title: Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets.
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.
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Berardi
authors.forename: A
authors.initials: A
authors.lastname: Caivano
authors.forename: R
authors.initials: R
authors.lastname: Ria
authors.forename: B
authors.initials: B
authors.lastname: Nico
authors.forename: R
authors.initials: R
authors.lastname: Savino
authors.forename: R
authors.initials: R
authors.lastname: Terracciano
authors.forename: G
authors.initials: G
authors.lastname: De Tullio
authors.forename: A
authors.initials: A
authors.lastname: Ferrucci
authors.forename: A
authors.initials: A
authors.lastname: De Luisi
authors.forename: M
authors.initials: M
authors.lastname: Moschetta
authors.forename: G
authors.initials: G
authors.lastname: Mangialardi
authors.forename: I
authors.initials: I
authors.lastname: Catacchio
authors.forename: A
authors.initials: A
authors.lastname: Basile
authors.forename: A
authors.initials: A
authors.lastname: Guarini
authors.forename: A
authors.initials: A
authors.lastname: Zito
authors.forename: P
authors.initials: P
authors.lastname: Ditonno
authors.forename: P
authors.initials: P
authors.lastname: Musto
authors.forename: F
authors.initials: F
authors.lastname: Dammacco
authors.forename: D
authors.initials: D
authors.lastname: Ribatti
authors.forename: A
authors.initials: A
authors.lastname: Vacca
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D002465:Cell Movement; D003285:Contractile Proteins / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D064448:Filamins; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010265:Paraproteinemias / Q000235:genetics / Q000473:pathology; D040901:Proteomics; D014746:Vimentin / Q000235:genetics; D038201:alpha-Crystallins / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D014746:Vimentin; D038201:alpha-Crystallins