Table 2.
Microenvironmental cues influence HGG cell phenotypes and therapeutic response
| Signalling molecule/ condition from microenvironment | Cell type of expression/ release | Interacting/ responsive molecule(s) of glioma cell | Effect on tumour | References |
|---|---|---|---|---|
| CXCL12 | Endothelial cells, astrocytes and neurons | CXCR4 | Promotes invasive phenotype, inhibits apoptosis and promotes proliferation | [98–100] |
| Bradykinin | Endothelial cells | B2R | Promotes motility of glioma cells towards blood vessels and deeper invasion of brain tissue | [101, 102] |
| Jagged and Delta-like ligands | Endothelial cells | NOTCH receptor | Maintains the GSC fraction by promoting GSC self-renewal, proliferation and expression of stemness-related genes. Promotes radioresistance | [103–107] |
| Nitric oxide | Endothelial cells | sGC | Promotes NOTCH signalling | [104, 107] |
| SHH | Endothelial cells | PTCH1 and PTCH2 | Increases expression of genes involved in proliferation, stemness, angiogenesis and survival | [108] |
| Interleukin-8 | Endothelial cells | CXCR2 | Increases invasion, expression of stemness-related genes and tumour growth | [109] |
| CD9 | Endothelial cells | Interleukin-6 receptor gp130 | Increases expression of stemness-related genes and the proliferation of GSCs | [110] |
| Long-term hypoxia | N/A | HIF2A | Promotes the expression of stemness-related genes and favours the survival of the mesenchymal GSC phenotype | [95] |
| Acute hypoxia | N/A | HIF1A | Induces a metabolic shift towards glycolysis and promotes quiescence | [111, 112] |
| Acute hypoxia | N/A | CD133, CD44 | Increases stemness properties | [113] |
| Acute hypoxia | N/A | HIF1A, BIRC3, FTL | Increases the resistance of HGG cells to radiotherapy and chemotherapy through mechanisms that include the inhibition of apoptosis | [114, 115] |
| Cycling hypoxia | N/A | HIF1A, GOT1, GSH | Reduces levels of intracellular reactive oxygen species to increase radioresistance | [116–118] |
| Cycling hypoxia | N/A | HIF1A, ABCB1 drug efflux pump | Increases resistance to chemotherapy by reducing intracellular accumulation of chemotherapeutics | [119–121] |
| Hypoxia | N/A | HIF1A, VEGF | Induces angiogenesis | [122, 123] |
| Acute hypoxia | N/A | HIF1A, CXCR4, CD133 | Promotes the expansion of CD133+ and CXCR4+ GSCs, inhibits differentiation and promotes migration | [98, 122, 124] |
| Acute and chronic hypoxia | N/A | HIF1A, HIF2A, NOTCH pathway, VEGF signalling | Promotes transdifferentiation of GSCs into endothelial cells | [125–128] |
| JAG1 | Neurons | NOTCH1 | Supports GSC maintenance, survival and migration | [129, 130] |
| NLGN3 | Neurons | FAK, PI3K-mTOR, SRC kinase and RAS signalling cascades | Promotes tumour cell proliferation. Increases expression of synapse-related genes and the formation of neuron-to-glioma synapses | [32, 131, 132] |
| Glutamate | Neurons | AMPARs | Induces glioma cell proliferation and increased migration speed | [132, 133] |
| CCL5 | TAMs | CaMKII, MMP2 | Promotes an invasive glioma cell phenotype | [134–136] |
| MMP14 | TAMs | pro-MMP2 | Supports invasion of glioma cells | [135, 136] |
| Pleiotrophin | TAMs | PTPRZ1 | Increases tumour growth and the SOX2+ GSC fraction | [33] |
| TGFB1 | TAMs | TGFBR2, MMP9 | Increases the invasive ability of CD133+ GSCs | [137] |
ABCB1, adenosine triphosphate-binding cassette subfamily B member 1. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor. B2R, bradykinin 2 receptor. BIRC3, baculoviral inhibitor of apoptosis repeat-containing protein 3. CaMKII, Ca2+/calmodulin-dependant protein kinase II. CCL5, C-C motif chemokine ligand 5. CD9, tetraspanin CD9. CD44, cluster of differentiation 44. CD133, cluster of differentiation 133 (prominin-1). CD44, cluster of differentiation 44. CXCL12, C-X-C motif chemokine ligand 12. CXCR2, C-X-C motif chemokine receptor 2. CXCR4, C-X-C motif chemokine receptor 4. FAK, focal adhesion kinase. FTL, ferritin light chain. GOT1, glutamic-oxaloacetic transaminase 1. gp130, glycoprotein 130. GSC, glioma stem cell. GSH, glutathione. HGG, high-grade glioma. HIF1A, hypoxia-inducible factor 1α. HIF2A, hypoxia-inducible factor 2α. JAG1, Jagged 1. MMP2, matrix metalloproteinase 2. MMP9, matrix metalloproteinase 9. MMP14, matrix matalloproteinase 14. NLGN3, neuroligin-3. NOTCH1, Notch receptor 1. PI3K-mTOR, phosphatidylinositol-3-kinase-mammalian target of rapamycin. PTCH1, patched 1. PTCH2, patched 2. PTPRZ1, protein tyrosine phosphate receptor type Z1. sGC, soluble guanylate cyclase. SHH, sonic hedgehog. SOX2, sex determining region Y-box 2. TAM, tumour-associated macrophage. TGFB1, transforming growth factor beta 1. TGFBR2, transforming growth factor beta receptor 2. VEGF, vascular endothelial growth factor