Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma

Annunziata De Luisi, Arianna Ferrucci, Addolorata M L Coluccia, Roberto Ria, Michele Moschetta, Emanuela De Luca, Luisa Pieroni, Michele Maffia, Andrea Urbani, Giulia Di Pietro, Attilio Guarini, Girolamo Ranieri, Paolo Ditonno, Simona Berardi, Antonella Caivano, Antonio Basile, Nicola Cascavilla, Silvana Capalbo, Giovanni Quarta, Franco DammaccoDomenico Ribatti, Angelo Vacca

Research output: Contribution to journalArticle

Abstract

Purpose: 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). Experimental Design: 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.

Original languageEnglish
Pages (from-to)1935-1946
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number7
DOIs
Publication statusPublished - Apr 1 2011

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Multiple Myeloma
Bone Marrow Cells
Endothelial Cells
Monoclonal Gammopathy of Undetermined Significance
Apoptosis
Vitronectin
Chorioallantoic Membrane
Extracellular Fluid
Human Umbilical Vein Endothelial Cells
Chemotaxis
Cytoskeleton
Reverse Transcriptase Polymerase Chain Reaction
Fibronectins
Cell Adhesion
Proteomics
Wound Healing
Energy Metabolism
Vascular Endothelial Growth Factor A
Endothelium
Cell Movement

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. / De Luisi, Annunziata; Ferrucci, Arianna; Coluccia, Addolorata M L; Ria, Roberto; Moschetta, Michele; De Luca, Emanuela; Pieroni, Luisa; Maffia, Michele; Urbani, Andrea; Di Pietro, Giulia; Guarini, Attilio; Ranieri, Girolamo; Ditonno, Paolo; Berardi, Simona; Caivano, Antonella; Basile, Antonio; Cascavilla, Nicola; Capalbo, Silvana; Quarta, Giovanni; Dammacco, Franco; Ribatti, Domenico; Vacca, Angelo.

In: Clinical Cancer Research, Vol. 17, No. 7, 01.04.2011, p. 1935-1946.

Research output: Contribution to journalArticle

De Luisi, A, Ferrucci, A, Coluccia, AML, Ria, R, Moschetta, M, De Luca, E, Pieroni, L, Maffia, M, Urbani, A, Di Pietro, G, Guarini, A, Ranieri, G, Ditonno, P, Berardi, S, Caivano, A, Basile, A, Cascavilla, N, Capalbo, S, Quarta, G, Dammacco, F, Ribatti, D & Vacca, A 2011, 'Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma', Clinical Cancer Research, vol. 17, no. 7, pp. 1935-1946. https://doi.org/10.1158/1078-0432.CCR-10-2381
De Luisi, Annunziata ; Ferrucci, Arianna ; Coluccia, Addolorata M L ; Ria, Roberto ; Moschetta, Michele ; De Luca, Emanuela ; Pieroni, Luisa ; Maffia, Michele ; Urbani, Andrea ; Di Pietro, Giulia ; Guarini, Attilio ; Ranieri, Girolamo ; Ditonno, Paolo ; Berardi, Simona ; Caivano, Antonella ; Basile, Antonio ; Cascavilla, Nicola ; Capalbo, Silvana ; Quarta, Giovanni ; Dammacco, Franco ; Ribatti, Domenico ; Vacca, Angelo. / Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 7. pp. 1935-1946.
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T1 - Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma

AU - De Luisi, Annunziata

AU - Ferrucci, Arianna

AU - Coluccia, Addolorata M L

AU - Ria, Roberto

AU - Moschetta, Michele

AU - De Luca, Emanuela

AU - Pieroni, Luisa

AU - Maffia, Michele

AU - Urbani, Andrea

AU - Di Pietro, Giulia

AU - Guarini, Attilio

AU - Ranieri, Girolamo

AU - Ditonno, Paolo

AU - Berardi, Simona

AU - Caivano, Antonella

AU - Basile, Antonio

AU - Cascavilla, Nicola

AU - Capalbo, Silvana

AU - Quarta, Giovanni

AU - Dammacco, Franco

AU - Ribatti, Domenico

AU - Vacca, Angelo

PY - 2011/4/1

Y1 - 2011/4/1

N2 - Purpose: 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). Experimental Design: 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.

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