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.

Keywords: Ewing sarcoma; extracellular vesicles; immunosuppression; metastasis; reprogramming; tumor microenvironment.

FIGURE 1

Biogenesis of extracellular vesicles. (A) Exosomes: Starts with endocytosis-associated invagination of plasma membrane and forms an early endosome, late endosome, and sorted multivesicular body (MVB) by accumulating intraluminal vesicles, sequentially. MVB fuses with plasma membrane to release exosomes via exocytosis. (B) Microvesicles: Calcium ions released into the cytoplasm by endoplasmic reticulum cause the budding of microvesicles from plasma membrane via calpain- or gelsolin-mediated pathways. (C) Apoptotic bodies: An apoptotic cell undergoes sequential steps of large protrusions and blebbing of plasma membrane to release apoptotic bodies.

FIGURE 2

Schematic representation of Ewing sarcoma extracellular vesicle-mediated reprogramming of cells in the tumor microenvironment. Ewing sarcoma (EwS)-derived extracellular vesicles (EVs) may cause transformation of normal fibroblasts into cancer-associated fibroblasts that majorly support the cancer development. EwS-derived EVs may cause tumor-associated macrophages and dendritic cells to produce excessive pro-inflammatory cytokines and cause suppression of tumor specific immune response, and support both the cancer development and its progression. EwS EVs may inhibit T cell-mediated response by decreasing activation associated signals, thereby causing cancer progression.