Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications

Aurelia Lamanuzzi, Ilaria Saltarella, Antonia Reale, Assunta Melaccio, Antonio Giovanni Solimando, Concetta Altamura, Grazia Tamma, Clelia Tiziana Storlazzi, Doron Tolomeo, Vanessa Desantis, Maria Addolorata Mariggiò, Jean François Desaphy, Andrew Spencer, Angelo Vacca, Benedetta Apollonio, Maria Antonia Frassanito

Research output: Contribution to journalArticleResearchpeer-review


Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM angiogenesis. We demonstrate that FBEVs’ cargo contains several angiogenic cytokines (i.e., VEGF, HGF, and ANG-1) that promote an early over-angiogenic effect independent from EVs uptake. Interestingly, co-culture of endothelial cells from MM patients (MMECs) with FBEVs for 1 or 6 h activates the VEGF/VEGFR2, HGF/HGFR, and ANG-1/Tie2 axis, as well as the mTORC2 and Wnt/β-catenin pathways, suggesting that the early over-angiogenic effect is a cytokine-mediated process. FBEVs internalization occurs after longer exposure of MMECs to FBEVs (24 h) and induces a late over-angiogenic effect by increasing MMECs migration, chemotaxis, metalloproteases release, and capillarogenesis. FBEVs uptake activates mTORC1, MAPK, SRC, and STAT pathways that promote the release of pro-angiogenic cytokines, further supporting the pro-angiogenic milieu. Overall, our results demonstrate that FBEVs foster MM angiogenesis through dual time-related uptake-independent and uptake-dependent mechanisms that activate different intracellular pathways and transcriptional programs, providing the rationale for designing novel anti-angiogenic strategies.

Original languageEnglish
Article number1400
Number of pages15
Issue number5
Publication statusPublished - May 2023


  • angiogenesis
  • angiogenic cytokines
  • extracellular vesicles
  • multiple myeloma

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