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Review
. 2019 Apr 2;18(1):75.
doi: 10.1186/s12943-019-0991-5.

Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance

Ladan Mashouri  1 , Hassan Yousefi  2 , Amir Reza Aref  3 , Ali Mohammad Ahadi  1 , Fatemeh Molaei  4 , Suresh K Alahari  5
Affiliations
Review

Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance

Ladan Mashouri et al. Mol Cancer. .

Abstract

Tumor-derived exosomes (TDEs) participate in formation and progression of different cancer processes, including tumor microenvironment (TME) remodeling, angiogenesis, invasion, metastasis and drug-resistance. Exosomes initiate or suppress various signaling pathways in the recipient cells via transmitting heterogeneous cargoes. In this review we discuss exosome biogenesis, exosome mediated metastasis and chemoresistance. Furthermore, tumor derived exosomes role in tumor microenvironment remodeling, and angiogenesis is reviewed. Also, exosome induction of epithelial mesenchymal transition (EMT) is highlighted. More importantly, we discuss extensively how exosomes regulate drug resistance in several cancers. Thus, understanding exosome biogenesis, their contents and the molecular mechanisms and signaling pathways that are responsible for metastasis and drug-resistance mediated by TDEs may help to devise novel therapeutic approaches for cancer progression particularly to overcome therapy-resistance and preventing metastasis as major factors of cancer mortality.

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Figures

Fig. 1
Fig. 1
Exosome biogenesis and secretion within endosomal system. Early endosomes (EEs) are formed by the fusion of endocytic vesicles. Two pathways shown by the EEs: returning to the plasma membrane or conversion into LEs/ MVBs via inward budding of the membrane which pack the cargoes into ILVs. Protein sorting of ILVs can be ESCRT dependent or independent. ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III are four components of ESCRT machinery which ubiquitinate the substrates on the part of the inward budding endosomal membrane. Later, targeted ILVs are ready to be degraded within lysosome or rescue by DUBs. Rab27A and Rab27B are the essential mediators to lead the MVBs toward the cell periphery. Finally, SNARE complex helps fusion of MVBs with plasma membrane to release ILVs into the extracellular space which now are called exosomes
Fig. 2
Fig. 2
Tumor-derived exosomes promotes angiogenesis. Tumor derived exosomes promotes vascular formation. VEGF, Platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), syndecan-4, Glypican-1, interleukin-8 (IL-8), Malat1, Dil4 and some microRNAs are some of the angiogenic stimulatory factors which can be carried by tumor exosomes
Fig. 3
Fig. 3
Tumor derived exosomes promote Epithelial Mesenchymal Transition (EMT) and Invasion. EMT initiators include TGF-β, HIF1α, β-catenin, IL-6, β-catenin or Vimentin, Casein Kinase and several miRNAs are among the essential EMT promoting factors that are carried by the tumor derived exosomes. Zeb family members are the main players in EMT transition
Fig. 4
Fig. 4
Exosome application in cancer therapy. Exosomes derived from DCs could be used to deliver Anti-cancer drugs such as chemotherapeutic agents and functional RNAs including siRNA and microRNA. Moreover, peptides also could be delivered to the target cancer cells especially CSCs. Such examples are TRAIL and mutated survivin. The specific markers of CSCs such as CD44, CD24, CD133, and CD200 can be used as targets for exosomes contain the antibodies against these proteins
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