C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway

Abstract

Background: The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal microRNAs (miRs) delivery. It is reported that miR-29b played an important role in regulating the tumor angiogenesis. Methods: In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions. Results: Our results showed that exosomes released from MM cells treated by C6-cer (Exo C6-cer) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by Exo C6-cer , while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the Exo C6-cer-induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA. Conclusions: Collectively, our data suggest that Exo C6-cer-mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

“…Devising novel anticancer strategies based on the modulation of lipid metabolism and the composition of the cell membrane was recently advised for the treatment of cancer and overcoming drug resistance, pioneering a novel field named membrane-lipid therapy [ 104 – 106 ]. Combination of chemotherapeutic drugs and Cer is presently increasingly used for tumor treatment [ 47 , 51 , 107 – 109 ]. Increasing the activity of nSMase 2 led to overcoming immune escape in melanoma cells [ 110 ].…”

Human myeloma cell‐ and plasma‐derived extracellular vesicles contribute to functional regulation of stromal cells

“…For the purpose of this work the mechanisms of MM-sEV uptake and its blockade were not evaluated but further investigation to inform its translational application in MM is warranted. Several studies have shown the involvement of sEV derived from both MM-derived tumor and stromal cells in cell proliferation [47], angiogenesis [52,90], immunosuppression [90], fibroblast reprogramming [89], bone lysis [51,52,49]. Consistently, in response to their interaction with both HMCL-sEV and MM-psEV, (non-MM) human stromal cells acquired pro-proliferative and pro-migratory phenotypes.…”

“…Specifically, no consensus exists on the type of starting material (e.g., plasma vs. serum) and isolation protocol [100], with most studies focused on RNA-based downstream applications [89,28,101,29] compared to functional or proteomic-based studies [102,82]. UC and precipitation are the most widely adopted methods in MM [52,28,47] despite their proven inadequacy for the removal of "contaminants"…”

“…sEV have also been shown to contribute to the dynamic co-evolution of MM PCs and the BM microenvironment favouring MM progression and drug resistance [49,50,47]. Accumulating evidence suggest a role for MM PCs-derived EVs in bone remodelling and breakdown [51,52,49] (a characteristic feature of MM [53]) and enhanced pro-tumoral activity of MM-BM stromal cells [54,52,50,55]. However, the specific EV-driven molecular mechanisms that promote PCs homing to selected distant sites (pre-metastatic niches) during MGUS-to-MM evolution remain undefined.…”

Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers

“…Some studies have reported that noncoding RNAs regulate the generation of ceramide or downstream of ceramide-mediated biological processes. For example, miR-34a causes ceramide accumulation [ 269 ], while ceramide inhibits the proangiogenic activity of multiple myeloma through miR-29b [ 270 ].…”