Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment l…

2019

Background Multiple myeloma (MM) is a clonal plasma cell malignancy associated with osteolytic bone disease. Recently, the role of MM-derived exosomes in the osteoclastogenesis has been demonstrated although the underlying mechanism is still unknown. Since exosomes-derived epidermal growth factor receptor ligands (EGFR) are involved in tumor-associated osteolysis, we hypothesize that the EGFR ligand amphiregulin (AREG) can be delivered by MM-derived exosomes and participate in MM-induced osteoclastogenesis. Methods Exosomes were isolated from the conditioned medium of MM1.S cell line and from bone marrow (BM) plasma samples of MM patients. The murine cell line RAW264.7 and primary human CD1…

PO-146 Multiple myeloma-derived exosomes carry amphiregulin and are responsible for the uncoupled bone remodelling

2018

Introduction Multiple myeloma (MM) is a hematologic malignancy associated with osteolytic bone disease caused by the perturbation of the functional balance between bone resorption and bone formation. Exosomes, nanosize lipoproteic structures, have been recently recognised as a new mechanism of cell to cell communication during tumour growth and progression. We have previously shown that MM-exosomes are involved in osteolytic lesions but the underlying mechanism is still understood. We hypothesise that the epidermal growth factor receptor ligand Amphiregulin (AREG) can be delivered by multiple myeloma-derived exosomes and participate in modulating the response of the bone microenvironment to…

The link between bone microenvironment and immune cells in multiple myeloma: Emerging role of CD38

2018

The relationship between bone and immune cells is well established both in physiological and pathological conditions. Multiple myeloma (MM) is a plasma cell malignancy characterized by an increase of number and activity of osteoclasts (OCLs) and a decrease of osteoblasts (OBs). These events are responsible for bone lesions of MM patients. OCLs support MM cells survival in vitro and in vivo. Recently, the possible role of OCLs as immunosuppressive cells in the MM BM microenvironment has been underlined. OCLs protect MM cells against T cell-mediated cytotoxicity through the expression of several molecules including programmed death-ligand (PD-L) 1, galectin (Gal) 9, CD200, and indoleamine-2,3…

Myeloma-Induced Alterations of Glutamine Metabolism Impair Bone Microenvironment Niche in Multiple Myeloma Patients

2018

Abstract Multiple myeloma (MM) cells are characterized by tight dependence on the bone marrow (BM) microenvironment that exerts a permissive role on cell growth and survival. In turn, MM cells markedly modify their microenvironment leading, in particular, to the development of osteolytic bone lesions. Recently, we demonstrated that metabolic alterations is a major feature of MM cells showing that BM plasma of MM patients is characterized by lower levels of Glutamine (Gln) and higher levels of Glutamate (Glu) and ammonium when compared with patients with smoldering MM (SMM) and Monoclonal Gammopathy of Uncertain Significance (MGUS). In the majority of MM patients MM cells are Gln-addicted si…

CD14+CD16+ Monocyte Binding to Myeloma Cells Is Required for Daratumumab Dependent Killing in Multiple Myeloma Patients

2018

Abstract Recently, the introduction of anti-CD38 monoclonal antibody, Daratumumab (DARA), in multiple myeloma (MM) therapy has improved the response rate of relapsed MM patients. However only a fraction of the DARA-treated patients respond, thus further studies on DARA mechanisms of action are needed. Because the antibody dependent cellular phagocytosis (ADCP) mediated by monocyte, is one of the mechanisms through DARA exerts its anti-MM activity, an ex-vivo approach was established in order to investigate which mechanisms or patient's immunological characteristics could influence DARA-mediated killing of MM cells. Bone marrow mononuclear cells (BM-MNCs) obtained from 25 MM patients (12 new…

Relationship between Bone Marrow PD-1 and PD-L1 Expression and the Presence of Osteolytic Bone Disease in Multiple Myeloma Patients

2018

Abstract Alterations of the bone marrow (BM) immune-microenvironment characterize the progression of monoclonal gammopathies and the development of osteolytic bone disease in multiple myeloma (MM). MM patients exhibit immune dysfunctions as impaired dendritic, NK and T cells, whereas the onset of MM osteolytic lesions is associated to an increased prevalence of Th17 cells. Recently, the pathophysiological role of the programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) pathway together with an increase of myeloid derived suppressor cells (MDSCs) in the induction of tumor tolerance and immune evasion has been underlined with a therapeutic relevance. However, unclear data on the express…

Curcumin modulates chronic myelogenous leukemia exosomes composition and affects angiogenic phenotype, via exosomal miR-21

2016

Abstract: Tumor derived exosomes are vesicles which contain proteins and microRNAs that mediate cell-cell communication and are involved in angiogenesis and tumor progression. Curcumin derived from the plant Curcuma longa, shows anticancer effects. Exosomes released by CML cells treated with Curcumin contain a high amount of miR-21 that is shuttled into the endothelial cells in a biologically active form. The treatment of HUVECs with CML Curcu-exosomes reduced RhoB expression and negatively modulated endothelial cells motility. We showed that the addition of CML control exosomes to HUVECs caused an increase in IL8 and VCAM1 levels, but Curcu-exosomes reversed these effects thus attenuating …

The Exosomes-derived EGFR Ligand Amphiregulin (AREG) is a new key player in Multiple Myeloma Bone Destruction

Il Mieloma Multiplo (MM) è caratterizzato dalla presenza di aree osteolitiche dovute alla presenza di plasmacellule (PC) neoplastiche che causano l'interruzione della normale omeostasi ossea, promuovendo l'attività degli osteoclasti (OC) ed inibendo la funzione degli (OB). Al momento, uno dei campi di ricerca nella fisiopatologia del MM è proprio lo studio dei meccanismi che regolano l’attività degli OC e degli OB così come l’identificazione di target terapeutici per la prevenzione ed il trattamento delle lesioni osteolitiche. Negli ultimi anni è emerso che le vescicole extracellulari (EV), ed in particolare gli esosomi, giocano un ruolo fondamentale nel mediare il cross-talk tra le cellule…

Additional file 1: of Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the b…

2019

Figure S1. Evaluation by quantitative Real Time PCR of mRNA expression of AREG in HMCLs (A) and in MM1.S cells and exosomes (B). (TIFF 2501 kb)

Additional file 2: of Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the b…

2019

Figure S2. Schematic representation of the role of MM-exosomes in bone microenvironment. (TIF 3372 kb)