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Inhibition of β1 integrin and IL-3Rβ common subunit interaction hinders tumour angiogenesis

Oncogene volume 29, pages 6581–6590 (2010)Cite this article

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Abstract

Integrin/cytokine receptor interaction provides permissive signals leading to neoangiogenesis, and integrins are crucial for differentiation of endothelial progenitor cells (EPCs). It is known that the inflammatory interleukin-3 (IL-3), released in the tumoral microenvironment, contributes to both angiogenesis and vasculogenic processes. Herein, we generated IL-3 receptor beta common (IL-3Rβc) extracellular domain-derived fusion proteins (Fc) to elucidate the molecular mechanisms regulating these processes. Three different Fc were generated, containing the entire extracellular domain of IL-3Rβc (Fc1.4), a fragment corresponding to domains 1–3 (Fc1.3) and a fragment corresponding to domain 4 (Fc4), respectively. The ability of the fusion proteins to interfere with IL-3Rβc/β1 integrin interaction was assessed on endothelial cells (ECs), EPCs and murine-derived ECs. Pull-down experiments showed that Fc1.4 and Fc4 fusion proteins specifically interacted with β1 integrin. Fc4 and Fc1.4 fragments prevented IL-3-mediated EPC expansion, arterial morphogenesis and tumour-derived EC migration, without affecting cell adhesion. Fc4 in vivo inhibited the IL-3-mediated vasculogenic process, as well as inflammatory and tumour vascular growth. In conclusion, these data identify the β1 integrin-interacting domain in the juxta-membrane IL-3Rβc extracellular domain, and provide the rational for targeting this interaction to impair vascular growth.

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Acknowledgements

This work was supported by grants from the Italian Association for Cancer Research (AIRC) to MFB and PD, Association for International Cancer Research (AICR), Regione Piemonte (OncoProt, Druidi, PIStem) and EU FP7 Metafight to PD We thank Dr Alessandra Baragli and Dr Natalie Lassen for critical reading and final editing of the paper.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Turin, Turin, Italy

    B Uberti, P Dentelli, A Rosso & M F Brizzi

  2. Molecular Biotechnology Center and Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy

    P Defilippi

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  1. B Uberti
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  3. A Rosso
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  4. P Defilippi
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Correspondence to M F Brizzi.

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Uberti, B., Dentelli, P., Rosso, A. et al. Inhibition of β1 integrin and IL-3Rβ common subunit interaction hinders tumour angiogenesis. Oncogene 29, 6581–6590 (2010). https://doi.org/10.1038/onc.2010.384

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  • DOI: https://doi.org/10.1038/onc.2010.384

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