Small extracellular vesicles (SEVs) are extracellular vesicles containing DNA, RNA, and proteins and are involved in intercellular communication and function, playing an essential role in the growth and metastasis of tumors. SEVs are present in various body fluids and can be isolated and extracted from blood, urine, and cerebrospinal fluid. Under both physiological and pathological conditions, SEVs can be released by some cells, such as immune, stem, and tumor cells, in a cytosolic manner. SEVs secreted by tumor cells are called tumor-derived exosomes (TEXs) because of their origin in the corresponding parent cells. Glioma is the most common intracranial tumor, accounting for approximately half of the primary intracranial tumors, and is characterized by insidious onset, high morbidity, and high mortality rate. Complete removal of tumor tissues by surgery is difficult. Chemotherapy can improve the survival quality of patients to a certain extent; however, gliomas are prone to chemoresistance, which seriously affects the prognosis of patients. In recent years, TEXs have played a vital role in the occurrence, development, associated immune response, chemotherapy resistance, radiation therapy resistance, and metastasis of glioma. This article reviews the role of TEXs in glioma progression, drug resistance, and clinical diagnosis. 

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Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma

COPYRIGHT © 2022 Bocci, Fabbri, Neves and Rossi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 10 August 2022 DOI 10.3389/fonc.2022.951158

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Editorial: Liquid biopsy: A tool for better understanding of the metastatic process ecosystem

Abstract Objective Head and neck squamous cell carcinoma (HNSCC) is a common and fatal cancer type worldwide. Competing endogenous RNA (ceRNA) plays an important role in tumor development and progression through circular RNAs (circRNAs). Therefore, in this study, we attempted to explore the mechanisms by which circRNA/miRNA/mRNA ceRNA networks regulate head and neck squamous cell carcinoma HNSCC. Methods The biopsy samples from patients with HNSCC were obtained intra-operatively before any therapeutic intervention. The expression profiles of circRNAs, miRNAs, and mRNAs were performed using whole-transcriptome resequencing. Then, significantly differentially expressed circRNAs, miRNAs and mRNAs were screened out. The circRNA/miRNA/mRNA ceRNA networks were constructed based on the predicted circRNA–miRNA interactions and miRNA–mRNA interactions. After that, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to elucidate the possible functions of mRNAs contained in the ceRNA network. Furthermore, the hub network was screened among the key pathways of enrichment analysis. Finally, the expression of RNAs in hub network were verified by QRT-PCR and the association between them was revealed by Spearman correlation analysis. Results A total of 421 circRNAs, 112 miRNAs, and 1074 mRNAs with differential expression were detected. Among these, the top 9 circRNAs, 28 miRNAs, and 334 mRNAs were screened to construct a ceRNA network. The KEGG signal pathway and GO enrichment analysis of 334 mRNAs showed that cell adhesion molecules (CAMs), amino acid metabolism and other related pathways, biological processes such as extracellular matrix histogenesis were significantly enriched. Among them, CD274 and other genes were mainly enriched in CAMs pathway. Ultimately, a subnetwork including hsa_circ_0044507, hsa_circ_0044517, hsa_circ_0026774, hsa-miR-4446-3p, and PD-L1 (CD274) was screened out. QRT-PCR validated that the expression of hsa_circ_0044507, hsa_circ_0044517, hsa_circ_0026774, and PD-L1 were significantly increased, and hsa-miR-4446-3p were expressed significantly less in tumor tissue than in adjacent tissue. Spearman correlation showed that the expression of hsa_circ_0044507, hsa_circ_0044517, hsa_circ_0026774 were negatively correlated with hsa-miR-4446-3p, and positively correlated with PD-L1. Conclusion CeRNA network including hsa_circ_0044507, hsa_circ_0044517, hsa_circ_0026774, hsa-miR-4446-3p, and PD-L1 may be key regulators for HNSCC, and may be potential targets for the pathogenesis and treatment development of HNSCC. 

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Identification of novel ceRNA networks associated with PD- L1 in head and neck squamous cell carcinoma based on whole-transcriptome sequencing

Simple Summary Tumor cells generate extracellular vesicles, which exert a critical role in intercellular communication through the delivery of their cargo, thus regulating many cell functions to promote the tumor’s progression. This review focuses on the formation of pre-metastatic niche, which is a key process in the early metastasis of tumor, and provides an overview of the role and mechanism of non-coding RNA derived from extracellular vesicles in mediating tumor-distant metastasis, and its predictive value for tumor diagnosis and evaluation as a potential target for anti-tumor metastasis. Abstract Metastasis is a critical stage of tumor progression, a crucial challenge of clinical therapy, and a major cause of tumor patient death. Numerous studies have confirmed that distant tumor metastasis is dependent on the formation of pre-metastatic niche (PMN). Recent studies have shown that extracellular vesicles (EVs) play an important role in PMN formation. The non-coding RNAs (ncRNAs) derived from EVs mediate PMN formation and tumor-distant metastasis by promoting an inflammatory environment, inhibiting anti-tumor immune response, inducing angiogenesis and permeability, and by microenvironmental reprogramming. Given the stability and high abundance of ncRNAs carried by EVs in body fluids, they have great potential for application in tumor diagnosis as well as targeted interventions. This review focuses on the mechanism of ncRNAs derived from EVs promoting tumor PMN formation and distant metastasis to provide a theoretical reference for strategies to control tumor metastasis.

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Non-Coding RNAs Derived from Extracellular Vesicles Promote Pre-Metastatic Niche Formation and Tumor Distant Metastasis

Extracellular vesicles released by tumors (tEVs) disseminate via circulatory networks and promote microenvironmental changes in distant organs favoring metastatic seeding. Despite their abundance in the bloodstream, how hemodynamics affect the function of circulating tEVs remains unsolved. We experimentally tuned flow profiles in vitro (microfluidics) and in vivo (zebrafish) and demonstrated that efficient uptake of tEVs occurs in endothelial cells subjected to capillary-like hemodynamics. Such flow profiles partially reroute internalized tEVs towards non-acidic and non-degradative Rab14-positive endosomes, at the expense of lysosomes, suggesting that endothelial mechanosensing diverts tEVs from degradation. Subsequently, tEVs promote the expression of pro-angiogenic transcription factors in flow-stimulated endothelial cells and favor vessel sprouting in zebrafish. Altogether, we demonstrate that capillary-like flow profiles potentiate the pro-tumoral function of circulating tEVs by promoting their uptake and rerouting their trafficking. We propose that tEVs contribute to pre-metastatic niche formation by exploiting endothelial mechanosensing in specific vascular regions with permissive hemodynamics.

Blood flow diverts extracellular vesicles from endothelial degradative compartments to promote angiogenesis

The intravascular behavior of tumor-derived extracellular vesicles (EVs) and circulating tumor cells (CTCs) lies at the heart of the metastatic cascade. Their capacity to disseminate and stop at specific vascular regions precedes and determines the formation of metastatic foci. We discuss in detail the central role of cellular adhesion molecules (CAMs) that are present on EV/CTC surface, as well as their endothelial ligands, in dictating their arrest site and their capacity to exit the vasculature. We focus on the differences and similarities between CAMs on CTCs and EVs, and speculate about their role in the organotropism of different cancer types. Better understanding of the binding mechanisms might pinpoint potential targets for novel therapies. 

Amandine Dupas

Papers

Circulating extracellular vesicles and tumor cells: sticky partners in metastasis.