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

Luisi, Annunziata De; Ferrucci, Arianna; Coluccia, Addolorata Maria Luce; Ria, Roberto; Moschetta, Michele; Luca, Emanuela de; Pieroni, Luisa; Maffia, Michele; Urbani, Andrea; Pietro, Giulia Di; Giacosa, Attilio; Ranieri, Girolamo; Ditonno, Paolo; Berardi, Simona; Caivano, Antonella; Basile, Antonio; Cascavilla, Nicola; Capalbo, Silvana; Quarta, Giovanni; Dammacco, Franco; Ribatti, Doménico; Vacca, Angelo

doi:10.1158/1078-0432.ccr-10-2381

Cited by 72 publications

(65 citation statements)

References 51 publications

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“…These results support the role of MM-MVs in angiogenesis, consistent with findings in other cancers [12,14,21] . Of note, the origin of MMendothelial cells is actually unknown [42,43] . The present study supports the idea that these cells are malignantly transformed endothelial cells, perhaps partly due to MM-MVs; this idea is highly consistent with the observation that TMVs can form niches that favor tumor development [22,44] .…”

Section: Discussionmentioning

confidence: 99%

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

et al. 2013

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Aim: To investigate whether human multiple myeloma (MM) cells secrete microvesicles (MVs) and whether the MVs secreted from MM cells (MM-MVs) promote angiogenesis. Methods: RPMI8226 human MM cells and EA.hy926 human umbilical vein cells were used. MVs isolated from RPMI 8226 cells were characterized under laser confocal microscopy, electron microscopy and with flow cytometry. The fusion of MM-MVs and EA.hy926 cells was studied under confocal microscopy, and the transfer of CD138 to EA.hy926 cells was demonstrated with flow cytometry. The proliferation, invasion and tube formation of EA.hy926 cells in vitro were evaluated using MTT, transwell migration and tube formation assays, respectively. The vasculization of EA.hy926 cells in vivo was studied using Matrigel plug assay. The expression of IL-6 and VEGF was analyzed with PCR and ELISA. Results: MM-MVs from the RPMI 8226 cells had the characteristic cup-shape with diameter of 100-1000 nm. Most of the MM-MVs expressed phosphatidylserine and the myeloma cell marker CD138, confirming that they were derived from myeloma cells. After added to EA.hy926 cells, the MM-MVs transferred CD138 to the endothelial cells and significantly stimulated the endothelial cells to proliferate, invade, secrete IL-6 and VEGF, two key angiogenic factors of myeloma, and form tubes in vitro and in vivo. Conclusion: Our results confirm the presence of MVs in MM cells and support the idea that MM-MVs are newfound mediators for myeloma angiogenesis and may serve as a therapeutic target to treat MM.

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Section: Discussionmentioning

confidence: 99%

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

et al. 2013

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“…92 Lenalidomide may suppress HSC motility similar to the way it reduces the motility of marrow endothelial cells in multiple myeloma. 93 The antiangiogenic effect of lenalidomide could also impair mobilization. 94 Long-term administration of imatinib has been associated with reduced bone turnover, 95 which could affect HSC niche function.…”

Section: How I Treat Poor Hsc Mobilizers 4533mentioning

confidence: 99%

How I treat patients who mobilize hematopoietic stem cells poorly

Levesque

Herbert

2011

Blood

218

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Transplantation with 2-5 ؋ 10 6 mobilized CD34 ؉ cells/kg body weight lowers transplantation costs and mortality. Mobilization is most commonly performed with recombinant human G-CSF with or without chemotherapy, but a proportion of patients/donors fail to mobilize sufficient cells. BM disease, prior treatment, and age are factors influencing mobilization, but genetics also contributes. Mobilization may fail because of the changes affecting the HSC/progenitor cell/BM niche integrity and chemotaxis. Poor mobilization affects patient outcome and increases resource use. Until recently increasing G-CSF dose and adding SCF have been used in poor mobilizers with limited success. However, plerixafor through its rapid direct blockage of the CXCR4/CXCL12 chemotaxis pathway and synergy with G-CSF and chemotherapy has become a new and important agent for mobilization. Its efficacy in upfront and failed mobilizers is well established.To maximize HSC harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor. These include when to mobilize in relation to chemotherapy, how to schedule and perform apheresis, how to identify IntroductionHematopoietic stem cell transplantation (HSCT) has revolutionized the curative approach to a number of malignancies and BM failure syndromes by providing hematopoietic and immune rescue after high-dose cytoreductive therapy and, in allogeneic transplantations, graft-versus-tumor effect. [1][2][3][4] The term "mobilization" was first used to describe a 4-fold increase of circulating myeloid progenitors (granulocyte macrophage CFU [CFU-GM]) after the administration of endotoxin to healthy volunteers in 1977. 5 High levels of CFU-GM after recovery from myelosuppressive chemotherapy in humans was first described in 1976. 6 However, it was not until the 1980s that the use of chemotherapy-mobilized HSCs for transplantation was established. [7][8][9] Subsequently, a single high-dose cyclophosphamide was developed as a generic mobilizer. 10 Prof Metcalf led the study that showed the potential of G-CSF in mobilization. 11 Subsequently, 2 Australian centers in Melbourne and Adelaide showed for the first time the use of G-CSF-mobilized HSCs for transplantation, 12 and reports of combined G-CSF and chemotherapy mobilization soon followed. 13 Now, virtually all autologous and three-quarters of allogeneic transplantations are performed with mobilized HSCs (CIBMTR reports). 14,15 The cell dose effect of HSCT describes a threshold of HSCs that, when transplanted, is associated with rapid and sustained blood count recovery. 16 The benefits of rapid recovery are reduced hospitalization, blood product usage, and infections. 12,17 The minimum threshold for autologous transplantation is currently defined as 2 ϫ 10 6 CD34 ϩ cells/kg body weight (BW). 18 Many centers use a minimum of 3 ϫ 10 6 CD34 ϩ cells/kg BW for myeloablative and nonmyeloablative allogeneic and matched unrelated transplantations. Furthermore, Ͼ 5 ϫ 10 6 CD3...

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“…12 Although a direct anti-angiogenic effect of LEN on endothelial cells has been demonstrated, 13 and also in vivo in a lymphoma mouse model, 14 other authors have failed to report a significant reduction in bone marrow MVD in MM patients treated with new drugs, including LEN.…”

Section: A B D E F G Cmentioning

confidence: 99%