Abstract
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.
Highlights
Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 mmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d
This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, giving new avenues for effective endothelium-targeted therapies in MM
To investigate whether lenalidomide could directly inhibit the MM-related angiogenesis, we first examined the in vivo chorioallantoic membrane (CAM) assay
Summary
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). We have previously shown that thalidomide is antiangiogenic by downregulating key genes involved in autocrine and paracrine angiogenic loops of MM patients [4]. Earlier studies have shown that in the bone marrow (BM) microenvironment, TNF-a increases cell–cell adhesion by inducing NF-kB–dependent upregulation of adhesion molecules on both MM and stromal cells. TNF-a only modestly triggers the MM plasma cell proliferation, the subsequent activation of NF-kB stimulates interleukin (IL)-6—another key survival signal—in stromal cells, and both factors are targeted by IMiDs [5]. Lenalidomide shows in vivo antitumor properties owing to stimulation of patients’ T cells and IL-2/IFN-g production and inhibition of TNF-a [6]. In peripheral blood mononuclear cells, it reduces the expression of angiogenic factors, such as VEGF and basic fibroblast growth factor (bFGF; ref. 3), TNF-a, www.aacrjournals.org
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