Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome

Clément, Florencia; Martín, Ayelén; Venara, Marcela; Calcagno, María de Luján; Mathó, Cecilia; Maglio, Silvana; Lombardi, Mercedes García; Bergadá, Ignacio; Pennisi, Patricia

doi:10.1007/s12672-018-0328-7

Cited by 8 publications

(10 citation statements)

References 192 publications

(246 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The association between nuclear IGF1R and clinical outcome in pediatric gliomas was recently studied by Clement et al [65]. Immunohistochemical analyses identified IGF1R staining in 47 out of 53 tumors, and nuclear IGF1R labelling was observed in 10/47 cases.…”

Section: The Role Of Nuclear Insr/igf1r In Cancermentioning

confidence: 94%

The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer

2021

View full text Add to dashboard Cite

Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology.

show abstract

Section: The Role Of Nuclear Insr/igf1r In Cancermentioning

confidence: 94%

The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer

2021

View full text Add to dashboard Cite

show abstract

“…In a previous study, we analyzed the mRNA expression of IGF1R in pediatric low- and high-grade gliomas ( 27 ). Considering these data, we selected U87WT and U87Mut clones as the ones which better represented high-grade gliomas, regarding the mRNA expression of IGF1R.…”

Section: Discussionmentioning

confidence: 99%

“…All experiments were performed using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA) following the manufacturer’s protocols. Stable clones were selected using G418 antibiotic (Sigma Aldrich, St Luis, MO, USA), and once established, RNA and proteins were obtained as previously described ( 27 ) to test the IGF1R expression levels.…”

Section: Methodsmentioning

confidence: 99%

“…There is also a study showing that IGF1R nuclear staining is a predictive biomarker for therapy response in sarcomas ( 26 ). In a previous study conducted by our group in which tumor samples from pediatric gliomas were analyzed, we have demonstrated that IGF1R nuclear localization is associated with higher-grade tumors and also related with worst clinical outcome of those patients ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Type 1 Insulin-Like Growth Factor Receptor Nuclear Localization in High-Grade Glioma Cells Enhances Motility, Metabolism, and In Vivo Tumorigenesis

et al. 2022

View full text Add to dashboard Cite

Gliomas are the most frequent solid tumors in children. Among these, high-grade gliomas are less common in children than in adults, though they are similar in their aggressive clinical behavior. In adults, glioblastoma is the most lethal tumor of the central nervous system. Insulin-like growth factor 1 receptor (IGF1R) plays an important role in cancer biology, and its nuclear localization has been described as an adverse prognostic factor in different tumors. Previously, we have demonstrated that, in pediatric gliomas, IGF1R nuclear localization is significantly associated with high-grade tumors, worst clinical outcome, and increased risk of death. Herein we explore the role of IGF1R intracellular localization by comparing two glioblastoma cell lines that differ only in their IGF1R capacity to translocate to the nucleus. In vitro, IGF1R nuclear localization enhances glioblastoma cell motility and metabolism without affecting their proliferation. In vivo, IGF1R has the capacity to translocate to the nucleus and allows not only a higher proliferation rate and the earlier development of tumors but also renders the cells sensitive to OSI906 therapy. With this work, we provide evidence supporting the implications of the presence of IGF1R in the nucleus of glioma cells and a potential therapeutic opportunity for patients harboring gliomas with IGF1R nuclear localization.

show abstract

“…In the nucleus, IGF-IR can act as a transcriptional co-activator with LEF/TCF, increasing promoter activity of the downstream target genes cyclin D1 and Axin2, upregulating their expression and promoting cell cycle progression [7]. In several human malignancies including clear cell renal cancer, colorectal carcinoma and pediatric glioma, nuclear IGF-IR was associated with advanced disease and adverse prognosis [8][9][10]. Codony-Servat el al.…”

Section: The Insulin-like Growth Factor (Igf)-axismentioning

confidence: 99%

Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug

Chen

Perrino

et al. 2020

Cells

View full text Add to dashboard Cite

The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap—a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.

show abstract

Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome

Cited by 8 publications

References 192 publications

The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer

The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer

Type 1 Insulin-Like Growth Factor Receptor Nuclear Localization in High-Grade Glioma Cells Enhances Motility, Metabolism, and In Vivo Tumorigenesis

Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug

Contact Info

Product

Resources

About