Expanding the scope of candidate prognostic marker IGFBP2 in glioblastoma

Lindström, Mikael S.

doi:10.1042/bsr20190770

Cited by 12 publications

(12 citation statements)

References 19 publications

(37 reference statements)

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“…Insulin-like growth factor binding protein 2, a well-established molecule of interest in GBM ( Yao et al, 2016 ), was found to be more highly expressed in STS and to have an impact on overall survival. IGFBP2 expression is said to be higher in all four (classical, mesenchymal, proneural, and neural) GBM subtypes ( Lindström, 2019 ). It also drives gene programs for immunosuppression in the mesenchymal subtype and is suggested as an immunotherapeutic target ( Liu et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…In non-mesenchymal subtypes (classical, proneural, and neural), it modulates cell proliferation ( Phillips et al, 2016 ; Cai et al, 2018 ). It has also been found to be a marker of tumor aggressiveness and a prognostic marker for survival ( Lindström, 2019 ). However, the molecular mechanism by which IGFBP2 affects disease progression and patient prognosis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

et al. 2021

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Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

et al. 2021

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“…Furthermore, the anatomy of brain tissue causes difficulties with drug administration [6,7]. Therefore, it is not surprising that the median survival of diagnosed GBM patients ranges between 12 and 14 months, and has not changed considerably over the years [1,8,9]. Recently, numerous growth factors (EGF, TGF-β) and cytokines (e.g., IL-6) have been reported to support tumor growth and spreading [10,11].…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor (EGF) Augments the Invasive Potential of Human Glioblastoma Multiforme Cells via the Activation of Collaborative EGFR/ROS-Dependent Signaling

Pudełek

Krol

Catapano

et al. 2020

IJMS

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Abnormal secretion of epidermal growth factor (EGF) by non-neuronal cells (e.g., glioma-associated microglia) establishes a feedback loop between glioblastoma multiforme (GBM) invasion and a functional disruption of brain tissue. Considering the postulated significance of this vicious circle for GBM progression, we scrutinized mechanisms of EGF-dependent pro-invasive signaling in terms of its interrelations with energy metabolism and reactive oxygen species (ROS) production. The effects of EGF on the invasiveness of human glioblastoma T98G cells were estimated using time-lapse video microscopy, immunocytochemistry, cell cycle assay, immunoblot analyses, and Transwell® assay. These techniques were followed by quantification of the effect of EGFR (Epidermal Growth Factor Receptor) and ROS inhibitors on the EGF-induced T98G invasiveness and intracellular ROS, ATP, and lactate levels and mitochondrial metabolism. The EGF remarkably augmented the proliferation and motility of the T98G cells. Responses of these cells were accompanied by cellular rear–front polarization, translocation of vinculin to the leading lamellae, and increased promptness of penetration of micropore barriers. Erlotinib (the EGFR inhibitor) significantly attenuated the EGF-induced T98G invasiveness and metabolic reprogramming of the T98G cells, otherwise illustrated by the increased mitochondrial activity, glycolysis, and ROS production in the EGF-treated cells. In turn, ROS inhibition by N-acetyl-L-cysteine (NAC) had no effect on T98G morphology, but considerably attenuated EGF-induced cell motility. Our data confirmed the EGFR/ROS-dependent pro-neoplastic and pro-invasive activity of EGF in human GBM. These EGF effects may depend on metabolic reprogramming of GBM cells and are executed by alternative ROS-dependent/-independent pathways. The EGF may thus preserve bioenergetic homeostasis of GBM cells in hypoxic regions of brain tissue.

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“…In particular, a rapid development of invasiveness/drug-resistance after therapeutic cycles determines the swift recurrences of GBM [ 15 , 16 , 17 , 18 , 19 , 20 ]. The median survival time of diagnosed GBM patients ranges between 12 and 14 months, and it remained constant over the recent decades [ 21 , 22 ]. Accordingly, the effective GBM treatment is regarded as the most prominent challenge for contemporary neurooncology.…”

Section: Introductionmentioning

confidence: 99%

Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)+ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

Kochanowski

Catapano

Pudełek

et al. 2021

IJMS

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Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMTlow (U87) and MGMThigh (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMThigh T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMTlow and MGMThigh cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMThigh T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.

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Expanding the scope of candidate prognostic marker IGFBP2 in glioblastoma

Cited by 12 publications

References 19 publications

IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

Epidermal Growth Factor (EGF) Augments the Invasive Potential of Human Glioblastoma Multiforme Cells via the Activation of Collaborative EGFR/ROS-Dependent Signaling

Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)+ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

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