In its IGF-dependent role, IGFBP-6 suppresses IGF-II-driven proliferation, survival, migration, and differentiation by reducing ligand engagement of IGF-1R (and IR-A), with consequent attenuation of downstream PI3K–AKT and RAS–MAPK signaling; in tumor models (e.g., glioma), enforced IGFBP-6 reduces IGF-1R/AKT activation and tumor cell expansion [23,24,25]. Here, IGFBP6 is linked to glioma.