Extracellular Vesicles Linking Inflammation, Cancer and Thrombotic Risks

Abstract

Extracellular vesicles (EVs) being defined as lipid-bilayer encircled particles are released by almost all known mammalian cell types and represent a heterogenous set of cell fragments that are found in the blood circulation and all other known body fluids. The current nomenclature distinguishes mainly three forms: microvesicles, which are formed by budding from the plasma membrane; exosomes, which are released, when endosomes with intraluminal vesicles fuse with the plasma membrane; and apoptotic bodies representing fragments of apoptotic cells. Their importance for a great variety of biological processes became increasingly evident in the last decade when it was discovered that they contribute to intercellular communication by transferring nucleotides and proteins to recipient cells. In this review, we delineate several aspects of their isolation, purification, and analysis; and discuss some pitfalls that have to be considered therein. Further on, we describe various cellular sources of EVs and explain with different examples, how they link cancer and inflammatory conditions with thrombotic processes. In particular, we elaborate on the roles of EVs in cancer-associated thrombosis and COVID-19, representing two important paradigms, where local pathological processes have systemic effects in the whole organism at least in part via EVs. Finally, we also discuss possible developments of the field in the future and how EVs might be used as biomarkers for diagnosis, and as vehicles for therapeutics.

Extracellular Vesicles: A Novel Tool in Nanomedicine and Cancer Treatment

“…Cancer-cell-derived EVs carry distinct pro-tumorigenic content that regulates several aspects of cancer promotion and progression. For example, cancer-cell-derived EVs carry pro-tumorigenic proteins such as growth factors (mutant EGFR) and oncogenes (e.g., KRAS) [ 42 ]. They also carry RNAs in order to target the recipient cell’s transcription machinery and promoter tumorigenesis [ 42 , 43 ].…”

“…For example, cancer-cell-derived EVs carry pro-tumorigenic proteins such as growth factors (mutant EGFR) and oncogenes (e.g., KRAS) [ 42 ]. They also carry RNAs in order to target the recipient cell’s transcription machinery and promoter tumorigenesis [ 42 , 43 ]. Cancer-cell-derived EVs suppress immunity and immune surveillance against tumors by, for example, delivering TGFβ to recipient cytotoxic T cells, affecting their function [ 42 ].…”

“…They also carry RNAs in order to target the recipient cell’s transcription machinery and promoter tumorigenesis [ 42 , 43 ]. Cancer-cell-derived EVs suppress immunity and immune surveillance against tumors by, for example, delivering TGFβ to recipient cytotoxic T cells, affecting their function [ 42 ]. Furthermore, they can also deliver FasL to activated T cells and induce their apoptosis, thus inhibiting their activation.…”

“…Furthermore, they can also deliver FasL to activated T cells and induce their apoptosis, thus inhibiting their activation. Cancer-cell-derived EVs can also carry PD-L1 to other cancer cells that are PD-L1-deficient, thus inhibiting cancer immunity mediated by T cells and promoting immune invasion by the tumor cells [ 42 ]. One good example of this has been shown in relation to breast cancer in the research of Yang et al, 2018 [ 44 ].…”

Therapeutic Strategy of Mesenchymal-Stem-Cell-Derived Extracellular Vesicles as Regenerative Medicine

“…Extracellular vesicles (EVs), which are nano- to micro-sized lipid bilayer membrane particles secreted by host cells, play critical roles in novel intercellular communication mechanisms, mediating the transduction of functional molecules with physiological activity, such as microRNAs, mRNAs, proteins, and lipids ( Figure 1 ) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ,…”