morphology - Markers: CD73+, CD105+, CD44+, CD90high or CD90low, CD31−, CD34−, CD14−, NG2−, PDGFRβ− - Differentiation into adipocytes, osteoblasts, and chondrocytes |
Heterogeneity of GASCs: - Two GASC subpopulations based on CD90 expression (CD90high and CD90low). Tumor-supporting function: - CD90high GASCs significantly promoted glioma cell growth whereas CD90low GASCs promoted angiogenesis via pericyte transition. |
[5,6] |
| GASCs | Human glioma specimens | - Primary cultures | - Adherence to plastic with spindle-shape morphology - Markers: CD105+, CD73+, CD90+, CD45- - Differentiation into mesodermal derivatives, such as endothelial-, osteoblast-, and myocyte-like cells - Non-tumorigenic behavior |
Tumor-supporting function: - GASCs support the malignant properties of both GB cell lines (A172 and U87) and human GSCs, mainly through the release of exosomes. - Exosomes released both from HGGs and LGGs were able to increase the in vitro aggressiveness of GB cells, although those from LGGs did so to a significantly lesser extent. Invasion function: - The strength of GSCs adhesion to GASCs appears to be significantly lower for cells derived from HGGs than for those derived from LGGs. - GSCs from HGGs firmly adhere to GASCs from LGGs, but not to those from HGGs. Prognostic role: - Ability of a score based on the expression of nine GASC surface markers (CD133, CD271, ABCG2, E-Cadherin, CD90, CD49a, CD49d, CD105, CD73) to predict OS and malignant PFS in LGG patients. - An NF-κB signature extrapolated from GASC predicts LGG prognosis. |
[18,19,20,26] |
BT-MSCs, brain tumor-derived MSCs; CAF-like cells, cancer associated fibroblast-like cells; GA-hMSCs, glioma-associated human MSCs; GASCs, glioblastoma-associated stromal cells or glioma-associated stem cells; GB, glioblastoma; GbMSCs, glioma-associated MSCs or glioblastoma-derived MSCs; gCSCs, glioma cancer stem cells; GSCs, glioma stem cells; GS-MSCs, glioma stroma-MSCs; GS-MSLCs, glioma stromal MSLCs; HA, hyaluronic acid; HAS2, HA synthase-2; HGGs, high grade gliomas; LGGs, low grade gliomas; MSCs, mesenchymal stem cells; MSLCs, mesenchymal stem-like cells; TME, tumor microenvironment; tMSCs, tumor MSCs; tMSLCs, tumor MSLCs; OS, overall survival; PFS, progression-free survival.