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Review
. 2019 Apr;1871(2):455-468.
doi: 10.1016/j.bbcan.2019.04.004. Epub 2019 Apr 30.

Exosomes in cancer development, metastasis, and immunity

Lin Zhang  1 , Dihua Yu  2
Affiliations
Review

Exosomes in cancer development, metastasis, and immunity

Lin Zhang et al. Biochim Biophys Acta Rev Cancer. 2019 Apr.

Abstract

Exosomes play essential roles in intercellular communications. The exosome was discovered in 1983, when it was found that reticulocytes release 50-nm small vesicles carrying transferrin receptors into the extracellular space. Since then, our understanding of the mechanism and function of the exosome has expanded exponentially that has transformed our perspective of inter-cellular exchanges and the molecular mechanisms that underlie disease progression. Cancer cells generally produce more exosomes than normal cells, and exosomes derived from cancer cells have a strong capacity to modify both local and distant microenvironments. In this review, we summarize the functions of exosomes in cancer development, metastasis, and anti-tumor or pro-tumor immunity, plus their application in cancer treatment and diagnosis/prognosis. Although the exosome field has rapidly advanced, we still do not fully understand the regulation and function of exosomes in detail and still face many challenges in their clinical application. Continued discoveries in this field will bring novel insights on intercellular communications involved in various biological functions and disease progression, thus empowering us to effectively tackle accompanying clinical challenges.

Keywords: Cancer; Exosome; Extracellular vesicles; Immunity; Intercellular communication; Metastasis.

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Figures

Figure 1.
Figure 1.. Exosomes and other extracellular vesicles: biogenesis and secretion in eukaryotic cells.
First, exosomes fuse into early endosomes and multivesicular bodies (MVBs). Late MVBs fuse with plasma membrane to release exosomes or with lysosomes for degradation. Exosomes can be further categorized as large exosomes and small exosomes. CD63, ALIX, TSG101, and HSC10 are enriched in exosomes; many mRNAs, microRNAs (miRNAs), proteins, and receptors are also carried by exosomes. Microvesicles bud directly from the plasma membrane, not from MVBs. CD42, integrins, and selectin are enriched in microvesicles; microvesicles also carry multiple receptors, proteins, miRNAs, and mRNAs. Apoptotic vesicles are derived from apoptotic cells. They contain DNAs and histone besides proteins, receptors, mRNAs, and miRNAs.
Figure 2.
Figure 2.. Functions of cancer cell-derived exosome in tumor progression and metastasis.
Tumor-derived exosomes (1) inhibit apoptosis of tumor cells through secretion of TGFβ1 or other ligands and (2) pump cytoplasmic DNA out for cellular homeostasis. (3) Exosomes expel cytotoxic drugs, resulting in tumor cell drug resistance. (4) Tumor-derived exosomes transfer their cargos (such as EGFRVIII, KRAS, SRC, TGFβ1, EMT drivers, PDL1, GSTP1, lncRNAs, or miRNAs) to other tumor cells to induce EMT, migration and invasion, or drug resistance in recipient cells, thereby promoting tumor progression and metastasis. Tumor exosomes can (5) reprogram the ECM through proteinase, MMP2, or tetraspanins, or (6) induce fibroblast differentiation to myofibroblasts through TGFβ1, which further induces ECM degradation; they also can (7) enhance endothelial cell proliferation and angiogenesis by transferring soluble E-cadherin (SE-Cad), DLL4, tetraspanins, or miRNAs, and (8) open tight junctions in endothelial cells by miRNAs, resulting in tumor progression and metastasis. (9) Tumor exosomes carry specific integrins, macrophage-inhibitory factor, mRNAs, or miRNAs, which allow them to establish pre-metastatic niches in lymph nodes, bone, liver, lung, and brain.
Figure 3.
Figure 3.. Examples of stromal cell-derived exosomes in tumor progression and metastasis.
1a) Activated fibroblasts secrete exosomes that are taken up by cancer cells and that transfer unshielded RNAs, protein ADAM10, metabolic cargos and other molecules, to induce inflammation, tumor growth, drug resistance, cancer cell motility and/or cancer stem cell phenotypic traits. 1b) Fibroblast-secreted CD81-positive exosomes are loaded with WNT11 by cancer cells, and these exosomes promote cancer cell motility and metastasis through an autocrine mechanism. 2) Macrophage-derived exosomes promote pancreatic cancer cell resistance to gemcitabine through miR-365. 3) Astrocytes promote the outgrowth of brain metastasis through exosomal miR-19a. 4) Bone marrow mesenchymal stem cells induce bone metastasis dormancy through exosomal miR-23b.
Figure 4.
Figure 4.. Exosomes’ functions in tumor immunity.
A. Anti-tumor immune response: Tumor exosomes present neo-antigens (such as HSP70, MART1) with MHC-I complex to dendritic cells (DCs) or directly to activate T cells. Tumor exosomes increase CD80, CD86, and MHC-II expression in DCs, which further activates CD4+ T cells. Exosomal DNAs trigger activation of DCs and CD8+ T cells. Tumor exosomes induce the activation of natural killer (NK) cells and macrophages by transferring HSP70. DCs release exosomes containing the antigens and MHC-I complex to activate cytotoxic T cells to inhibit tumor growth. B. Pro-tumor immune response: tumor exosomes also repress the function of DCs, T cells, and NK cells, enhancing the populations of myeloid derived suppressive cells (MDSCs) and regulatory T cells (Treg) and skewing macrophage function toward the M2 phenotype through various signaling pathways. Tumor exosomes carry PD-L1 from tumor cells and transfer it to DCs or macrophages, and then block T cell function.
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