Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma

• Published in: Clinical cancer research Vol. 17; no. 7; pp. 1935 - 1946
• Main Authors: DE LUISI, Annunziata, FERRUCCI, Arianna, GUARINI, Attilio, RANIERI, Girolamo, DITONNO, Paolo, BERARDI, Simona, CAIVANO, Antonella, BASILE, Antonio, CASCAVILLA, Nicola, CAPALBO, Silvana, QUARTA, Giovanni, DAMMACCO, Franco, COLUCCIA, Addolorata M. L, RIBATTI, Domenico, VACCA, Angelo, RIA, Roberto, MOSCHETTA, Michele, DE LUCA, Emanuela, PIERONI, Luisa, MAFFIA, Michele, URBANI, Andrea, DI PIETRO, Giulia
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-04-2011
• Subjects: Adult; Aged; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic agents; Apoptosis Regulatory Proteins - biosynthesis; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - physiology; Cell Movement - drug effects; Chemokine CCL2 - biosynthesis; Chemokine CXCL12 - biosynthesis; Chickens; Chorioallantoic Membrane - drug effects; Chorioallantoic Membrane - metabolism; Culture Media, Conditioned; Endothelial Cells - drug effects; Endothelial Cells - physiology; Female; Fibroblast Growth Factor 2 - biosynthesis; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Intracellular Signaling Peptides and Proteins - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Membrane Proteins - biosynthesis; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Proteome - metabolism; Proto-Oncogene Proteins - biosynthesis; Selenoprotein W - biosynthesis; Signal Transduction; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Thalidomide - therapeutic use; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Antineoplastic agent; Human; Immunopathology; Endothelial cell; Immunoglobulinopathy; Lenalidomide; Lymphoproliferative syndrome; Bone marrow; Patient; Malignant hemopathy; Myeloma; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-2381

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).
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.
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.
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.