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Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Oncogene volume 31, pages 2258–2269 (2012)Cite this article

Abstract

Bone marrow (BM) angiogenesis has an important role in the initiation and progression of multiple myeloma (MM). We looked at novel mechanisms of vessel formation in patients with MM through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with active MM (MMECs) and ECs of patients with monoclonal gammopathy of undetermined significance (MGECs) and of subjects with benign anemia (normal ECs). Four proteins were found overexpressed in MMECs: filamin A, vimentin, α-crystallin B and 14-3-3ζ/δ protein, not yet linked to overangiogenic phenotype. These proteins gave a typical distribution in the BM of MM patients and in MMECs versus MGECs, plausibly according to a different functional state. Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis. Their silencing RNA knockdown affected critical MMEC angiogenesis-related functions, such as spreading, migration and tubular morphogenesis. A gradual stabilization of 14-3-3ζ/δ protein was observed, with transition from normal ECs to MGECs and MMECs that may be a critical step for the angiogenic switch in MMECs and maintenance of the cell overangiogenic phenotype. These proteins were substantially impacted by anti-MM drugs, such as bortezomib, lenalidomide and panobinostat. Results suggest that these four proteins could be new targets for the antiangiogenic management of MM patients.

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro, Investigator Grant and Special Program Molecular Clinical Oncology 5 per mille n. 9965, Milan, and the Ministry of Health, Progetto Oncologia 2006, Humanitas Mirasole S.p.A., Rome, Italy. The sponsors of this study are public or non-profit organizations that support science in general. They had no role in gathering, analyzing or interpreting the data. The authors are fully responsible for the content and editorial decisions for this manuscript. We thank Dr Maurilio Ponzoni, San Raffaele Institute, Milan, Italy, for collaboration on the mouse model.

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  1. S Berardi and A Caivano: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy

    S Berardi, R Ria, G De Tullio, A Ferrucci, A De Luisi, M Moschetta, I Catacchio, A Basile, F Dammacco & A Vacca

  2. Department of Onco-Hematology, Molecular Oncology Unit, IRCCS Referral Basilicata Cancer Center, Potenza, Italy

    A Caivano

  3. Department of Human Anatomy, Histology and Embryology, University of Bari Medical School, Bari, Italy

    B Nico & D Ribatti

  4. Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy

    R Savino & R Terracciano

  5. Department of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, UK

    G Mangialardi

  6. Hematology Unit, National Cancer Institute Giovanni Paolo II, Bari, Italy

    A Guarini

  7. Pathology Unit, Di Venere Hospital, Bari, Italy

    A Zito

  8. Hematology Unit, Di Venere Hospital, Bari, Italy

    P Ditonno

  9. Unit of Hematology and Stem Cell Transplantation, IRCCS Referral Basilicata Cancer Center, Potenza, Italy

    P Musto

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Correspondence to A Vacca.

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Berardi, S., Caivano, A., Ria, R. et al. Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets. Oncogene 31, 2258–2269 (2012). https://doi.org/10.1038/onc.2011.412

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