Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer.
AuthorSoh, C-L; McNeil, K; Owczarek, CM; Hardy, MP; Fabri, LJ; Pearse, M; Delaine, CA; Forbes, BE
Source TitleBritish Journal of Cancer
PublisherSpringer Science and Business Media LLC
University of Melbourne Author/sHardy, Matthew Philip
Document TypeJournal Article
CitationsSoh, C. -L., McNeil, K., Owczarek, C. M., Hardy, M. P., Fabri, L. J., Pearse, M., Delaine, C. A. & Forbes, B. E. (2014). Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer.. Br J Cancer, 110 (12), pp.2855-2864. https://doi.org/10.1038/bjc.2014.232.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056053
BACKGROUND: Insulin-like growth factors (IGF-I and IGF-II) signal via the type 1 IGF receptor (IGF-1R) and IGF-II also activates the insulin receptor isoform A (IR-A). Signalling via both receptors promotes tumour growth, survival and metastasis. In some instances IGF-II action via the IR-A also promotes resistance to anti-IGF-1R inhibitors. This study assessed the efficacy of two novel modified IGF-binding protein-2 (IGFBP-2) proteins that were designed to sequester both IGFs. The two modified IGFBP-2 proteins were either protease resistant alone or also lacked the ability to bind extracellular matrix (ECM). METHODS: The modified IGFBP-2 proteins were tested in vitro for their abilities to inhibit cancer cell proliferation and in vivo to inhibit MCF-7 breast tumour xenograft growth. RESULTS: Both mutants retained low nanomolar affinity for IGF-I and IGF-II (0.8-2.1-fold lower than IGFBP-2) and inhibited cancer cell proliferation in vitro. However, the combined protease resistant, non-matrix-binding mutant was more effective in inhibiting MCF-7 tumour xenograft growth and led to inhibition of angiogenesis. CONCLUSIONS: By removing protease cleavage and matrix-binding sites, modified IGFBP-2 was effective in inhibiting tumour growth and reducing tumour angiogenesis.
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