Extracellular vesicles in the development of organ‐specific metastasis

Abstract

Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most cancer-related mortalities. This process is orchestrated by many complex biological interactions and processes that are mediated by a combination of anatomical, genetic, pathophysiological and biochemical factors. Recently, extracellular vesicles (EVs) are increasingly being demonstrated as critical mediators of bi-directional tumour-host cell interactions, controlling organ-specific infiltration, adaptation and colonization at the secondary site. EVs govern organotropic metastasis by modulating the pre-metastatic microenvironment through upregulation of pro-inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotypespecific differentiation and recruitment of specific stromal cell types. This review discusses EV-mediated metastatic organotropism in visceral (brain, lung, liver, and lymph node) and skeletal (bone) metastasis, and discusses how the pre-metastatic education by EVs transforms the organ into a hospitable, tumour cell-friendly milieu that supports the growth of metastatic cells. Decoding the organ-specific traits of EVs and their functions in organotropic metastasis is essential in accelerating the clinical application of EVs in cancer management. K E Y WO R D SCancer, extracellular vesicles, intercellular communication, metastasis, organotropism  INTRODUCTIONMetastasis to distant organs is a fundamental feature of malignant neoplasms and is its most lethal attribute that accounts for > 90% of mortality from cancer. The conceptual framework of tumour progression towards metastasis has been welldescribed and simplified into a stepwise sequence of cell-biological events, which are collectively termed the invasion-metastasis cascade (Valastyan & Weinberg, 2011). Cumulative evidence has shown that each type of cancer exhibits striking disparities in the temporal course (relapse within a range of organs) of metastasis, kinetics (time to relapse/recur) of metastatic progression and the severity of metastasis in vital target organs (Nguyen et al., 2009). While genetics can determine the metastatic traits of each cancer type, these traits can be acquired by disseminated tumour cells (DTCs; tumour cells with a metastatic propensity residing in the permissive target tissues of distant organs) through organ-selective evolution or adaptation of metastatic cell populations (Nguyen et al., 2009). A large body of evidence has underscored the significance of host tissue characteristics such as theThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The Functional Role of Extracellular Matrix Proteins in Cancer

“…EVs can be generally divided into exosomes, microvesicles, apoptotic bodies and recently identified matrix-bound nanovesicles (MBV) [ 198 , 199 , 200 ]. Exosomes have been shown to play a major role in different stages of cancer progression, including cell proliferation, angiogenesis, invasion and metastasis [ 201 , 202 , 203 ]. MBVs, vesicles integrated within the dense fibrillar network of the ECM [ 200 ], are differ from exosomes in membrane composition and luminal cargo [ 204 ].…”

Tumor metastasis: Mechanistic insights and therapeutic interventions

“…EVs secreted by tumors are the key mediators of cell‐to‐cell contact in the local and remote microenvironments. 184 EVs are exceptional cargo for various nucleic acid, proteins, and lipids in TME, and play a prominent role in the metastasis of the tumor to distant organs. 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 Tumor‐associated EVs in breast cancer can promote breast cancer colonization by changing the composition and structure of lung tissue fibroblasts.…”

“… 184 EVs are exceptional cargo for various nucleic acid, proteins, and lipids in TME, and play a prominent role in the metastasis of the tumor to distant organs. 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 Tumor‐associated EVs in breast cancer can promote breast cancer colonization by changing the composition and structure of lung tissue fibroblasts. 185 It was found that EVs secreted by bladder cancer cells mediate their intercellular communication with human lymphatic endothelial cells through long non‐coding RNA (lncRNA) ELNAT1 and promote lymph node metastasis in a SUMOylation‐dependent manner.…”

Extracellular Vesicles: The Landscape in the Progression, Diagnosis, and Treatment of Triple-Negative Breast Cancer

“…Especially, exosomes are originated via budding from the plasma membrane of cells and undergoing the formation of late endosome and late multivesicular bodies (MVBs). The MVBs traffic to and fuse with the plasma membrane and consequently release exosomes into the extracellular milieu ( Urabe et al, 2021 ). EVs interact with and are internalized by recipient cells via three mechanisms receptor-ligand interactions, direct fusion, and endocytosis ( Figure 1 ).…”