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Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma

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Abstract

Erythropoietin (Epo) is the crucial cytokine regulator of red blood cell production, and recombinant human erythropoietin (rHuEpo) is widely used in clinical practice for the treatment of anemia, primarily in kidney disease and in cancer. Increasing evidence suggests several biological roles for Epo and its receptor, Epo-R, unrelated to erythropoiesis, including angiogenesis. Epo-R has been found expressed in various non-haematopoietic cells and tissues, and in cancer cells. Here, we detected the expression of Epo-R in bone marrow-derived macrophages (BMMAs) from multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients and assessed whether Epo/Epo-R axis plays a role in MM macrophage-mediated angiogenesis. We found that Epo-R is over-expressed in BMMAs from MM patients with active disease compared to MGUS patients. The treatment of BMMAs with rHuEpo significantly increased the expression and secretion of key pro-angiogenic mediators, such as vascular endothelial growth factor, hepatocyte growth factor and monocyte chemotactic protein (MCP-1/CCL-2), through activation of JAK2/STAT5 and PI3 K/Akt pathways. In addition, the conditioned media harvested from rHuEpo-treated BMMAs enhanced bone marrow-derived endothelial cell migration and capillary morphogenesis in vitro, and induced angiogenesis in the chorioallantoic membrane of chick embryos in vivo. Furthermore, we found an increase in the circulating levels of several pro-angiogenic cytokines in serum of MM patients with anemia under treatment with Epo. Our findings highlight the direct effect of rHuEpo on macrophage-mediated production of pro-angiogenic factors, suggesting that Epo/Epo-R pathway may be involved in the regulation of angiogenic response occurring in MM.

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Acknowledgments

This work was supported by Associazione Italiana per la Ricerca sul Cancro, Investigator Grant and Special Program Molecular Clinical Oncology five per mille n.9965, Milan, Italy; the Ministry of Health (Progetto PRIN 2012 to AV), Rome, Italy; and European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n.278570 to DR and n.278706 to AV. 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.

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Authors and Affiliations

  1. Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy

    Annunziata De Luisi, Laura Binetti, Roberto Ria, Simona Ruggieri, Simona Berardi, Ivana Catacchio, Vito Racanelli & Angelo Vacca

  2. Hematology Unit, Fondazione Ospedale Cardinale “G. Panico”, Tricase, Lecce, Italy

    Vincenzo Pavone & Bernardo Rossini

  3. Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy

    Simona Ruggieri & Domenico Ribatti

  4. National Cancer Institute “Giovanni Paolo II”, Bari, Italy

    Domenico Ribatti

Authors
  1. Annunziata De Luisi
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  2. Laura Binetti
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  3. Roberto Ria
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  4. Simona Ruggieri
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  6. Ivana Catacchio
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  7. Vito Racanelli
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  8. Vincenzo Pavone
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  9. Bernardo Rossini
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  10. Angelo Vacca
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  11. Domenico Ribatti
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Correspondence to Domenico Ribatti.

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De Luisi, A., Binetti, L., Ria, R. et al. Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma. Angiogenesis 16, 963–973 (2013). https://doi.org/10.1007/s10456-013-9369-2

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  • DOI: https://doi.org/10.1007/s10456-013-9369-2

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