The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis

Abstract

Current research has demonstrated that extracellular vesicles (EVs) and circulating tumor cells (CTCs) are very closely related in the process of distant tumor metastasis. Primary tumors are shed and released into the bloodstream to form CTCs that are referred to as seeds to colonize and grow in soil-like distant target organs, while EVs of tumor and nontumor origin act as fertilizers in the process of tumor metastasis. There is no previous text that provides a comprehensive review of the role of EVs on CTCs during tumor metastasis. In this paper, we reviewed the mechanisms of EVs on CTCs during tumor metastasis, including the ability of EVs to enhance the shedding of CTCs, protect CTCs in circulation and determine the direction of CTC metastasis, thus affecting the distant metastasis of tumors.

Keywords: Biomarkers; Circulating tumor cells; Extracellular vesicles; Liquid biopsy; Pre-metastatic niche; Tumor metastasis.

Fig. 1

The composition of EVs and their role in tumor metastasis. The main substances of EVs are proteins, nucleic acids and lipids, which are the structural and functional basis of EVs. EVs play a role in key processes of tumor metastasis, such as promoting epithelial-mesenchymal transition (EMT), remodeling the extracellular matrix (ECM), promoting angiogenesis, activating platelets, immunosuppression, determining organotropism and promoting pre-metastatic niche (PMN) formation (Figure was created with BioRender.com).

Fig. 2

Role of EVs on CTCs during tumor metastasis. Tumor metastasis via the circulation involves several processes: invasion, intravasation, intravascular survival, extravasation, and secondary site colonization. At the beginning of metastasis, EVs enhance the shedding of CTCs by promoting epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling, as well as promoting angiogenesis and increasing vascular permeability; during metastasis, EVs protect CTCs by activating platelets and inducing immunosuppression; finally, EVs determine the metastatic direction of CTCs, participate in the formation of the pre-metastatic niche (PMN) and promote the metastasis and colonization of CTCs. The figure also summarizes the cargoes carried by EVs of different systemic tumor origins (Figure was created with BioRender.com).

Fig. 3

EVs determine CTC colonization in different distant metastatic sites. EVs of various tumor origins promote the metastasis of CTCs to bone, lung, liver and brain, and the mechanisms by which EVs promote lymph node metastasis are also illustrated in the figure (Figure was created with BioRender.com).