title: Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma.
abstract: OBJECTIVE
  To determine the in vivo and in vitro antiangiogenic power of lenalidomide, a "lead compound" of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC).
  
  
  METHODS
  The antiangiogenic effect in vivo was studied using the chorioallantoic membrane (CAM) assay. Functional studies in vitro (angiogenesis, "wound" healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels.
  
  
  RESULTS
  Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 μmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. In vitro, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin- and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways.
  
  
  CONCLUSIONS
  This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies 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: Arianna
authors.initials: A
authors.lastname: Ferrucci
authors.forename: Addolorata M L
authors.initials: AM
authors.lastname: Coluccia
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.forename: Emanuela
authors.initials: E
authors.lastname: de Luca
authors.forename: Luisa
authors.initials: L
authors.lastname: Pieroni
authors.forename: Michele
authors.initials: M
authors.lastname: Maffia
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.forename: Giulia
authors.initials: G
authors.lastname: Di Pietro
authors.forename: Attilio
authors.initials: A
authors.lastname: Guarini
authors.forename: Girolamo
authors.initials: G
authors.lastname: Ranieri
authors.forename: Paolo
authors.initials: P
authors.lastname: Ditonno
authors.forename: Simona
authors.initials: S
authors.lastname: Berardi
authors.forename: Antonella
authors.initials: A
authors.lastname: Caivano
authors.forename: Antonio
authors.initials: A
authors.lastname: Basile
authors.forename: Nicola
authors.initials: N
authors.lastname: Cascavilla
authors.forename: Silvana
authors.initials: S
authors.lastname: Capalbo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarta
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000077269:Lenalidomide; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D020543:Proteome / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051151:Selenoprotein W / Q000096:biosynthesis; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D051017:Apoptosis Regulatory Proteins; C090121:BNIP3 protein, human; C111835:CCL2 protein, human; C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; C099815:IER3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020543:Proteome; D011518:Proto-Oncogene Proteins; C495240:SELENOW protein, human; D051151:Selenoprotein W; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077269:Lenalidomide