title: Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies.
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.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Phillips
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cogdell
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
authors.forename: Corrine Yingxuan
authors.initials: CY
authors.lastname: Chua
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, 6500, Nijmegen, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Huisinga
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: R Hess
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.|ISB-MDA Genome Data Analysis Center, The Cancer Genome Atlas, Houston, Texas, USA.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.|ISB-MDA Genome Data Analysis Center, The Cancer Genome Atlas, Houston, Texas, USA.|Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing; D001932:Brain Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009857:Oncogenes; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; D018971:Insulin-Like Growth Factor Binding Protein 2; D004318:Doxycycline
keywords: IGFBP2; RCAS mouse model; glioma