Exosomes and cancer - Diagnostic and prognostic biomarkers and therapeutic vehicle

Abstract

Exosomes belong to a subpopulation of extracellular vesicles secreted by the dynamic multistep endocytosis process and carry diverse functional molecular cargoes, including proteins, lipids, nucleic acids (DNA, messenger and noncoding RNA), and metabolites to promote intercellular communication. Proteins and noncoding RNA are among the most abundant contents in exosomes; they have biological functions and are selectively packaged into exosomes. Exosomes derived from tumor, stromal and immune cells contribute to the multiple stages of cancer progression as well as resistance to therapy. In this review, we will discuss the biogenesis of exosomes and their roles in cancer development. Since specific contents within exosomes originate from their cells of origin, this property allows exosomes to function as valuable biomarkers. We will also discuss the potential use of exosomes as diagnostic and prognostic biomarkers or predictors for different therapeutic strategies for multiple cancers. Furthermore, the applications of exosomes as direct therapeutic targets or engineered vehicles for drugs are an important field of exosome study. Better understanding of exosome biology may pave the way to promising exosome-based clinical applications.

Fig. 1. Overview of exosome biosynthesis and uptake pathways.

Intraluminal vesicles (ILVs) are synthesized from endosomes through cargo-sorting machineries and concurrent membrane invagination. The ILVs-containing multi-vesicle bodies (MVBs) then bypass lysosomal degradation and are transported to the plasma membrane, where they undergo vesicle docking, resulting in the release of exosomes into the extracellular space. Exosomes interact with the recipient cells by receptor-ligand interaction, membrane fusion, or phagocytosis or endocytosis. Being phagocytosed or endocytosed, exosomes bypass endosome-lysosome pathway and release their contents in the cytoplasm. Four exosomal protein sorting machineries (ESCRT-, tetraspanins-, Rabs-, and ceramide- dependent machineries) are depicted in the zoom-in view.

Fig. 2. The interplay among stromal cells, immune cells, and tumor cells in the TME.

Tumor cell-derived exosomes transfer malignant features to recipient cells, inducing the pro-tumoral roles of stromal cells and an immunosuppressive TME. Stromal cell-derived exosomes enhance the malignant properties of tumors cells in a feedback loop manner. Different types of immune cells play multifaceted roles through exosomes. TAM tumor-associated macrophage, Treg regulatory T cell, DC dendritic cell, NK natural killer cell, MDSC myeloid-derived suppressor cell, M2 M2 macrophage, TAN tumor-associated neutrophil, CAF cancer-associated fibroblast.