RESUMO
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.
Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Animais , Animais Recém-Nascidos , Anticorpos Neutralizantes , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Doxiciclina , Glioma/induzido quimicamente , Glioma/patologia , Glioma/terapia , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Camundongos , Oncogenes , Prognóstico , Transdução de SinaisRESUMO
The molecular basis underlying the particularly aggressive nature of pancreatic ductal adenocarcinoma (PDAC) still remains unclear. Here we report evidence that the insulin-like growth factor-binding protein IGFBP2 acts as a potent oncogene to drive its extremely malignant character. We found that elevated IGFBP2 expression in primary tumors was associated with lymph node metastasis and shorter survival in patients with PDAC. Enforced expression of IGFBP2 promoted invasion and metastasis of PDAC cells in vitro and in vivo by inducing NF-κB-dependent epithelial-mesenchymal transition (EMT). Mechanistic investigations revealed that IGFBP2 induced the nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKß pathway. Conversely, enforced expression of PTEN blunted this signaling pathway and restored an epithelial phenotype to PDAC cells in the presence of overexpressed IGFBP2. Overall, our results identify IGFBP2 as a pivotal regulator of an EMT axis in PDAC, the activation of which is sufficient to confer the characteristically aggressive clinical features of this disease. Cancer Res; 76(22); 6543-54. ©2016 AACR.