Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy

Abstract

Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.

Keywords: anticancer therapy; drug resistance; exosomal cargoes; protumorigenic effect; tumor-derived exosomes.

Figure 1

Structure of exosome with membrane proteins and cargoes. Exosomes consist of many constituents of a cell including DNA, RNAs, amino acids, proteins, metabolites, enzymes, lipids (cholesterol) and Hsps along with several cytosolic and cell-surface signaling proteins which are involved in intercellular communications. Exosomal membrane is rich in transmembrane proteins (tetraspanins such as CD81, CD63 and CD9), flotillin, ICAMs, integrins and adhesion molecules. They consist of immune components including MHC class I and class II molecules. Abbreviations: CD, cluster of differentiation; DNA, deoxyribonucleic acids; Hsps, heat shock proteins; ICAMs, intercellular adhesion molecules; MHC, major histocompatibility complex; mRNA, messenger RNA; miRNA, microRNA.

Figure 2

Mechanisms of internalization of exosomes. The exosomes inside the MVBs are extruded out from the donor cells by exocytosis on merging with plasma membrane. The released exosomes are then internalized via different modes: soluble/juxtacrine signaling; phagocytosis; fusion; micropinocytosis and lipid raft mediated endocytosis. The lipid raft mediated endocytosis can be either clathrin or caveolin protein dependent. Exosomes internalized by soluble/juxtacrine signaling affect the signaling cascade of the recipient cell. During phagocytosis, the exosomes undergo degradation, whereas, in the fusion event, genetic material is released that causes cellular response. In macropinocytosis and lipid raft-mediated endocytosis, the exosomes either undergo lysosomal degradation or mediate cellular response. Abbreviations: mRNA, messenger RNA; miRNA, microRNA; MVBs, multivesicular bodies.

Figure 3

Exosomes in tumor microenvironment. Exosomes secreted from tumor cells containing MVBs exhibited a dynamic signaling between tumor cells and the TME. Exosomes may lead to immune suppression by downregulating macrophages, DC, T cells and NK cells and upregulating immunosuppressive cells like Tregs, MDSCs and TAMs. Exosomes induced differentiation of fibroblasts, activation of CAFs and degradation of ECM, which are associated with TME construction. They are involved in the alteration of ECM, hypoxia-mediated angiogenesis and the formation of pre-metastatic niches that trigger the metastatic escape of tumor cells. Abbreviations: CAFs, cancer-associated fibroblasts; ECM, extracellular matrix; DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells; NK cells, natural killer cells; TAMs, tumor-associated macrophages; TME, tumor microenvironment; Tregs, tumor regulatory cells.

Figure 4

Exosomes in therapeutic approaches. Exosomes derived from DCs, APCs and stem cells can be utilized for immunotherapy, gene therapy, stem cell therapy and adjuvant therapy. Exosome based gene therapy is obtained by genetically engineered exosomes loaded with miRNA, siRNA and plasmids of interest. Stem cell or DC-derived exosomes can be implemented alone as vaccines and confer stem cell-based therapy or immunotherapy. The exosomes can also be utilized for drug delivery vectors by modifying them with drugs of interest. The DC-, APC- and stem cell-derived exosomes administered into the patient help in triggering immune response in combating cancer by targeting and regulating the mechanisms against which the exosomes are implemented. Abbreviations: APCs, antigen presenting cells; DCs, dendritic cells; miRNA, microRNA; siRNA, small interfering RNA.