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 phenotype-specific 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.

Keywords: Cancer; extracellular vesicles; intercellular communication; metastasis; organotropism.

FIGURE 1

Decoding the role of extracellular vesicles in visceral metastasis. Several EV‐mediated pathways have been identified to drive metastasis in the brain (a), lungs (b), liver (c), and lymph node (d). The pre‐conditioning of secondary metastatic sites is a prerequisite for successful adaptation and colonization of engrafted tumour cells. EVs released by tumour cells have been proposed to travel to distant sites and help re‐organisation of the secondary site for successful tumour colonization via a number of pathways, including upregulation of pro‐inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotype‐specific differentiation, increased angiogenesis, vascular remodelling, modulation of matrix biology, deregulation of cellular bioenergetics and recruitment of specific stromal cell types

FIGURE 2

Schematic representation of the role of extracellular vesicles and tumour‐secreted factors in establishing pre‐metastatic niche and osteolytic/osteoblastic metastatic outgrowth in the bone. Primary tumour‐derived molecular components including tumour‐derived secreted factors and EVs play important roles in the modulation of the bone microenvironment, thus promoting metastasis. Prior to the arrival of tumour cells in the bone, EVs can facilitate the establishment of a pre‐metastatic niche in the bone via mechanisms such as the transfer of MET to BMDCs. (a) On establishing a foothold in the bone marrow niche, the osteolytic cancer cells (e.g. from breast cancer) secrete growth factors and cytokines that act on osteoclasts and osteoblasts in the bone microenvironment, such as PTHrP, VEGF, IL‐1, IL‐6, PGE2, TNF‐α, ET‐1 and BMPs. These factors increase the production of M‐CSF and RANKL, an osteoclast differentiating factor, while decreasing OPG (an osteoclastogenesis inhibitory factor) secretion from osteoblasts. The up‐regulated RANKL binds to its receptor RANK on the pre‐osteoclast surface and promotes the maturation of osteoclast precursors into functional osteoclasts and thus, osteolytic activation. Tumour cells also secrete osteolytic factors, most of which act via osteoblast RANKL, that further stimulate osteoclastic bone resorption. Bone resorption causes the release of PDGFs, BMPs, TGF‐β, IGF‐1 and calcium ions that in turn promote cancer cell proliferation, enable continued expression of osteoclast initiating factors and eventually perpetuate a cycle of osteolytic macrometastatic outgrowth. (b) Osteoblastic cancer cells (e.g. from prostate cancer) that have migrated to the bone, adapt to and modify the surrounding microenvironment by secreting osteoblast‐promoting molecules which increase osteoblast differentiation and proliferation including uPA, TGF‐β, VEGF, BMPs, TNF‐α, IGF‐1, Wnt1, WNT3A, ET‐1, PTHrP and adrenomedullin. Activation of the Wnt pathway and the decreased expression of the Wnt antagonist DKK‐1 stimulates osteoblast activity. In turn, enhanced osteoblast activity drives tumour progression by releasing IGF‐1, IL‐6 and IL‐8. Osteoclast activity is also activated in a predominantly osteoblastic lesion through osteoblast‐mediated osteoclastogenesis governed by the increased osteoblastic expression of RANKL and M‐CSF. Accelerated bone matrix degradation promotes the release of growth factors that further enrich the local milieu. Abbreviations: VCAM1, Vascular Cell Adhesion Molecule 1; CXCL12, CXC chemokine ligand 12; PTHrP, Parathyroid hormone‐related protein; PGE2, Prostaglandin E2; ET‐1, Endothelin‐1; BMPs, Bone Morphogenetic Proteins; M‐CSF, Macrophage colony‐stimulating factor; OPG, Osteoprotegerin; PDGF, Platelet‐Derived Growth Factor; IGF‐1, Insulin‐like growth factor 1; uPA, urokinase‐type Plasminogen Activator; and Wnt1, Wingless‐type MMTV integration site 1

FIGURE 3

Mechanisms of extracellular vesicle‐mediated metastasis in skeletal metastatic cancers. In NSCLC, EVs carry pro‐osteoclastogenic miRNAs and EGFR ligands such as AREG that prompt NSCLC‐induced osteoclastogenesis and osteolytic bone invasion. Similarly, MM‐derived EVs enriched with AREG, lncRNA and onco‐miRs contribute to uncoupled bone remodelling and tumour‐induced osteolysis by blocking osteogenesis and stimulating osteoclast differentiation and function. Osteotropic BCa cells release EVs that condition the bone microenvironment toward an osteolytic phenotype via pro‐osteoclastogenic cargo and regulation of the osteoblast secretome. In PCa, EVs shuttle an array of osteoblast‐stimulating factors that facilitate osteoblast differentiation and activity and induce characteristic osteoblastic lesions in the bone metastatic microenvironment. Abbreviations: PDGF‐BB, Platelet‐Derived Growth Factor BB; FGF2, Fibroblast growth factor 2; EFNA3, Ephrin A3; CCL3, Chemokine (C‐C motif) ligand 3; and CCL4, Chemokine (C‐C motif) ligand 4