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. 2016 Jul;239(3):355-64.
doi: 10.1002/path.4734. Epub 2016 Jun 10.

Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies

Lynette M Phillips  1 , Xinhui Zhou  1 , David E Cogdell  1 , Corrine Yingxuan Chua  1   2 , Anouk Huisinga  3 , Kenneth R Hess  4 , Gregory N Fuller  1   2   5 , Wei Zhang  1   2   5   6
Affiliations

Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies

Lynette M Phillips et al. J Pathol. 2016 Jul.

Abstract

Insulin-like growth factor binding protein 2 (IGFBP2) overexpression is common in high-grade glioma and is both a strong biomarker of aggressive behaviour and a well-documented prognostic factor. IGFBP2 is a member of the secreted IGFBP family that functions by interacting with circulating IGFs to modulate IGF-mediated signalling. This traditional view of IGFBP2 activities has been challenged by the recognition of the diverse functions and cellular locations of members of the IGFBP family. IGFBP2 has been previously established as a driver of glioma progression to a higher grade. In this study, we sought to determine whether IGFBP2-overexpressing tumours are dependent on continued oncogene expression and whether IGFBP2 is a viable therapeutic target in glioma. We took advantage of the well-characterized RCAS/Ntv-a mouse model to create a doxycycline-inducible IGFBP2 model of glioma and demonstrated that the temporal expression of IGFBP2 has dramatic impacts on tumour progression and survival. Further, we demonstrated that IGFBP2-driven tumours are dependent on the continued expression of IGFBP2, as withdrawal of this oncogenic signal led to a significant decrease in tumour progression and prolonged survival. Inhibition of IGFBP2 also impaired tumour cell spread. To assess a therapeutically relevant inhibition strategy, we evaluated a neutralizing antibody against IGFBP2 and demonstrated that it impaired downstream IGFBP2-mediated oncogenic signalling pathways. The studies presented here indicate that IGFBP2 not only is a driver of glioma progression and a prognostic factor but is also required for tumour maintenance and thus represents a viable therapeutic target in the treatment of glioma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: IGFBP2; RCAS mouse model; glioma.

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Figures

Figure 1
Figure 1
Early IGFBP2 expression drives HGG. A. Kaplan-Meier survival curves for Ntv-a mice injected with RCAS-PDGFB, RCAN-TRE-IGFBP2, and RCAS-Tet-On. IGFBP2 induction was mediated by doxycycline (dox) administration at the times indicated (arrows). B, C. Age of animals at the time of symptom development in each group. High-grade gliomas are indicated with red symbols. C. Plot showing only high-grade gliomas from each group.
Figure 2
Figure 2
Inducible IGFBP2-driven tumours resemble human glioma. Representative H&E-stained sections and immunohistochemical staining of sections from mice with and without doxycycline-mediated IGFBP2 induction. Lower grade gliomas (LGGs) display uniform round nuclei and a characteristic “fried egg” appearance (grey arrows). High-grade gliomas (HGGs) display pseudopalisading necrosis (black arrows). Arrowheads indicate regions of high cellularity with intense IGFBP2 and LSD1 concordant staining. Insets represent higher magnification of the outlined regions, scale bar is 100 μm.
Figure 3
Figure 3
IGFBP2 inhibition impairs tumour progression. A. Kaplan-Meier survival curves for Ntv-a mice injected with RCAS-PDGFB, RCAN-TRE-IGFBP2, and RCAS-Tet-On. IGFBP2 induction is mediated by doxycycline administration from birth, and the duration of doxycycline-mediated IGFBP2 expression is indicated by the dotted lines. B. Size of tumours relative to IGFBP2 status. Animals were grouped on the basis of overall IGFBP2 induction. ** p= 0.0019 comparing all three groups by the Kruskal-Wallis test using StatXact 11.0. C. Number of mice exhibiting bilateral tumours representing contralateral spread. Animals were grouped on the basis of overall IGFBP2 induction. * p=0.0136, Fisher Exact test, GraphPad Prism.
Figure 4
Figure 4
Inhibition of IGFBP2 impairs oncogenic signalling pathways. A. U251 cells were serum starved overnight and incubated with increasing doses of IGFBP2-neutralizing antibody (nAb). A Western blot analysis was performed on whole cell extracts (WCEs). B. U87MG cells were serum starved overnight and incubated with rhIGFBP2 for the indicated times. Western blot analyses were performed on WCEs and isolated histone fractions.
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