Abstract 2120: Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth

Multiple myeloma, one of the most common hematological malignancies, will often manifest osteolytic lesions during disease development, throughout the whole body. MM is still considered an incurable malignancy, with a supportive micro-environment in the bone marrow. Extracellular vesicles such as exosomes are known to play an important tumor-promoting role in this micro-environment, by inducing angiogenesis and immune suppression. The aim of our study was to examine the effects of MM exosomes on osteolysis in vitro and in vivo, and to determine whether inhibition of exosome secretion can lead to a delay in tumor growth and prevent bone loss. We used the 5TGM1 model which is a syngeneic murine MM model, presenting typical MM characteristics such as osteolysis, angiogenesis and a serum M-spike. We examined the effects of conditioned medium from these MM cells and MM-derived exosomes on cell viability and proliferation of the MC3T3 pre-osteoblast cell line and on their ability to produce alkaline phosphatase (ALP). We saw a decrease in viability and ALP activity when adding exosomes or conditioned medium of the 5TGM1 myeloma cells to the osteoblasts. Moreover, RT-PCR analysis showed a decrease of various osteogenic differentiation genes when osteoblasts were exposed to 5TGM1 exosomes, demonstrating a diminished capacity of osteoblastic differentiation. We next added the exosome secretion inhibitor GW4869 to the 5TGM1 cells, thereby reducing the number of exosomes in the conditioned medium. This was confirmed through western blot of the typical exosome markers. The negative effects of the 5TGM1 conditioned medium on osteoblasts could be overturned by reducing the exosome content therein. In vivo, we injected 5TGM1 exosomes intravenously in healthy mice for three weeks and examined the effects on osteolysis by microCT and TRAP staining. We saw an increase in osteolysis, comparable to the typical osteolytic lesions in tumor-bearing mice. Furthermore, when inhibiting the exosome secretion in vivo in 5TGM1 mice, we observed a significant reduction in tumor load. Through this study we can conclude that exosomes from multiple myeloma cells can induce osteolytic lesions by inhibiting osteoblast proliferation and differentiation. These effects can be reversed by inhibiting the secretion of exosomes. Citation Format: Sylvia T. Faict, Kim De Veirman, Ken Maes, Elke De Bruyne, Roy Heusschen, Jo Caers, Karin Vanderkerken, Rik Schots, Eline Menu. Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2120.