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Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells, which are predominantly localized in the bone marrow. Myeloid-derived suppressor cells (MDSC) are described to promote MM progression by immunosuppression and induction of angiogenesis. However, their direct role in drug resistance and tumor survival is still unknown. In this study, we performed co-culture experiments of myeloma cells with 5TMM derived MDSC in vitro, leading to increased survival and proliferation of MM cells. Co-culture experiments resulted in MDSC-induced AMPK phosphorylation in MM cells, which was associated with an increase in the anti-apoptotic factors MCL-1 and BCL-2, and the autophagy-marker LC3II. In addition, 5TMM cells inoculated in mice showed a clear upregulation of AMPK phosphorylation in vivo. Targeting the AMPK pathway by Compound C resulted in apoptosis of human myeloma cell lines, primary MM cells and 5TMM cells. Importantly, we observed that the tumor-promoting effect of MDSC was partially mediated by AMPK activation. In conclusion, our data clearly demonstrate that MDSC directly increase the survival of MM cells, partially through AMPK activation, identifying this pathway as a new target in the treatment of MM patients. [ABSTRACT FROM AUTHOR]

The interplay between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells performs a crucial role in MM pathogenesis by secreting growth factors, cytokines, and extracellular vesicles. Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and they mediate local cell-to-cell communication by transferring mRNAs, miRNAs, and proteins. Although BMSC-induced growth and drug resistance of MM cells has been studied, the role of BMSC-derived exosomes in this action remains unclear. Here we investigate the effect of BMSC-derived exosomes on the viability, proliferation, survival, migration, and drug resistance of MM cells, using the murine 5T33MM model and human MM samples. BMSCs and MM cells could mutually exchange exosomes carrying certain cytokines. Both naive and 5T33 BMSC-derived exosomes increased MM cell growth and induced drug resistance to bortezomib. BMSC-derived exosomes also influenced the activation of several survival relevant pathways, including c-Jun N-terminal kinase, p38, p53, and Akt. Exosomes obtained from normal donor and MM patient BMSCs also induced survival and drug resistance of human MM cells. Taken together, our results demonstrate the involvement of exosome-mediated communication in BMSC-induced proliferation, migration, survival, and drug resistance of MM cells. [ABSTRACT FROM AUTHOR]

Abstract: One of the greatest challenges in multiple myeloma (MM) treatment is to overcome drug resistance. Many pathways are involved including Notch signaling. Notch receptors are expressed by MM cells and Notch ligand Dll1 is present on bone marrow (BM) stromal cells. In this study, we demonstrate that Dll1 can activate Notch signaling mostly through Notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human MM cells. Blocking the Notch pathway by DAPT (gamma secretase inhibitor) could reverse this effect and increased sensitivity to bortezomib. We describe the upregulation of CYP1A1, a Cytochrome P450 enzyme involved in drug metabolism, as a possible mechanism of Dll1/Notch induced bortezomib resistance. This was confirmed by inhibition experiments using α-Naphthoflavone or CYP1A1-siRNA that resulted in an increased sensitivity to bortezomib. In addition, in vivo data showed that combination treatment of DAPT with bortezomib was able to increase bortezomib sensitivity and prolonged overall survival in the 5T33MM mouse model. Our data provide a potential strategy to overcome bortezomib resistance by Notch inhibition in MM therapy. [Copyright &y& Elsevier]