Extracellular vesicles in the development of organ-specific metastasis.

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.

Urabe F ，Patil K ，Ramm GA ，Ochiya T ，Soekmadji C ... -  《Journal of Extracellular Vesicles》

Tumor-derived extracellular vesicles: The metastatic organotropism drivers.

The continuous growing, spreading, and metastasis of tumor cells depend on intercellular communication within cells resident in a tissue environment. Such communication is mediated through the secretion of particles from tumor cells and resident cells known as extracellular vesicles (EVs) within a microenvironment. EVs are a heterogeneous population of membranous vesicles released from tumor cells that transfer many types of active biomolecules to recipient cells and induce physiologic and phenotypic alterations in the tissue environment. Spreading the 'seeds' of metastasis needs the EVs that qualify the 'soil' at distant sites to promote the progress of arriving tumor cells. Growing evidence indicates that EVs have vital roles in tumorigenesis, including pre-metastatic niche formation and organotropic metastasis. These EVs mediate organotropic metastasis by modifying the pre-metastatic microenvironment through different pathways including induction of phenotypic alternation and differentiation of cells, enrolment of distinct supportive stromal cells, up-regulation of the expression of pro-inflammatory genes, and induction of immunosuppressive status. However, instead of pre-metastatic niche formation, evidence suggests that EVs may mediate reawakening of dormant niches. Findings regarding EVs function in tumor metastasis have led to growing interests in the interdisciplinary significance of EVs, including targeted therapy, cell-free therapy, drug-delivery system, and diagnostic biomarker. In this review, we discuss EVs-mediated pre-metastatic niche formation and organotropic metastasis in visceral such as lung, liver, brain, lymph node, and bone with a focus on associated signaling, causing visceral environment hospitable for metastatic cells. Furthermore, we present an overview of the possible therapeutic application of EVs in cancer management.

Rezaie J ，Ahmadi M ，Ravanbakhsh R ，Mojarad B ，Mahbubfam S ，Shaban SA ，Shadi K ，Berenjabad NJ ，Etemadi T ... -  《-》

Extracellular vesicle-associated organotropic metastasis.

Metastasis refers to the progressive dissemination of primary tumour cells and their colonization of other tissues and is associated with most cancer-related mortalities. The disproportional and systematic distribution pattern of distant metastasis in different cancers has been well documented, as is termed metastatic organotropism, a process orchestrated by a combination of anatomical, pathophysiological, genetic and biochemical factors. Extracellular vesicles (EVs), nanosized cell-derived membrane-bound particles known to mediate intercellular communication, are now considered crucial in organ-specific metastasis. Here, we review and summarize recent findings regarding EV-associated organotropic metastasis as well as some of the general mechanisms by which EVs contribute to this important process in cancer and provide a future perspective on this emerging topic. We highlight studies that demonstrate a role of tumour-derived EVs in organotropic metastasis via pre-metastatic niche modulation. The bioactive cargo carried by EVs is of diagnostic and prognostic values, and counteracting the functions of such EVs may be a novel therapeutic strategy targeting metastasis. Further investigations are warranted to better understand the functions and mechanisms of EVs in organotropic metastasis and accelerate the relevant clinical translation.

Mo Z ，Cheong JYA ，Xiang L ，Le MTN ，Grimson A ，Zhang DX ... -  《-》

The influence of tumour-derived extracellular vesicles on local and distal metastatic dissemination.

Extracellular vesicles (EVs) are key mediators of intercellular communication that have been ignored for decades. Tumour cells benefit from the secretion of vesicles as they can influence the behaviour of neighbouring tumour cells within the tumour microenvironment. Several studies have shown that extracellular vesicles play an active role in pre-metastatic niche formation and importantly, they are involved in the metastatic organotropism of different tumour types. Tumour-derived EVs carry and transfer molecules to recipient cells, modifying their behaviour through a process defined as "EV-driven education". EVs favour metastasis to sentinel lymph nodes and distal organs by reinforcing angiogenesis, inflammation and lymphangiogenesis. Hence, in this review we will summarize the main mechanisms by which tumour-derived EVs regulate lymph node and distal organ metastasis. Moreover, since some cancers metastasize through the lymphatic system, we will discuss recent discoveries about the presence and function of tumour EVs in the lymph. Finally, we will address the potential value of tumour EVs as prognostic biomarkers in liquid biopsies, specially blood and lymphatic fluid, and the use of these tools as early detectors of metastases.

Nogués L ，Benito-Martin A ，Hergueta-Redondo M ，Peinado H ... -  《-》

Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner.

Primary tumours can establish long-range communication with distant organs to transform them into fertile soil for circulating tumour cells to implant and proliferate, a process called pre-metastatic niche (PMN) formation. Tumour-derived extracellular vesicles (EV) are potent mediators of PMN formation due to their diverse complement of pro-malignant molecular cargo and their propensity to target specific cell types (Costa-Silva et al., 2015; Hoshino et al., 2015; Peinado et al., 2012; Peinado et al., 2017). While significant progress has been made to understand the mechanisms by which pro-metastatic EVs create tumour-favouring microenvironments at pre-metastatic organ sites, comparatively little attention has been paid to the factors intrinsic to recipient cells that may modify the extent to which pro-metastatic EV signalling is received and transduced. Here, we investigated the role of recipient cell cholesterol homeostasis in prostate cancer (PCa) EV-mediated signalling and metastasis. Using a bone metastatic model of enzalutamide-resistant PCa, we first characterized an axis of EV-mediated communication between PCa cells and bone marrow that is marked by in vitro and in vivo PCa EV uptake by bone marrow myeloid cells, activation of NF-κB signalling, enhanced osteoclast differentiation, and reduced myeloid thrombospondin-1 expression. We then employed a targeted, biomimetic approach to reduce myeloid cell cholesterol in vitro and in vivo prior to conditioning with PCa EVs. Reducing myeloid cell cholesterol prevented the uptake of PCa EVs by recipient myeloid cells, abolished NF-κB activity and osteoclast differentiation, stabilized thrombospondin-1 expression, and reduced metastatic burden by 77%. These results demonstrate that cholesterol homeostasis in bone marrow myeloid cells regulates pro-metastatic EV signalling and metastasis by acting as a gatekeeper for EV signal transduction.

Henrich SE ，McMahon KM ，Plebanek MP ，Calvert AE ，Feliciano TJ ，Parrish S ，Tavora F ，Mega A ，De Souza A ，Carneiro BA ，Thaxton CS ... -  《Journal of Extracellular Vesicles》