Extracellular Vesicles in Reprogramming of the Ewing Sarcoma Tumor Microenvironment

Abstract

Ewing sarcoma (EwS) is a highly aggressive cancer and the second most common malignant bone tumor of children and young adults. Although patients with localized disease have a survival rate of approximately 75%, the prognosis for patients with metastatic disease remains dismal (<30%) and has not improved in decades. Standard-of-care treatments include local therapies such as surgery and radiotherapy, in addition to poly-agent adjuvant chemotherapy, and are often associated with long-term disability and reduced quality of life. Novel targeted therapeutic strategies that are more efficacious and less toxic are therefore desperately needed, particularly for metastatic disease, given that the presence of metastasis remains the most powerful predictor of poor outcome in EwS. Intercellular communication within the tumor microenvironment is emerging as a crucial mechanism for cancer cells to establish immunosuppressive and cancer-permissive environments, potentially leading to metastasis. Altering this communication within the tumor microenvironment, thereby preventing the transfer of oncogenic signals and molecules, represents a highly promising therapeutic strategy. To achieve this, extracellular vesicles (EVs) offer a candidate mechanism as they are actively released by tumor cells and enriched with proteins and RNAs. EVs are membrane-bound particles released by normal and tumor cells, that play pivotal roles in intercellular communication, including cross-talk between tumor, stromal fibroblast, and immune cells in the local tumor microenvironment and systemic circulation. EwS EVs, including the smaller exosomes and larger microvesicles, have the potential to reprogram a diversity of cells in the tumor microenvironment, by transferring various biomolecules in a cell-specific manner. Insights into the various biomolecules packed in EwS EVs as cargos and the molecular changes they trigger in recipient cells of the tumor microenvironment will shed light on various potential targets for therapeutic intervention in EwS. This review details EwS EVs composition, their potential role in metastasis and in the reprogramming of various cells of the tumor microenvironment, and the potential for clinical intervention.

The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic Targets

“…For sarcomas to thrive in their new environment, it is of utmost importance for the PMN to protect the metastatic sarcoma cells from being apoptosed upon entering the metastatic site [ 85 ]. Exosomes produced by tumor cells can support their escape from immune surveillance [ 86 , 87 , 88 ]. Exosomes can upregulate the expression of proinflammatory factors and induce the secretion of some proinflammatory chemokines and cytokines, such as IL10, TGF-β2, and IL-35, in the tumor local inflammatory microenvironment, thus weakening antitumor immune responses [ 87 , 89 , 90 ].…”

Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness

“…Unlike epithelial cancers, the current understanding of the origin and contribution of CAFs in sarcomas is very limited. Studies in Ewing sarcoma 144 and osteosarcoma 145 have demonstrated that extracellular vesicles and associated cargo secreted from tumor cells drive the transformation of normal fibroblasts into CAFs. On the contrary, rhabdomyosarcoma cells do not rely on CAFs to prime the ECM for local tumor expansion, but rather produce their own ECM with minimal involvement of CAFs 146 .…”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Our knowledge remains sparse for other types of solid malignancies of non-epithelial origin, e.g., in sarcomas. Except for Ewing sarcoma [42] and osteosarcoma [43], the role of CAFs in sarcomas of different origins is unclear. Further, CAFs have not been extensively studied in haematological malignancies so far.…”