IGF1R activation and the in vitro antiproliferative efficacy of IGF1R inhibitor are inversely correlated with IGFBP5 expression in bladder cancer

BMC Cancer

Research Article

Thierry Lebret¹  Yann Neuzillet²  Leanne De Koning³  François Radvanyi⁴  Elodie Chapeaublanc⁴  Clémentine Krucker⁴  Isabelle Bernard-Pierrot⁵ 

[1] Hôpital Foch, Département d’Urologie, 40 Rue Worth, 92151, Suresnes, France;Université de Versailles – Saint-Quentin-en-Yvelines, 78000, Versailles, France;Hôpital Foch, Département d’Urologie, 40 Rue Worth, 92151, Suresnes, France;Université de Versailles – Saint-Quentin-en-Yvelines, 78000, Versailles, France;Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, 75005, Paris, France;Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France;Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, 75005, Paris, France;Département de Recherche Translationnelle, Cedex 05, 75248, Paris, France;Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, 75005, Paris, France;Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France;Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, 75005, Paris, France;Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR144, 75005, Paris, France;UMR 144 CNRS/IC, Institut Curie, 26 rue d’Ulm, CEDEX 05, 75248, Paris, France;

关键词: Bladder cancer;    Oncogenesis;    IGF;    IGFR;    IGFBP;    IGF1R inhibitor;   

DOI  :  10.1186/s12885-017-3618-5

 received in 2016-12-14, accepted in 2017-08-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundThe insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer. We characterized the expression of components of the IGF pathway — insulin growth factor receptors (INSR, IGF1R, IGF2R), ligands (INS, IGF1, IGF2), and binding proteins (IGFBP1–7, IGF2BP1–3) — in bladder cancer and its correlation with IGF1R activation, and the anti-proliferative efficacy of an IGF1R kinase inhibitor in this setting.MethodsWe analyzed transcriptomic data from two independent bladder cancer datasets, corresponding to 200 tumoral and five normal urothelium samples. We evaluated the activation status of the IGF pathway in bladder tumors, by assessing IGF1R phosphorylation and evaluating its correlation with mRNA levels for IGF pathway components. We finally evaluated the correlation between inhibition of proliferation by a selective inhibitor of the IGF1R kinase (AEW541), reported in 13 bladder cancer derived cell lines by the Cancer Cell Line Encyclopedia Consortium and mRNA levels for IGF pathway components.ResultsIGF1R expression and activation were stronger in non-muscle-invasive than in muscle-invasive bladder tumors. There was a significant inverse correlation between IGF1R phosphorylation and IGFBP5 expression in tumors. Consistent with this finding, the inhibition of bladder cell line viability by IGF1R inhibitor was also inversely correlated with IGFBP5 expression.ConclusionThe IGF pathway is activated and therefore a potential therapeutic target for non muscle-invasive bladder tumors and IGFBP5 could be used as a surrogate marker for predicting tumor sensitivity to anti-IGF therapy.

【 授权许可】

CC BY   
© The Author(s). 2017