Extracellular Vesicles and Metastasis

Abstract

Secretion of cell contents through extracellular vesicles (EVs), such as exosomes and microvesicles, is a fundamental cell behavior. Compared with their normal counterparts, cancer cells are different in the amount and composition of EVs they secrete as a result of intrinsic and extrinsic (microenvironmental) alterations. Although EVs were originally recognized as a means to remove undesired cell components, recent studies show their critical role in mediating intercellular interaction through cargo transport. In cancer, EVs can be transferred between different cancer cell subpopulations and between cancer and normal cells localized inside and outside of the tumor. By regulating various aspects of cellular functions, EVs contribute to tumor heterogeneity and plasticity, vascular remodeling, cancer-niche coevolution, immunomodulation, and establishment of premetastatic niche, all of which are important to the process of metastasis. Recent discoveries on EV-mediated mechanisms lead to a new understanding of the multifaceted changes in tumor and nontumor tissues before and after cancer metastasis, paving the way for new therapeutic strategies.

Figure 1.

Biogenesis and receipt of extracellular vesicles (EVs). Exosomes are generated from an early endosome, which undergoes subsequent membrane inward invagination and captures a variety of cytosolic components including DNA, RNA, and proteins to form exosomes within the lumen. The resultant multivesicular bodies (MVBs) may fuse with the plasma membrane to release the exosomes, or turn into a lysosome for content degradation. In contrast, microvesicles are generated through outward budding of the plasma membrane. On receipt by a target cell, the possible fates of EVs include binding to cell surface to trigger intracellular signaling, fusing to the plasma membrane to release EV contents, and internalization through endocytosis, phagocytosis, or macropinocytosis, to eventually release EV contents into the cytoplasm.

Figure 2.

The one-to-many and many-to-one intercellular communication mediated by extracellular vesicles (EVs). A secreting cell can generate different subpopulations of EVs with different contents, which target their corresponding groups of target cells through recognition of the EVs by the recipient cell surface (the one-to-many communication). On the other hand, EVs secreted by different types of cells and carrying different contents can target the same recipient cell through receptor-dependent or -independent interaction (the many-to-one communication). In all cases, the bulk delivery mode of EVs allows simultaneous transfer of groups of signaling molecules for precise communication.

Figure 3.

Effect of metabolic stresses on extracellular vesicle (EV)-mediated communication in a solid tumor. As a tumor grows in size, metabolic stresses, such as hypoxia and acidity, are frequently experienced in some tumor areas, and can influence EV secretion, composition, and uptake in the tumor microenvironment to promote angiogenesis and metastasis. The spatiotemporal metabolic patterns in a tumor thus contribute to EV heterogeneity.

Figure 4.

Cancer-derived extracellular vesicles (EVs) in the primary tumor microenvironment mediate tumor evolution and progression. Exchange of EVs within the tumor facilitates phenotypic transfer between different subpopulations of cancer cells to spread metastatic traits during tumor evolution. EVs carrying extracellular matrix (ECM) proteins can serve as the “stepping stones” for directional cell movement to promote cancer cell invasion. EVs secreted by cancer cells also influence other cell types including endothelial cells, immune cells, and fibroblasts, leading to coevolution of the tumor microenvironment and tumor progression. The various types of cells in the tumor microenvironment also secrete EVs to influence cancer cell behaviors.

Figure 5.

Disseminated tumor-derived extracellular vesicles (EVs) promote formation of a premetastatic niche and distant metastasis. EVs can inherit the organotropism of their producing cancer cells and specifically target a distant organ to initiate premetastatic niche formation. Tumor-derived EVs recruit bone marrow-derived cells (BMDCs) to a premetastatic niche and influence other niche cells to create a permissive environment for cancer metastasis.