The Impact of Extracellular Vesicles on Inflammation in the Tumor Microenvironment of Sarcomas: A Literature Review

Abstract

Introduction: Sarcomas are a diverse group of tumours encompassing over 100 different subtypes occurring in bone, muscle, and cartilage. The sarcoma tumour microenvironment (TME) contains various immune modulators and is influenced by the specific sarcoma subtype. The sarcoma TME is modulated by secretion of cytokines, chemokines, and extracellular vesicles (EVs). EVs play a role in inflammatory and immune responses in the TME. EVs effects are attributed to their cargo, consisting of mRNAs, proteins, miRNAs, chemokines, and cytokines. Sarcoma cells release tumour-derived EVs, facilitating communication, tumour progression, and inflammation.

Methods: We conducted a literature search for keywords and concepts associated with EVs and inflammatory responses in sarcomas on the PubMed database. Keyword combinations included relevance to EVs, sarcomas and inflammation. Only studies from peer reviewed journals, written in English, and published between 2013-2024 were considered. Sarcoma subtypes viewed included: rhabdomyosarcoma, Ewing sarcoma, chondrosarcoma, liposarcoma, and osteosarcoma.

Results: Ewing sarcoma EVs carry miRNA and mRNAs including EWS/FLI-1 mRNA, and surface proteins causing upregulation of inflammatory pathways, and contributing to the release of pro-inflammatory cytokines. Rhabdomyosarcoma EVs carry miRNAs and PAX3/7-FOXO1 mRNA stimulating inflammatory pathways to release cytokines and chemokines. Chondrosarcoma’s hypoxic TME causes increased EV secretion, favouring M2 polarisation, and the production of immunosuppressive markers. Liposarcoma EVs enriched with miRNAs and MDM2 induced an inflammatory response in macrophages. Osteosarcoma EVs contained TGF-β and miRNA cargo which influenced macrophage polarisation.

Discussion: Sarcoma-derived EVs contain a wide range of mRNAs and miRNAs, with Ewing sarcoma and Rhabdomyosarcoma also containing the fusion oncogenes EWS/FLI-1 and PAX3/7-FOXO1, respectively. Surface proteins on Ewing sarcoma and osteosarcoma EVs were better understood compared to other sarcomas. Various sarcoma-derived EV cargo demonstrated potential to influence inflammatory pathways within macrophages. Macrophage polarisation is fundamental to immune function, determining pro-inflammatory and anti-inflammatory responses.

Conclusion: By understanding the role of EVs in the inflammatory process, a deeper insight in tumour progression and tumour cell-cell communication can be achieved. The uniqueness of EV cargo to certain sarcoma subtypes could potentially indicate a future as biomarkers for early cancer detection. Further research into inflammatory effects by EVs can provide potential as novel therapeutics.