Tumor-Derived Extracellular Vesicles: Multifunctional Entities in the Tumor Microenvironment

Abstract

Tumor cells release extracellular vesicles (EVs) that can function as mediators of intercellular communication in the tumor microenvironment. EVs contain a host of bioactive cargo, including membrane, cytosolic, and nuclear proteins, in addition to noncoding RNAs, other RNA types, and double-stranded DNA fragments. These shed vesicles may deposit paracrine information and can also be taken up by stromal cells, causing the recipient cells to undergo phenotypic changes that profoundly impact diverse facets of cancer progression. For example, this unique form of cellular cross talk helps condition the premetastatic niche, facilitates evasion of the immune response, and promotes invasive and metastatic activity. These findings, coupled with those demonstrating that the number and content of EVs produced by tumors can vary depending on their tumor of origin, disease stage, or response to therapy, have raised the exciting possibility that EVs can be used for risk stratification, diagnostic, and even prognostic purposes. We summarize recent developments and the current knowledge of EV cargoes, their impact on disease progression, and implementation of EV-based liquid biopsies as tumor biomarkers.

Keywords: EV cargoes; carcinoma-associated fibroblasts; cell migration; exosomes; extracellular vesicles; liquid biopsies; microvesicles; tumor invasion; tumor-infiltrating cells.

Figure 1

EVs in the TME. The TME encompasses diverse cell types that include heterogeneous cancer cells, immune cells, stromal cells, and other tissue-specific cell types; the blood and lymphatic vascular networks; the ECM; and secreted factors such as EVs. It is increasingly understood that EVs, which include large oncosomes, TMVs, sEVs, and exosomes, facilitate both bidirectional communication in the TME and matrix degradation, inducing both local and systemic effects. Circulating EVs represent promising platforms for biomarker development, as highlighted in this review. Abbreviations: CAF, cancer-associated fibroblast; ECM, extracellular matrix; EV, extracellular vesicle; NK, natural killer; sEV, small EV; TME, tumor microenvironment; TMV, tumor-derived microvesicle. Figure adapted from images created with BioRender.com.

Figure 2

EVs have multiple documented roles within the TME. Due to the abundant bioactive cargo contained within EVs, they are capable of affecting multiple biological processes within the TME. Many of these effects, a selection of which are highlighted, can be mediated through both the direct action of EV cargo and/or the transfer of bioactive molecules to recipient cells. Abbreviations: CAF, cancer-associated fibroblast; dsDNA, double-stranded DNA; EV, extracellular vesicle; FN, fibronectin; MDSC, myeloid-derived suppressor cell; MMP, matrix metalloprotease; OXPHOS, oxidative phosphorylation; PDAC, pancreatic ductal adenocarcinoma; TAM, tumor-associated macrophage; TME, tumor microenvironment. Center image created with BioRender.com.