Exosomes in cancer: small particle, big player

Abstract

Exosomes have emerged as a novel mode of intercellular communication. Exosomes can shuttle bioactive molecules including proteins, DNA, mRNA, as well as non-coding RNAs from one cell to another, leading to the exchange of genetic information and reprogramming of the recipient cells. Increasing evidence suggests that tumor cells release excessive amount of exosomes, which may influence tumor initiation, growth, progression, metastasis, and drug resistance. In addition, exosomes transfer message from tumor cells to immune cells and stromal cells, contributing to the escape from immune surveillance and the formation of tumor niche. In this review, we highlight the recent advances in the biology of exosomes as cancer communicasomes. We review the multifaceted roles of exosomes, the small secreted particles, in communicating with other cells within tumor microenvironment. Given that exosomes are cell type specific, stable, and accessible from body fluids, exosomes may provide promising biomarkers for cancer diagnosis and represent new targets for cancer therapy.

Fig. 1

Biogenesis, release, structure, and uptake of exosomes. Exosomes are produced from the multivesicular bodies (MVBs) (also known as late endosomes). The membrane of the MVBs bulges inward to form exosomes. During this process, proteins (e.g., receptor, cytoplasmic proteins, tetraspanin), nucleic acids (e.g., DNA, mRNA, miRNA), and lipids (e.g., cholesterol, ceramide) are packed into exosomes in a cell type-dependent manner. MVBs fuse with the cellular membrane to release exosomes into the extracellular space. Several mechanisms have been suggested to mediate the uptake of exosomes, including a exosome fusion with the cellular membrane of the recipient cell, leading to the release of the exosomal cargo into the cytoplasm, b juxtracrine signaling through receptor-ligand interactions, c and endocytosis by phagocytosis

Fig. 2

Roles of exosomes in cancer. Exosomes are critically involved in tumor initiation, growth, progression, metastasis, and drug resistance by transferring oncogenic proteins and nucleic acids. Tumor-derived exosomes can activate endothelial cells to support tumor angiogenesis and thrombosis. Tumor-derived exosomes can convert fibroblasts and MSCs into myofibroblasts to facilitate tumor angiogenesis and metastasis. Tumor-derived exosomes contribute to create an immunosuppressive microenvironment by inducing apoptosis and impairing the function of effector T cells and NK cells, inhibiting DC differentiation, expanding MDSCs, as well as promoting Treg cell activity. Tumor-derived exosomes can mobilize neutrophils and skew M2 polarization of macrophages to promote tumor progression. Moreover, tumor-derived exosomes can help tumor cells develop drug resistance by transferring multidrug-resistant proteins and miRNAs, exporting tumoricidal drugs, and neutralizing antibody-based drugs. In turn, exosomes from activated T cells, macrophages, and stromal cells can promote tumor metastasis and drug resistance