Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer.
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.
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia.
C-L
CL
Soh
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia.
K
K
McNeil
CSL Limited, Parkville, Victoria, Australia.
C M
CM
Owczarek
CSL Limited, Parkville, Victoria, Australia.
M P
MP
Hardy
CSL Limited, Parkville, Victoria, Australia.
L J
LJ
Fabri
CSL Limited, Parkville, Victoria, Australia.
M
M
Pearse
1] School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia [2] School of Medicine, Flinders University of South Australia, Bedford Park, South Australia 5042, Australia.
C A
CA
Delaine
1] School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia [2] School of Medicine, Flinders University of South Australia, Bedford Park, South Australia 5042, Australia.
B E
BE
Forbes
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000008:administration & dosage / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D018971:Insulin-Like Growth Factor Binding Protein 2; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II