Osteosarcoma cell-derived exosomes affect tumor microenvironment by specific packaging of microRNAs

Abstract

<jats:title>Abstract</jats:title> <jats:p>Bone microenvironment provides growth and survival signals essential for osteosarcoma (OS) initiation and progression. OS cells regulate communications inside tumor microenvironment through different ways and, among all, tumor-derived exosomes support cancer progression and metastasis. To define the contribution of OS-derived exosomes inside the microenvironment, we investigated the effects induced in bone remodeling mechanism and tumor angiogenesis. We demonstrated that exosomes promoted osteoclasts differentiation and bone resorption activity. Furthermore, exosomes potentiated tube formation of endothelial cells and increased angiogenic markers expression. We therefore investigated the micro RNA (miRNA) cargo from exosomes and their parental cells by performing small RNA sequencing through NGS Illumina platform. Hierarchical clustering highlighted a unique molecular profile of exosomal miRNA; bioinformatic analysis by DIANA-mirPath revealed that miRNAs identified take part in various biological processes and carcinogenesis. Among these miRNAs, some were already known for their involvement in the tumor microenvironment establishment, as miR-148a and miR-21-5p. Enforced expression of miR-148a and miR-21-5p in Raw264.7 and hTert immortalized umbilical vein endothelial cells recapitulated the effects induced by exosomes. Overall, our study highlighted the importance of OS exosomes in tumor microenvironment also by a specific packaging of miRNAs.</jats:p>

Exosomal transfer of miR-15b-3p enhances tumorigenesis and malignant transformation through the DYNLT1/Caspase-3/Caspase-9 signaling pathway in gastric cancer

“…Interestingly, exosomes can carry numerous miR-NAs that act locally or enter into circulation to act at distal sites, since internal miRNAs are protected from being digested by RNase, as a result of the protection offered by the lipid membrane of the exosomes [12,13]. New evidence has demonstrated that exosomal miRNAs (exo-miRNAs) transmitted between cells perform a crucial regulatory function in apoptosis, invasion, migration, proliferation, as well as chemoresistance of multifarious tumors, including GC [13][14][15][16][17].…”

Plasma exosomal miRNAs involved in endothelial injury in microscopic polyangiitis patients

“…Noticeably, studies found that exosomes were significantly different in composition in various diseases, which was mainly owing to changes in the cytoplasmic physiology 9,10 . For instance, osteosarcoma cell‐derived exosomes affected the tumor microenvironment by specific packaging of microRNA 11 . These differentially expressed bioinformatic molecules in exosomes are one of the important factors affecting the development of the disease.…”

Exosomes in Bone Sarcomas: Key Players in Metastasis

“…Validation studies using metastatic and non-metastatic exosome transfer and mimic treatments confirmed that the uptake of miR-675 via exosomes led to the downregulation of CALN1 expression associated with migration [100]. A more recent study has investigated if OS-derived exosomes could induce changes to macrophages, osteoclasts, and endothelial cells, important components of the TME [101]. Exosome internalization by macrophages induced osteoclast gene expression profile and an increase in the number of osteoclast-like cells.…”

“…Exosome internalization by macrophages induced osteoclast gene expression profile and an increase in the number of osteoclast-like cells. In addition, osteoclasts cultured with OS-derived exosomes had higher bone resorption activity in vitro [101], suggesting that OS could induce changes in the bone microenvironment via macrophage and osteoclast modulation. Moreover, the uptake of OS-derived exosomes by endothelial cells induced an increase in pro-angiogenic factors and the formation of capillary structures in vitro, thus confirming that OS could modulate the invasiveness of cancer cells by modulating the TME [101].…”

“…In addition, osteoclasts cultured with OS-derived exosomes had higher bone resorption activity in vitro [101], suggesting that OS could induce changes in the bone microenvironment via macrophage and osteoclast modulation. Moreover, the uptake of OS-derived exosomes by endothelial cells induced an increase in pro-angiogenic factors and the formation of capillary structures in vitro, thus confirming that OS could modulate the invasiveness of cancer cells by modulating the TME [101]. Profiling of the miRNA content of these exosomes identified miR-148a and miR-21-5p as being behind the change in the phenotype of osteoclast and endothelial activities upon exosome uptake, as overexpression of these miRNAs in recipient cells induced the expression of osteoclast markers and increased bone resorption and angiogenesis in vitro [101].…”