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Inhibition of tumor-associated αvβ3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo

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Abstract

A more complete understanding of the mechanisms that regulate the angiogenic switch, which contributes to the conversion of small dormant tumors to actively growing malignancies, is important for the development of more effective anti-angiogenic strategies for cancer therapy. While significant progress has been made in understanding the complex mechanisms by which integrin αvβ3 expressed in endothelial cells governs angiogenesis, less is known concerning the ability of αvβ3 expressed within the tumor cell compartment to modulate the angiogenic output of a tumor. Here we provide evidence that αvβ3 expressed in melanoma cells may contribute to the suppression of IGFBP-4, an important negative regulator of IGF-1 signaling. Given the multiple context-dependent roles for αvβ3 in angiogenesis and tumor progression, our novel findings provide additional molecular insight into how αvβ3 may govern the angiogenic switch by a mechanism associated with a p38 MAPK and matrix metalloproteinases-dependent regulation of the endogenous angiogenesis inhibitor IGFBP-4.

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Acknowledgments

This work was supported in part by National Institutes of Health grants CA91645 (to P.C.B), Grant HL65301 (to R.F), Grants HL083151 and P20RR15555 (Protein, Nucleic Acid Analysis) to (C.P.H.V.), and Grant P20 RR181789 (Bioinformatics Core) to D. M. Wojchowski. This work was also supported by NIH Center of Biomedical Research Excellence 5P30GM103392 (PI: R. Friesel), the Maine Cancer Foundation (MCF) grant to L. W. C., and by institutional support from the Maine Medical Center.

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Authors and Affiliations

  1. Maine Medical Center Research Institute, Center for Molecular Medicine, 81 Research Drive, Scarborough, ME, 04074, USA

    Liangru W. Contois, Abebe Akalu, Jennifer M. Caron, Eric Tweedie, Terry Henderson, Lucy Liaw, Robert Friesel, Calvin Vary & Peter C. Brooks

  2. University of Pennsylvania, 3451 Walnut Street, Philadelphia, PA, 19104, USA

    Alexandra Cretu

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  1. Liangru W. Contois
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  2. Abebe Akalu
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  10. Peter C. Brooks
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Correspondence to Peter C. Brooks.

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Contois, L.W., Akalu, A., Caron, J.M. et al. Inhibition of tumor-associated αvβ3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 18, 31–46 (2015). https://doi.org/10.1007/s10456-014-9445-2

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