Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis
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…
The link between bone microenvironment and immune cells in multiple myeloma: Emerging role of CD38
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
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
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
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…
Additional file 1: of Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis
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 bone microenvironment leading to osteoclastogenesis
Figure S2. Schematic representation of the role of MM-exosomes in bone microenvironment. (TIF 3372 kb)