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. 2021 Feb 2;10:612385. doi: 10.3389/fonc.2020.612385

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Copyright © 2021 Tirrò, Massimino, Romano, Martorana, Pennisi, Stella, Pavone, Di Gregorio, Puma, Tomarchio, Vitale, Manzella and Vigneri

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Expression and function of the insulin/insulin-like growth factor system in glioblastoma cells. (A) The pathogenesis and progression of glioblastoma multiforme (GBM) is mainly linked to the activation of Insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor (InsR). The stimulation of IGF-IR and the activation of InsR promote the recruitment of IRS-1 and the activation of the mitogenic and pro-survival mediators Akt and ERK1/2 that contribute to increase (upward red arrow) GBM cell growth, cell proliferation and cell migration. (B) A pivotal role in regulating IGF-system action in GBM pathogenesis is provided by IGFBP-2. (1) The improper activity of protease that cleaves IGFBP-2 causes an increase of circulating-free IGFs (upward red arrow) and the subsequent activation of downstream pathway causing an increase on cell growth, cell proliferation and cell migration. The intracytoplasmatic and intranuclear activity of IGFBP-2 determines the activation of EGFR-STAT-3 (2) or HIF1a (3) signaling and the improvement of the transcription of their target genes. IGFBP-2 activates also the integrin signaling (4) which lead to the activation of the IGFBP-2/Integrin/ILK/NF-kB pathway that is responsible of the transcription of genes linked to adhesion and migration. Finally, stimuli induced by IGF-I, NF-kB, HIF1a, steroid and growth hormones (5) increase IGFBP-2 expression (upward red arrow) causing the activation of pathway linked to GBM progression.