Exosomes in cancer development and clinical applications

Abstract

Exosomes participate in cancer progression and metastasis by transferring bioactive molecules between cancer and various cells in the local and distant microenvironments. Such intercellular cross-talk results in changes in multiple cellular and biological functions in recipient cells. Several hallmarks of cancer have reportedly been impacted by this exosome-mediated cell-to-cell communication, including modulating immune responses, reprogramming stromal cells, remodeling the architecture of the extracellular matrix, or even endowing cancer cells with characteristics of drug resistance. Selectively, loading specific oncogenic molecules into exosomes highlights exosomes as potential diagnostic biomarkers as well as therapeutic targets. In addition, exosome-based drug delivery strategies in preclinical and clinical trials have been shown to dramatically decrease cancer development. In the present review, we summarize the significant aspects of exosomes in cancer development that can provide novel strategies for potential clinical applications.

Keywords: biomarker; cancer malignancy; cancer therapy; drug resistance; exosome.

Figure 1

Biogenesis of exosomes. First, endocytosis could be mediated by either a clathrin‐dependent pathway or a clathrin‐independent pathway, which often actively occurs at the lipid raft containing a variety of tumor‐specific receptors and signaling proteins (eg, growth factor receptors, oncoproteins) in addition to common membrane proteins, such as tetraspanins (eg, CD9, CD63, CD81), MHC I and II, and adhesion molecules (eg, integrins, cadherins). Using the endosomal network, the biogenesis of exosomes is achieved in an endosomal sorting complexes required for transport (ESCRT)‐dependent or ESCRT‐independent method. Accordingly, intraluminal vesicles (exosomes) show inward budding of the multivesicular bodies (MVB). Indeed, numerous cytoplasmic (eg, ubiquitin‐related proteins, heat shock proteins, microRNAs [miRNAs], mRNAs, cytoskeleton proteins etc.) and nuclear molecules (eg, transcriptional factors, longnoncoding RNAs [lncRNAs], DNAs etc.) can be selectively loaded into MVB in a cancer type‐specific and/or stage‐specific way. Furthermore, multivesicular bodies are fused with the plasma membrane, leading to the release of exosomes toward the extracellular space in an exocytic way. Several Rab GTPases, including Rab11/35, Rab7, and Rab27, have been reported to be involved in exosome secretion. Finally, tumor‐derived exosomes are transferred to the local tumor microenvironment and distinct organs to regulate tumorigenesis or metastasis, respectively. rER, rough endoplasmic reticulum; sER, smooth endoplasmic reticulum

Figure 2

Summary of tumor‐derived exosome‐mediated functions. Tumor‐derived exosomes regulate the autocrine/paracrine induction of cancers, activation of angiogenesis, modulation of the immune system, re‐education of stromal cells, organotropic metastasis, and remodeling the extracellular matrix, contributing to cancer progression and metastasis. For example, tumor‐derived exosomes transfer epidermal growth factor receptor (eEGFR) vIII oncogenic receptor or ZFAS1 lncRNA from aggressive cancers to nonaggressive cancers, inducing cancer progression. Also, tumor‐derived exosomes that show tetraspanins or microRNA (miRNA) clusters induce endothelial migration and tube formation. Furthermore, tumor‐derived exosomes containing miRNAs, such as miR‐222‐3p, induce polarization of M2 macrophages. Additionally, tumor‐derived exosomes deliver miRNA, such as miR‐9, miR‐105, and miR‐181c, from cancers to normal fibroblasts or vascular endothelial barriers, subsequently enhancing cancer malignancy. Moreover, integrins direct tumor‐derived exosomes to specific distinct target organs, leading to metastatic organotropism. By delivery of extracellular matrix remodeling enzymes, tumor‐derived exosomes contribute to cancer metastasis