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Myeloma

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

Leukemia volume 27, pages 1697–1706 (2013)Cite this article

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Abstract

Hypoxia-inducible transcription factor-1 (HIF-1α) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1α inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1α suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1α inhibition in MM cells downregulates the pro-angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1α. The effect of HIF-1α inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1α inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1α inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1α suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1α as a potential therapeutic target in MM.

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Acknowledgements

This study was supported by grants from the ‘International Myeloma Foundation’; and ‘Associazione Italiana per la Ricerca sul Cancro’ A.I.R.C, IG2009 no. 8530 (N.G.), no. IG4569 (A.N.) and no. 13018 (I.A.); Special Program Molecular Clinical Oncology 5 per mille no. 9965 (N.G.) and no. 9980 (A.N.), the Multiple Myeloma Research Foundation and grant support R01 AR059679, R21 CA141426, R01AR057308, and Merit Review funds from the Veterans Administration. (G.D.R.). We thanks Ministero Italiano dell’ Istruzione, Università e Ricerca (MIUR) and Italian Association against Leukemia, Lymphoma and Myeloma (AIL). We thanks Carla Palumbo and Marzia Ferretti for their support in the histological analysis.

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  1. P Storti and M Bolzoni: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Hematology, University of Parma, Parma, Italy

    P Storti, M Bolzoni, D Guasco, D Toscani, F Aversa & N Giuliani

  2. Dipartimento di Scienze Medico-Veterinarie, University of Parma, Parma, Italy

    G Donofrio & V Franceschi

  3. Department of Experimental and Laboratory Medicine, A.I.R.C. Laboratory of Immunology and Tumors, Istituto Giannina Gaslini, Genova, Italy

    I Airoldi

  4. Anatomia e Istologia patologica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    E Martella & C Mancini

  5. Department of Biosciences, University of Parma, Parma, Italy

    M Lazzaretti

  6. Department of Clinical Sciences and Community Health, University of Milan, and Hematology 1, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    L Agnelli & A Neri

  7. Department of Medicine, Division of Hematology/Oncology and the Center for Bone Biology of UPMC, University of Pittsburgh, Pittsburgh, PA, USA

    K Patrene

  8. INSERM, U892, University of Nantes, CNRS, UMR 6299, Nantes, France,

    S Maïga & M Amiot

  9. MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    S Colla

  10. Division of Hematology Oncology, Indiana University School of Medicine Department of Medicine, Indianapolis, IN, USA

    J Anderson & G David Roodman

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  1. P Storti
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Correspondence to N Giuliani.

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Storti, P., Bolzoni, M., Donofrio, G. et al. Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia 27, 1697–1706 (2013). https://doi.org/10.1038/leu.2013.24

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