Abstract
Simple SummaryDue to their systemic nature, metastatic lesions are a major problem for curative cancer treatment. According to a common model for metastasis, tumor cells disseminate by local invasion, survival in the blood stream and extravasation into suitable tissue environments. At secondary sites, metastatic cells adapt, proliferate and foster vascularization to satisfy nutrient and oxygen demand. In recent years, tumors were shown to extensively communicate with cells in the local microenvironment and future metastatic sites by secreting small extracellular vesicles (sEVs, exosomes). sEVs deliver bioactive cargos, e.g., proteins, and in particular, several nucleic acid classes to reprogram target cells, which in turn facilitate tumor growth, cell motility, angiogenesis, immune evasion and establishment of pre-metastatic niches. sEV-cargos also act as biomarkers for diagnosis and prognosis. This review discusses how tumor cells utilize sEVs with nucleic acid cargos to progress through metastasis, and how sEVs may be employed for prognosis and treatment.Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery.
Highlights
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Simple Summary: Due to their systemic nature, metastatic lesions are a major problem for curative cancer treatment
We have discussed the role of small extracellular vesicles (sEVs) and the important major cargo class, nucleic acids, in the progression of tumors through different aspects of the metastatic cascade (Figure 2, Table 1), as well as their role as biomarker platforms and vehicles for treatment (Table 2)
Extensive research in the last years has indicated that tumor sEVs and sEV-based crosstalk with other cell populations in the tumor microenvironment (TME) influence local invasion of tumor cells by facilitating epithelial-to-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, stroma reprogramming, immune evasion and angiogenesis (Sections 3 and 4)
Summary
Cancer is a complex disease, that is driven both by the acquisition of genetic defects and environmental cues. Further research has indicated that sEVs can function as vital mediators of intercellular communication by transferring a wide array of bioactive cargos, including proteins, lipids and many different nucleic acids species [8,9]. It was reported that ILVs formed in MVBs even when vital ESCRT subunits were silenced, indicating ESCRT-independent biogenesis [39] These mechanisms are dependent on tetraspanins and lipids, such as ceramide that is generated by neutral sphingomyelinase 2 (nSMase). Once released into the extracellular milieu or the circulation, sEVs can interact with recipient cells by different mechanisms They can either bind to membrane receptors and activate specific signaling pathways, or cargo is transferred upon uptake into the respective cells. Molecular and cellular stress conditions were shown to modify sEV-release and -uptake rates, as well as their respective cargo composition [9]
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