Multiple myeloma cell-derived microvesicles are enriched in CD147 expression and enhance tumor cell proliferation

// Bonnie K. Arendt 1 , Denise K. Walters 1 , Xiaosheng Wu 1 , Renee C. Tschumper 1 and Diane F. Jelinek 1,2 1 Department of Immunology, Mayo Clinic, College of Medicine, Rochester, MN 2 Division of Hematology, Department of Medicine, Mayo Clinic, College of Medicine, Rochester, MN Correspondence: Diane F. Jelinek , email: // Keywords : MPT0G030, PKCδ, E-cadherin, HDAC, differentiation Received : June 20, 2014 Accepted : July 2, 2014 Published : July 3, 2014 Abstract Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells within the bone marrow. There is a growing literature that tumor cells release biologically active microvesicles (MVs) that modify both local and distant microenvironments. In this study, our goals were to determine if MM cells release MVs, and if so, begin to characterize their biologic activity. Herein we present clear evidence that not only do both patient MM cells and human MM cell lines (HMCLs) release MVs, but that these MVs stimulate MM cell growth. Of interest, MM-derived MVs were enriched with the biologically active form of CD147, a transmembrane molecule previously shown by us to be crucial for MM cell proliferation. Using MVs isolated from HMCLs stably transfected with a CD147-GFP fusion construct (CD147 GFP ), we observed binding and internalization of MV-derived CD147 with HMCLs. Cells with greater CD147 GFP internalization proliferated at a higher rate than did cells with less CD147 GFP association. Lastly, MVs obtained from CD147 downregulated HMCLs were attenuated in their ability to stimulate HMCL proliferation. In summary, this study demonstrates the significance of MV shedding and MV-mediated intercellular communication on malignant plasma cell proliferation, and identifies the role of MV-enriched CD147 in this process.