Emerging diversity in extracellular vesicles and their roles in cancer

Abstract

Extracellular vesicles have undergone a paradigm shift from being considered as 'waste bags' to being central mediators of cell-to-cell signaling in homeostasis and several pathologies including cancer. Their ubiquitous nature, ability to cross biological barriers, and dynamic regulation during changes in pathophysiological state of an individual not only makes them excellent biomarkers but also critical mediators of cancer progression. This review highlights the heterogeneity in extracellular vesicles by discussing emerging subtypes, such as migrasomes, mitovesicles, and exophers, as well as evolving components of extracellular vesicles such as the surface protein corona. The review provides a comprehensive overview of our current understanding of the role of extracellular vesicles during different stages of cancer including cancer initiation, metabolic reprogramming, extracellular matrix remodeling, angiogenesis, immune modulation, therapy resistance, and metastasis, and highlights gaps in our current knowledge of extracellular vesicle biology in cancer. We further provide a perspective on extracellular vesicle-based cancer therapeutics and challenges associated with bringing them to the clinic.

Keywords: cancer; exophers; exosomes; extracellular vescicles; metastasis; migrasomes.

Figure 1

Extracellular vesicle heterogeneity and emerging subtypes. Extracellular vesicles subtypes include exosomes, microvesicles, migrasomes, mitovesicles, apoptotic vesicles, and exophers. There are other types not illustrated in the figure, which includes ‘oncosomes’ – microvesicles that contain oncogenic cargo, ‘megavesicles’ – an atypically large vesicle, synaptic vesicles and other vesicles secreted by specialized cells. Exosomes are the only EVs that form via intraluminal budding of late endosomes. The late endosomes can also fuse with a phagosome to form ‘amphisome’, which can then release soluble protein or damaged DNA cargo – a process described as ‘secreted autophagy’. Microvesicles form by plasma membrane budding and can vary in their size. Mitovesicles are EVs that can be double-layered and contain mitochondrial fragments including mitochondrial protein and lipid composition. Migrasomes form along the trailing fibers of a migrating cell and can have multi-layered vesicles or several vesicles within one. Exophers are a type of megavesicles involved in cellular protein and mitochondrial homeostasis. Apoptotic vesicles are formed during the membrane blebbing or apoptopodia formation steps of apoptosis. The size of the apoptotic vesicles depends on how they form – larger if formed via membrane blebs and smaller if formed via apoptopodia. EVs have also been described to have a protein corona on their surface that mediates angiogenesis, which is discussed in the main text. The emerging EV subtypes – mitovesicles, migrasomes, oncosomes, megavesicles and exophers, are discussed in greater detail in the main text.

Figure 2

Extracellular vesicles’ role in cancer. An overview of the EV mode of action at different stages of cancer – (i) carcinogenesis, (ii) metabolic reprogramming, (iii) extracellular matrix remodeling, (iv) angiogenesis, (v) immune evasion, and (vi) metastasis. During carcinogenesis, it is not known if EVs provide proliferative advantage to cancer initiating cell over neighboring mutant/non-mutant normal epithelium. Possible mechanisms by which EVs can confer proliferation advantage to precancerous cells are illustrated. Regarding metabolic reprogramming, cancer EVs have been shown to reprogram normal fibroblasts and monocytes/macrophages to tumor-supporting phenotypes. Whether EVs from cancer initiating cell or other neighboring cell types facilitate reprogramming of cancer cells remains to be seen. Extracellular matrix remodeling and angiogenesis can be mediated by both cancer cell EVs and cancer-associated fibroblast EVs. The EV cargo involved is highlighted in the figure and detailed in Table 2. In immune evasion, cancer EVs suppress the maturation of dendritic cells, promote macrophage differentiation to M2 state, and directly inhibit T cell function. T cell function is also suppressed by immature dendritic cell- and M2 macrophage-derived EVs. During cancer metastasis, integrin expression on the surface of cancer EVs determines homing to specific organs. Cancer EV cargo can also reprogram tissue-resident cell types such as lung-resident fibroblasts and brain-resident endothelial and microglial cells. Furthermore, cancer EVs can suppress differentiation of bone marrow progenitor cells leading to systemic of site-specific immune suppression.