Abstract
Simple SummaryMultiple myeloma (MM) is a disease that extensively involves bone, and angiogenesis and immunosuppression are important processes in the development of MM. Proteasome inhibitors and immunomodulatory drugs remarkably improve the survival of MM patients. However, MM is still an incurable disease that rapidly becomes resistant to these drugs. There is robust evidence that extracellular vesicles (EVs) contribute to cancer metastasis. Osteoclasts, in addition to immunosuppressive cells in the bone marrow (BM), are key players in osteolysis and immunosuppression. BM stromal cells and MM cells secrete EVs through which they communicate with each other: EVs, in fact, contain proteins, small RNAs, and long non-coding RNAs that mediate this communication and contribute to angiogenesis, osteolysis, and cancer dissemination and drug resistance. Ectoenzymes are expressed in myeloma cells, osteoclasts, and stromal cells and produce immunosuppressive adenosine. Recently, an antibody targeting CD38, an ectoenzyme, has been shown to improve the survival of patients with MM. Thus, understanding the properties of EV and ectoenzymes will help elucidate key processes of MM development.Angiogenesis and immunosuppression promote multiple myeloma (MM) development, and osteolysis is a primary feature of MM. Although immunomodulatory drugs and proteasome inhibitors (PIs) markedly improve the survival of patients with MM, this disease remains incurable. In the bone marrow niche, a chain of ectoenzymes, including CD38, produce immunosuppressive adenosine, inhibiting T cell proliferation as well as immunosuppressive cells. Therefore, anti-CD38 antibodies targeting myeloma cells have the potential to restore T cell responses to myeloma cells. Meanwhile extracellular vesicles (EVs) containing microRNAs, proteins such as cytokines and chemokines, long noncoding RNAs, and PIWI-interacting RNAs have been shown to act as communication tools in myeloma cell/microenvironment interactions. Via EVs, mesenchymal stem cells allow myeloma cell dissemination and confer PI resistance, whereas myeloma cells promote angiogenesis, myeloid-derived suppressor cell proliferation, and osteoclast differentiation and inhibit osteoblast differentiation. In this review, to understand key processes of MM development involving communication between myeloma cells and other cells in the tumor microenvironment, EV cargo and the non-canonical adenosinergic pathway are introduced, and ectoenzymes and EVs are discussed as potential druggable targets for the treatment of MM patients.
Highlights
TThheessee cceellllssbbuuiillddaanniicchheettoossuuppppoorrttMMMMcceellllggrroowwtthh,ppaarrttiiccuullaarrllyyiinntthheehhyyppooxxiiccssttaattee,iinn wwhhiicchhththeennonocnacnaonnoinciaclaaldaedneonsoinseinrgeircgpicatphawthawy aisypirsedporemdionmanintlaynftalcyilfliatcaitlelidta(tFeidgu(rFeig1u) r[e121]). [12].Recently, extensive evidence has shown that MM and stromal cells of the BMM use extracellular vesicles (EVs) [11,13,14,15,16,17,18], including exosomes [19,20,21,22,23,24], as a communication tool; MM cells educate MSCs [13,25], and MSCs contribute to MM cell spreading [20]
These findings indicated that, in total, bulk MVs extracted from patients with MM were enriched in a mixture of ectoenzymes (CD39, CD38, CD73, and CD203a) derived from different cell components in the BM, producing adenosine by conversion of adenosine triphosphate (ATP) and/or NAD+ in the BMM niche [10]
By targeting myeloma cells and reducing the levels of immunosuppressive adenosine, the anti-CD38 antibody daratumumab is expected to improve the quality of remission in patients with MM
Summary
Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by the accumulation of monoclonal neoplastic plasma cells at multiple sites in tthhee bboonnee mmaarrrrooww ((BBMM)) [[11]]. The MM BMM includes high levels of extracellular nucleotides, such as adenosine triphosphate (ATP) and NAD+, which are converted to adenosine in reactions catalyzed by cell surface proteins called ectoenzymes (Figure 1) [37]. According to the same group, MVs isolated from the BM of patients with symptomatic MM revealed higher levels of all ectoenzymes than those from patients with MGUS/smoldering MM (SMM), and adenosine production was higher in the MVs from patients with symptomatic MM than in those from patients with MGUS/SMM [10] These findings indicated that, in total, bulk MVs extracted from patients with MM were enriched in a mixture of ectoenzymes (CD39, CD38, CD73, and CD203a) derived from different cell components in the BM, producing adenosine by conversion of ATP (via the canonical pathway) and/or NAD+ (via the noncanonical pathway) in the BMM niche [10]. Because adenosine suppresses T cell proliferation and cytotoxicity, the BM niche provides an ideal location in which myeloma cells can utilize adenosine to construct a microenvironment for their survival and evasion from host immune cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
