Background and implications
Extracellular vesicles (EVs) are nano-sized vesicles (exosomes and microvesicles) secreted by almost every cell type under both normal and pathologic conditions. EVs contain a variety of proteins such as transcription factors as well as nucleic acids such as DNA and non-coding regulatory RNAs (1, 2). Exosomes are originated from endocytic compartments (3), relevantly reflecting the cytoplasmic content of their parent cells; microvesicles are shed directly from plasma membrane, comparatively reflecting the biology of cell surfaceome. It is important to consider that the molecular content and the secreted levels of EVs are differentially reflected in each cancer type and grade, making EVs a potential source of cancer biomarkers (3, 4).
Extracellular vesicles act as conveners of intercellular communication by exchanging biological information between cells (5–7) and are largely implicated in determining cell fates (8). Based on their inherent capability of transferring regulatory elements, EVs may elicit a newly evolved mechanism of trans-regulation between cells and confer genomic instability in recipient cells (1). The oncogenic content of EVs transferred from cancer cells to normal recipient cells could consequently induce malignant phenotypes (9–11). In a similar way, EVs could mediate an intercellular transfer of phosphatase and tensin homolog (PTEN)-targeting microRNAs to primary tumor cells in order to bypass tumor suppressor checkpoint and enable primary tumor cells to metastasize (12). As such, the EV-mediated dissemination of bioactive content contributes to cell phenotypic transitions, immune modulation, and re-shaping of tumor microenvironment (13). The most profound input of cancer-associated EVs is their participation in pre-metastatic niche formation by enabling cells to mobilize at new regions (14, 15). As such, EVs from various tumor types forecast organ-specific metastasis (organotropism) by preferentially fusing at their predicted destinations in target organs through EV-linked distinct integrins (16). Thus, EVs promote tumor organotropic metastasis and prepare favorable pre-metastatic niche for future metastasis.
Since cancer needs successful co-option with extracellular environment, tumor-derived EVs can condition tumor microenvironment for successful co-option of cancer cells in a given niche (12). For this, EVs transport pro-angiogenic growth factors that cope with nutrient requirements in microenvironment and favor the formation of blood vessels (17), or may undergo vessel co-option. It is tempting to escalate that tumor cells have evolved yet another mean of co-option through suppressing anti-tumor immune cells by secreting EVs loaded with immune-suppressing ligands (18). In fact, EVs carrying such ligands interact with corresponding receptors presented on immune cells and induce suppression or apoptosis of T cells and normal killer cells. This mechanism facilitates cancer cells to co-exist in tumor microenvironment by suppressing anti-tumor immune cells (18). Thus, given all observations together, EVs facilitate stochastic patterns of cancer physiology.
Despite multifaceted roles of EVs in cancer biology, some important questions about their regulatory mechanisms and their clinical applications are yet to be answered. On the biotech front, the answers to the above questions will improve the way of designing more precise therapeutic strategy for cancer patients. Collective efforts from academia and biotech industries are expected to translate EVs into a platform of innovative and personalized therapies.
I acknowledge FAPESP (Sao Paulo Research Foundation, Proc. No. 12/24574–3), and CAPES (Coordination for the Improvement of Higher Education Personnel, Proc. No. BEX 7057/15-6)—Brazil.
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Affiliation and email
Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.