Exosomes: From Garbage Bins to Promising Therapeutic Targets

Abstract

Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents.

Keywords: biomarkers; exosome-based therapeutics; intercellular communication; non-coding RNAs; tumor-derived exosomes.

Figure 1

Exosome biogenesis, cargo sorting, and release. Illustration of loading into exosomes of cargo such as nucleic acid and proteins. Endocytosis of the plasma membrane (A) results in the uptake of proteins, nucleic acids, and membrane-associated molecules, and formation of the early endosome (EE) (B); Upon transformation of the early endosome into the late endosome (LE) (C), exosomes are formed by inward budding of the late endosome/multivesicular body (MVB) with the content in a similar orientation as in the plasma membrane (D); Fusion of the MVB with the plasma membrane allows for the release of exosomes into the extracellular space (E); Alternatively, the MVB may fuse with the lysosome for degradation (F). ER: Endoplasmic reticulum.

Figure 2

Molecular composition of exosomes. Exosomes are membrane-derived nanovesicles (30–100 nm in diameter) secreted from several cell types. They pack a variety of cellular components, including nucleic acids (e.g., DNA, mRNA, and miRNA), lipids (e.g., cholesterol and ceramide), mRNAs, membrane trafficking proteins (e.g., annexin, Rab 27, SNAP25), chaperones (e.g., Hsp70 and Hsp90), and various tissue-specific proteins involved in antigen presentation as integrins and tetraspanins (CD9, CD63, CD81, and CD82) as well as MHC-I and -II (Major Histocompatibility Complex).

Figure 3

Biological functions of exosomes in tumorigenesis. Exosomes released from tumor cells affect the local tumor microenvironment and are critically involved in tumor initiation, growth, progression, and metastasis by transferring oncogenic proteins and nucleic acids. (A) Exosomes travel to distant sites to promote generation of the pre-metastatic niche; (B) Angiogenesis is increased and endothelial and stromal cell differentiation is induced, leading to a pro-tumor environment; (C) Exosomes have immunosuppressive effects and assist cancers in immune evasion. Cytotoxic T cells are induced to apoptosis, while natural killer cell proliferation is impaired, and T-helper cells differentiate toward a T-regulatory cell phenotype; (D) Bone marrow-derived cells are recruited to tumor and pre-tumor tissue where they contribute to cancer development; (E) Exosomes are also responsible for the recruitment and activation of tumor-associated macrophages (TAMs) by promoting their polarization. TAMs support diverse phenotypes within the primary tumor, including growth, angiogenesis, and invasion, by secreting a plethora of pro-tumorigenic proteases, cytokines, and growth factors; (F) Exosomes can functionally modify fibroblasts by reprogramming these cells to cancer-associated fibroblasts (CAFs), which exhibit myofibroblastic differentiation. Red arrows indicates a negative contribution or repression and green arrows indicate an activation or positive function.

Figure 4

Exosome-based Diagnostics and Therapeutics. Exosomes hold a potential to be used as therapeutic or diagnostics tools. (A) Therapeutics: Exogenous or autologous exosomes can be isolated to deliver a desired payload in combination with chemotherapeutics, adjuvants of chemotherapy or as immunotherapy; (B) Diagnostics: Biomarkers can be determined to evaluate the expression of proteins, inflammation markers or nc-RNA present in exosomes from biological fluids.