Prognostic and Therapeutic Roles of the Insulin Growth Factor System in Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain malignancy and is often resistant to conventional treatments due to its extensive cellular heterogeneity. Thus, the overall survival of GBM patients remains extremely poor. Insulin-like growth factor (IGF) signaling entails a complex system that is a key regulator of cell transformation, growth and cell-cycle progression. Hence, its deregulation is frequently involved in the development of several cancers, including brain malignancies. In GBM, differential expression of several IGF system components and alterations of this signaling axis are linked to significantly worse prognosis and reduced responsiveness to temozolomide, the most commonly used pharmacological agent for the treatment of the disease. In the present review we summarize the biological role of the IGF system in the pathogenesis of GBM and comprehensively discuss its clinical significance and contribution to the development of resistance to standard chemotherapy and experimental treatments.

Keywords: IGF-binding protein; drug resistance; glioblastoma; insulin-like growth factor signaling pathway; insulin/insulin-like growth factor system.

Figure 1

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.

Figure 2

Therapeutic strategies to block insulin-like growth factor signaling in glioblastoma multiforme cells. Approaches tested to inhibit insulin-like growth factor (IGF) signaling in glioblastoma (GBM) patients include antisense oligonucleotides against IGF-I and IGF-IR mRNA (1) or the employ of IGF-I triple helix gene therapy (2) to induce a block of tumor progression. IGF-IR direct inhibitors, IGF-IR TKIs (3) and IGF-IR mAbs (4) are also tested on GBM cell lines to reduce IGF downstream signaling.