diagnostics Review Cell-Secreted Vesicles: Novel Opportunities in Cancer Diagnosis, Monitoring and Treatment Cristina Catoni 1 , Veronica Di Paolo 2 , Elisabetta Rossi 3, * , Luigi Quintieri 2, * ,† and Rita Zamarchi 1,†   Citation: Catoni, C.; Di Paolo, V.; Rossi, E.; Quintieri, L.; Zamarchi, R. Cell-Secreted Vesicles: Novel Opportunities in Cancer Diagnosis, Monitoring and Treatment. Diagnostics 2021, 11, 1118. https:// doi.org/10.3390/diagnostics11061118 Academic Editor: Pamela Pinzani Received: 18 May 2021 Accepted: 15 June 2021 Published: 19 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; cristina.catoni@iov.veneto.it (C.C.); rita.zamarchi@unipd.it (R.Z.) 2 Laboratory of Drug Metabolism, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy; veronica.dipaolo@unipd.it 3 Departmentof Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; * Correspondence: elisabetta.rossi@unipd.it (E.R.); luigi.quintieri@unipd.it (L.Q.) † Luigi Quintieri and Rita Zamarchi are co-last authors. Abstract: Extracellular vesicles (EVs) are important mediators of intercellular communication playing a pivotal role in the regulation of physiological and pathological processes, including cancer. In particular, there is significant evidence suggesting that tumor-derived EVs exert an immunosup- pressive activity during cancer progression, as well as stimulate tumor cell migration, angiogenesis, invasion and metastasis. The use of EVs as a liquid biopsy is currently a fast-growing area of research in medicine, with the potential to provide a step-change in the diagnosis and treatment of cancer, allowing the prediction of both therapy response and prognosis. EVs could be useful not only as biomarkers but also as drug delivery systems, and may represent a target for anticancer therapy. In this review, we attempted to summarize the current knowledge about the techniques used for the isolation of EVs and their roles in cancer biology, as liquid biopsy biomarkers and as therapeutic tools and targets. Keywords: extracellular vesicles; cancer biology; liquid biopsy; therapeutic tools 1. Introduction For a long time since their discovery, the role of extracellular vesicles (EVs) in cancer remained poorly understood. EVs are currently considered the main transporters of specific cargoes, including the molecular components of parent cells, thus mediating a wide variety of cellular activities in both normal and neoplastic tissues. These vesicles are secreted by several cell types (e.g., tumor cells, macrophages and fibroblasts) and are widely distributed in the blood, urine, ascites, synovial fluid, breast milk and other bodily fluids [1]. They have been identified as key messengers of intracellular communication in healthy and neoplastic cells. Tumor cell-derived EVs have become a popular research topic in the field of cancer studies [2], and there have been many reports on EVs in cancer. Liquid biopsy monitors tumor development through non-invasive sampling. Recently, EVs have started to attract attention as a component of liquid biopsy and among disease biomarkers. This is because EVs have multiple advantages, for example, their abundance in biofluids and protection of proteins and nucleic acids from degradation through their lipid bilayer membrane [3]. They have emerged as among the most promising liquid biopsies, and several studies have demonstrated that EVs could reflect tumor development and progression [4]. At the same time, EVs are very interesting for theragnostic purposes. In fact, their inhibition, control of EV-related gene expression and hemofiltration of EVs all prevent or reduce intercellular communication between cancer cells [5]. Another way to use EVs could be as drug delivery nanocarriers, cancer vaccines, cell surface modulators, therapeutic agents and therapeutic targets [6]. Diagnostics 2021, 11, 1118. https://doi.org/10.3390/diagnostics11061118 https://www.mdpi.com/journal/diagnostics