Exogenous administration of protease-resistant, non matrix-binding IGFBP-2 inhibits tumor growth in a murine model of breast cancer.

cher soh, Kerrie McNeil, Catherine Owczarek, Matthew Hardy, Louis Fabri, Martin Pearse, Carlie Delaine, Briony Forbes

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)2855-2864
    Number of pages10
    JournalBritish Journal of Cancer
    Volume110
    Issue number12
    DOIs
    Publication statusPublished - 2014

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