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

• Published in: British journal of cancer Vol. 110; no. 12; pp. 2855 - 2864
• Main Authors: Soh, C-L, McNeil, K, Owczarek, C M, Hardy, M P, Fabri, L J, Pearse, M, Delaine, C A, Forbes, B E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.06.2014; Nature Publishing Group
• Subjects: 631/154/51/2314; 631/67/1347; Amino Acid Sequence; Angiogenesis; Angiogenesis Inhibitors - therapeutic use; Animals; Binding sites; Binding Sites - genetics; Bioavailability; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell growth; Cell Proliferation - drug effects; Drug Resistance; Epidemiology; Extracellular matrix; Extracellular Matrix - genetics; Female; Gynecology. Andrology. Obstetrics; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 2 - administration & dosage; Insulin-Like Growth Factor Binding Protein 2 - therapeutic use; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor II - metabolism; Insulin-like growth factors; Kinases; Ligands; Mammary gland diseases; Mammary Neoplasms, Experimental - drug therapy; MCF-7 Cells; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Molecular Sequence Data; Monoclonal antibodies; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neovascularization, Pathologic - drug therapy; Oncology; Protein Binding; Proteins; Recombinant Proteins - therapeutic use; Signal transduction; Translational Therapeutics; Tumors; Xenograft Model Antitumor Assays; Australia; South Australia Australia; IGFBP; vascularisation; breast cancer; xenograft; Insulin-like growth factor; Animal model; Breast disease; Transplantation; Heterotransplantation; Vascularization; Insulin like growth factor binding protein; Insulin like growth factor; Cancerology; Surgery; Graft; Insulin-like growth factor binding protein 2; Enzyme; Rodentia; Breast cancer; Malignant tumor; Resistance; Mammary gland diseases; Peptidases; Vertebrata; Mammalia; Treatment; Tumor growth; Mouse; Animal; Hydrolases; Inhibitor; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.232

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.