Simulation Predicts IGFBP2-HIF1α Interaction Drives Glioblastoma Growth

Abstract

Tremendous strides have been made in improving patients’ survival from cancer with one glaring exception: brain cancer. Glioblastoma is the most common, aggressive and highly malignant type of primary brain tumor. The average overall survival remains less than 1 year. Notably, cancer patients with obesity and diabetes have worse outcomes and accelerated progression of glioblastoma. The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway. However, while the process of invasive glioblastoma progression has been extensively studied macroscopically, it has not yet been well characterized with regards to intracellular insulin signaling. In this study we connect for the first time microscale insulin signaling activity with macroscale glioblastoma growth through the use of computational modeling. Results of the model suggest a novel observation: feedback from IGFBP2 to HIF1α is integral to the sustained growth of glioblastoma. Our study suggests that downstream signaling from IGFI to HIF1α, which has been the target of many insulin signaling drugs in clinical trials, plays a smaller role in overall tumor growth. These predictions strongly suggest redirecting the focus of glioma drug candidates on controlling the feedback between IGFBP2 and HIF1α.

Overexpression of IGFBP2 mRNA predicts poor survival in patients with glioblastoma

“…IGFBP2 expression in the tumor has been proved in many researches that was associated with a variety of pathological conditions, including hypoxia [24] and regeneration [25]. In the present study, we founded IGFBP2 high cells accumulate in the immediate vicinity of focal necrosis of some tumors.…”

Identification of Immune-Related Genes Contributing to the Development of Glioblastoma Using Weighted Gene Co-expression Network Analysis

“…Analysis of reverse-phase protein array data (RPPA; a high-throughput antibody-based technique) from the TCGA GBM dataset yielded proteins significantly associated with TREM1, including IFGBP2, TGM2 VEGFR2, and NDRG1, many of which have also been linked to hypoxia ( Figures 5B,G–I ). IGFBP2 has been reported to exert an oncogenic effect by enhancing invasiveness, angiogenesis, and VM formation and as part of a negative feedback loop with HIF1α in glioma ( 24 – 26 ). It has also been correlated with classic immunosuppressive biomarkers in glioma, such as CHI3L1, TNFRSF1A, LGALS1, TIMP1, VEGFA, ANXA1 , and LGALS3 ( 27 ).…”

Metabolic Reprogramming in Glioma

“…Downstream signaling from insulin-like growth factor (IGF1) through Ras to HIF-1α upregulates mRNA encoding IGFBP2, thus autoregulating HIF by decreasing IGF1 signaling (Feldser et al, 1999 ; Sinha et al, 2011 ). IGFBP2 is often upregulated in GBM, promoting tumor development, progression, and invasion (Lin et al, 2015 ). Through modeling it was shown that IGFBP2 plays an integral role in sustaining HIF-1α signaling in an oxygen-independent manner due to its negative effect on IGF1 signaling (Lin et al, 2015 ).…”

“…IGFBP2 is often upregulated in GBM, promoting tumor development, progression, and invasion (Lin et al, 2015 ). Through modeling it was shown that IGFBP2 plays an integral role in sustaining HIF-1α signaling in an oxygen-independent manner due to its negative effect on IGF1 signaling (Lin et al, 2015 ).…”