Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy

Molecular Cancer

Research

Andre J. van Wijnen¹  Si Kee Tan²  Edwin Cheung³  Ting Hwee Goh⁴  Ling Ling⁴  Simon M. Cool⁵  Victor Nurcombe⁵ 

[1] Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, MedSci 3-69, 55905, Rochester, MN, USA;Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, #02-01 Genome, 138672, Singapore, Singapore;Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, #02-01 Genome, 138672, Singapore, Singapore;Faculty of Health Sciences, University of Macau, E12 Avenida da Universidade, Taipa, Macau, China;Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore, Singapore;Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore, Singapore;Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 119074, Singapore, Singapore;

关键词: Targeted therapy;    Tumor;    Cell death;    Cell growth;    Neutralizing antibody;    Heparan sulfate;   

DOI  :  10.1186/s12943-015-0391-4

 received in 2014-10-08, accepted in 2015-05-21,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundAberrant activation of fibroblast growth factor receptors (FGFRs) deregulates cell proliferation and promotes cell survival, and may predispose to tumorigenesis. Therefore, selective inactivation of FGFRs is an important strategy for cancer therapy. Here as a proof-of-concept study, we developed a FGFR1 neutralizing antisera, IMB-R1, employing a novel strategy aimed at preventing the access of essential heparan sulfate (HS) co-receptors to the heparin-binding domain on FGFR1.MethodsThe mRNA and protein expression level of FGFR1 and other FGFRs were examined in several lines of breast cancer and osteosarcoma cells and corresponding normal cells using Taqman real-time quantitative PCR and Western blot analysis. The specificity of IMB-R1 against FGFR1 was assessed with various ELISA-based approaches and Receptor Tyrosine Kinase array. Proliferation assay and apoptosis analysis were performed to assess the effect of IMB-R1 on cancer cell growth and apoptosis, respectively, in comparison with known FGFR1 inhibitors. The IMB-R1 induced alteration of intracellular signaling and gene expression were analysed using Western blot and microarray approaches. Immunohistochemical staining of FGFR1 using IMB-R1 were carried out in different cancer tissues from clinical patients. Throughout the study, statistical differences were determined by Student’s t test where appropriate and reported when a p value was less than 0.05.ResultsWe demonstrate that IMB-R1 is minimally cross-reactive for other FGFRs, and that it potently and specifically inhibits binding of heparin to FGFR1. Furthermore, IMB-R1 blocks the interaction of FGF2 with FGFR1, the kinase activity of FGFR1 and activation of intracellular FGFR signaling. Cancer cells treated with IMB-R1 displayed impaired FGF2 signaling, were unable to grow and instead underwent apoptosis. IMB-R1-induced cell death correlated with a disruption of antioxidative defense networks and increased expression of several tumor suppressors and apoptotic proteins, including p53. Immunostaining with IMB-R1 was stronger in human cancer tissues in which the FGFR1 gene is amplified.ConclusionOur study suggests that blocking HS interaction with the heparin-binding domains of FGFR1 inhibited cancer cell growth, which can be an attractive strategy to inactivate cancer-related heparin-binding proteins.

【 授权许可】

Unknown   
© Ling et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.