title: Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma.
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.
authors.affiliation: Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Annunziata
authors.initials: A
authors.lastname: De Luisi
authors.forename: Laura
authors.initials: L
authors.lastname: Binetti
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.forename: Simona
authors.initials: S
authors.lastname: Ruggieri
authors.forename: Simona
authors.initials: S
authors.lastname: Berardi
authors.forename: Ivana
authors.initials: I
authors.lastname: Catacchio
authors.forename: Vito
authors.initials: V
authors.lastname: Racanelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pavone
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rossini
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000098:blood supply*; D001854:Bone Marrow Cells; D002196:Capillaries / Q000648:ultrastructure; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D002867:Chromones / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000494:pharmacology* / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000503:physiopathology*; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000097:blood / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D042501:Angiogenic Proteins; D002867:Chromones; D017077:Culture Media, Conditioned; D016207:Cytokines; C554270:EPO protein, human; D009025:Morpholines; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000068817:Epoetin Alfa; D000077191:Wortmannin