Insulin-Like Growth Factor Binding Protein-2: A Possible Regulator of Invasive Growth in Glioblastoma

Kataoka, Hiroaki

doi:10.5772/22461

Cited by 25 publications

(32 citation statements)

References 70 publications

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“…GPNMB (glycoprotein nonmetastatic melanoma protein B) encodes for a transmembrane protein implicated in a variety of biological process including cell differentiation, inflammation, tissue regeneration, and invasion and metastasis of malignant tumors (Huang et al, 2012). IGFBP2 encodes insulin-like growth factor-binding protein 2 which inhibits insulin-like growth factor and is overexpressed in glioblastomas (Fukushima and Kataoka, 2007); no definite seizure-related mechanism has been described. Insulin-like growth factor regulation is altered in brains after ketogenic diets although IGFBP2 does not appear involved (Cheng et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study

et al. 2014

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Tumor associated seizures (TAS) are common and cause significant morbidity. Both imaging and gene expression features play significant roles in determining TAS, with strong interactions between them. We describe gene expression imaging tools which allow mapping of brain regions where gene expression has significant influence on TAS, and apply these methods to study 77 patients who underwent surgical evaluation for supratentorial glioblastomas. Tumor size and location were measured from MRI scans. A 9-set gene expression profile predicting long-term survivors was obtained from RNA derived from formalin-fixed paraffin embedded tissue. A total of 32 patients (42%) experienced preoperative TAS. Tumor volume was smaller (31.1 vs 58.8 cubic cm, p<0.001) and there was a trend toward median survival being higher (48.4 vs 32.7 months, p = 0.055) in patients with TAS. Although the expression of only OLIG2 was significantly lower in patients with TAS in a groupwise analysis, gene expression imaging analysis revealed regions with significantly lower expression of OLIG2 and RTN1 in patients with TAS. Gene expression imaging is a powerful technique that demonstrates that the influence of gene expression on TAS is highly region specific. Regional variability should be evaluated with any genomic or molecular markers of solid brain lesions.

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Section: Discussionmentioning

confidence: 99%

Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study

et al. 2014

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“…12,40,48 The overexpression of some IGFBP isoforms has been well documented in gliomas, in particular, glioblastoma (GBM). 15,16,32,43,46 A previous study by our group identified IGFBP-3 as a novel biomarker associated with an adverse GBM prognosis. 46 Additionally, IGFBP-3 has been recognized as a hypoxia-induced gene in a study on a malignant glioma cell line (U251).…”

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confidence: 99%

STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma

Thota¹,

Arivazhagan²,

Thennarasu

et al. 2014

JNS

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Object Insulin-like growth factor binding proteins (IGFBPs) have been implicated in the pathogenesis of glioma. In a previous study the authors demonstrated that IGFBP-3 is a novel glioblastoma biomarker associated with poor survival. Since signal transducer and activator of transcription 1 (STAT-1) has been shown to be regulated by IGFBP-3 during chondrogenesis and is a prosurvival and radioresistant molecule in different tumors, the aim in the present study was to explore the functional significance of IGFBP-3 in malignant glioma cells, to determine if STAT-1 is indeed regulated by IGFBP-3, and to study the potential of STAT-1 as a biomarker in glioblastoma. Methods The functional significance of IGFBP-3 was investigated using the short hairpin (sh)RNA gene knockdown approach on U251MG cells. STAT-1 regulation by IGFBP-3 was tested on U251MG and U87MG cells by shRNA gene knockdown and exogenous treatment with recombinant IGFBP-3 protein. Subsequently, the expression of STAT-1 was analyzed with real-time reverse transcription–polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) in glioblastoma and control brain tissues. Survival analyses were done on a uniformly treated prospective cohort of adults with newly diagnosed glioblastoma (136 patients) using Kaplan-Meier and Cox regression models. Results IGFBP-3 knockdown significantly impaired proliferation, motility, migration, and invasive capacity of U251MG cells in vitro (p < 0.005). Exogenous overexpression of IGFBP-3 in U251MG and U87MG cells demonstrated STAT-1 regulation. The mean transcript levels (by real-time RT-PCR) and the mean labeling index of STAT-1 (by IHC) were significantly higher in glioblastoma than in control brain tissues (p = 0.0239 and p < 0.001, respectively). Multivariate survival analysis revealed that STAT-1 protein expression (HR 1.015, p = 0.033, 95% CI 1.001–1.029) along with patient age (HR 1.025, p = 0.005, 95% CI 1.008–1.042) were significant predictors of shorter survival in patients with glioblastoma. Conclusions IGFBP-3 influences tumor cell proliferation, migration, and invasion and regulates STAT-1 expression in malignant glioma cells. STAT-1 is overexpressed in human glioblastoma tissues and emerges as a novel prognostic biomarker.

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“…31 IGFBP is a pleiotropic factor involved in cellular proliferation, motility, and differentiation of microvessel ECs and SMCs. [32][33][34][35][36][37][38] IGFBP2 enhances the cellular invasive capability and upregulates invasionenhancing proteins, such as MMP2. 33,[36][37][38][39] The invasiveness of cells parallels many of the processes in angiogenesis, such as the loss of tumor suppressor genes APC, PTEN, and p53 as well as activating similar signaling pathways and their downstream effectors.…”

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Comparison of Mixed and Lamellar Coculture Spatial Arrangements for Tissue Engineering Capillary NetworksIn Vitro

Peters

Christoforou

Leong

et al. 2013

Tissue Engineering Part A

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Coculture of endothelial cells (ECs) and smooth muscle cells (SMCs) in vitro can yield confluent monolayers or EC networks. Factors influencing this transition are not known. In this study, we examined whether the spatial arrangement of EC-SMC cocultures affected EC migration, network morphology, and angiogenic protein secretion. Human umbilical cord blood-derived ECs (hCB-ECs) were grown in coculture with human aortic SMCs in either a mixed or lamellar spatial geometry and analyzed over a culture period of 12 days. The hCB-ECs cultured on SMCs in a mixed system had higher cell speeds, shorter persistence times, and lower random motility coefficients than ECs in a lamellar system. By day 12 of coculture, mixed systems demonstrated greater anastomoses and capillary loop formation than lamellar systems as evidenced by a higher number of branch points, angle of curvature between branch points, and percentage of imaged area covered by networks. The network morphology was more uniform in the mixed systems than the lamellar systems with fewer EC clusters present after several days in culture. Proliferation of hCB-ECs was higher for mixed cocultures during the first 24 h of coculture, and then declined dramatically suggesting that proliferation only contributed to network formation during the early stages of coculture. Proteome assay results show reduced solution levels, but no change in intracellular levels of angiogenic proteins in lamellar systems compared to mixed systems. These data suggest that mixing ECs and SMCs together favors the formation of EC networks to a greater extent than a lamellar arrangement in which ECs form a cell layer above a confluent, quiescent layer of SMCs.

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Insulin-Like Growth Factor Binding Protein-2: A Possible Regulator of Invasive Growth in Glioblastoma

Cited by 25 publications

References 70 publications

Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study

Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study

STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma

Comparison of Mixed and Lamellar Coculture Spatial Arrangements for Tissue Engineering Capillary NetworksIn Vitro

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