Abstract
The sustained growth, invasion, and metastasis of cancer cells depend upon bidirectional cell-cell communication within complex tissue environments. Such communication predominantly involves the secretion of soluble factors by cancer cells and/or stromal cells within the tumour microenvironment (TME), although these cell types have also been shown to export membrane-encapsulated particles containing regulatory molecules that contribute to cell-cell communication. These particles are known as extracellular vesicles (EVs) and include species of exosomes and shed microvesicles. EVs carry molecules such as oncoproteins and oncopeptides, RNA species (for example, microRNAs, mRNAs, and long non-coding RNAs), lipids, and DNA fragments from donor to recipient cells, initiating profound phenotypic changes in the TME. Emerging evidence suggests that EVs have crucial roles in cancer development, including pre-metastatic niche formation and metastasis. Cancer cells are now recognized to secrete more EVs than their nonmalignant counterparts, and these particles can be isolated from bodily fluids. Thus, EVs have strong potential as blood-based or urine-based biomarkers for the diagnosis, prognostication, and surveillance of cancer. In this Review, we discuss the biophysical properties and physiological functions of EVs, particularly their pro-metastatic effects, and highlight the utility of EVs for the development of cancer diagnostics and therapeutics.
Highlights
Abstract | The sustained growth, invasion, and metastasis of cancer cells depend upon bidirectional cell–cell communication within complex tissue environments
ADAM, disintegrin and metalloproteinase domain-containing protein; BMDC, bone marrow-derived cells; BM-MSC, bone marrow mesenchymal stem cell; cancer-associated fibroblasts (CAFs), cancer-associated fibroblast; DDX58, probably ATP-dependent RNA helicase DDX58; DLL4, Delta-like protein 4; EGFRvIII, EGFR variant III; EGLN, EGL nine homologue; FN, fibronectin; GLuc, Gaussia luciferase; HIF1α, hypoxia-inducible factor 1α; HMVEC, microvascular endothelial cell; HUVEC, umbilical vein endothelial cell; long non-coding RNAs (lncRNAs)-ARSR, long non-coding RNA activated in RCC with sunitinib resistance; MIF, macrophage migration inhibitory factor ; Multiple reaction monitoring (MRM), multiple reaction monitoring; PCP, planar cell polarity ; PDAC, pancreatic ductal adenocarcinoma; PEDF, pigment epithelium-derived factor ; PTEN, phosphatase and tensin homologue; RCC, renal cell carcinoma; RGD, Arg–Gly–Asp; RN7SL1, RNA, 7SL, cytoplasmic 1; shRNA, short hairpin RNA ; siRNA, small interfering RNA ; SMAD, mothers against decapentaplegic; TG, transglutaminase
MIF was found to be present at markedly higher levels in circulating exosomes derived from patients with stage I PDAC who later developed liver metastasis than in those derived from patients with pancreatic tumours that did not progress[120]. These findings suggest that exosomal MIF primes the liver for metastasis and is a prognostic marker for the development of liver metastasis in PDAC. c | Exosomes containing the microRNA miR-122 released from human breast cancer cells (MDA-MB-231 or MCFDCIS cell lines) home to the lungs and brain, where they are transferred to fibroblasts and astrocytes, respectively[122]
Summary
Exosomes and shed microvesicles are two classes of small lipid-encapsulated extracellular vesicles (EVs) that transmit molecular messengers (functional proteins and nucleic acids) between cells to alter the phenotype of recipient cells. Pre-metastatic niche A microenvironment induced by factors released from the primary tumour in a distant organ that supports metastatic cell seeding, survival, and outgrowth In addition to their function in normal physiology, EVs participate in pathological processes such as the progression of neurodegenerative diseases[23] and cancer[24,25,26]. EVs have been implicated in many facets of cancer development and progression[29,30] and are, ideal candidates as biomarkers and/or therapeutic tools for anticancer treatment In this Review, we discuss the biophysical properties and biogenesis of the two major EV classes, exosomes and sMVs; describe their cargos, including oncoproteins and oncopeptides, RNA species (for example, microRNAs (miRNAs), mRNAs, and long non-coding RNAs (lncRNAs)), lipids, and DNA fragments; describe their role in the tumour microenvironment (TME) and pre-metastatic niche; and highlight the utility of EVs for the development of cancer diagnostics and therapeutics. C5; DR4, death receptor 4 ( known as TNFRSF10A); DR5, death receptor 5 ( known as TNFRSF10B); EPCAM, epithelial cell adhesion molecule; FAS, apoptosis-mediating surface antigen FAS; FASL , FAS antigen ligand ( known as FASLG); MHC, major histocompatibility complex; PD-L 1, programmed cell death 1 ligand 1; PSGL1, P-selectin glycoprotein ligand 1; SDCBP, syntenin 1; sFASL , soluble FASL; sTRAIL , soluble TRAIL; TCR , T cell receptor ; TNFR , TNF receptor ; TRAIL , TNF-related apoptosis-inducing ligand; TSG101, tumour susceptibility gene 101 protein; TSPAN8, tetraspanin 8; VPS4, vacuolar protein sorting-associated protein 4
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