## 5 Future Challenges and Conclusions
Further knowledge and classification of the proteins, lipids, and metabolites of EVs will be useful in order to gain deeper insight about their role in transmitting information between cells, as well as our understanding of disease biogenesis and progression. Online databases have been created for the purpose of cataloguing EV content. There, highly accessible websites are used to compare sequences, and upload new ones [81; 82; 83]. Despite their promising utility as cancer biomarkers, the use of EVs in the clinical setting is still far from use in everyday practice, due to difficulties in isolation through standard analysis techniques. Conceptualization, A.M. and F.C. ; original draft preparation, G.A. and C.M.S.-L.; supervision, C.C. and R.S. ; writing and editing, G.A., C.M.S.-L., A.A. and A.M. All authors have read and agreed to the last version of the manuscript. G.A., R.S., C.C. and F.C. were partially supported by IMET and IEMEST. This is IMET contribution number IMET 21-001. C.M.S.-L. and A.M. are supported by grants PID2019-105713 GB-I00, funded by MCIN/AEI/ 10.13039/501100011033, Spain; and grant PROMETEO 2020/071 funded by the Con-selleria de Educacion, Cultura y Deporte of Generalitat Valenciana. C.M.S.L is supported by grant PRE2020-092458 funded by MCIN/ AEI/ 10.13039/501100011033, Spain. The research group is part of \"Red Traslacional para la Aplicacion Clinica de Vesiculas Extracellulares\" (RED2018-102411-T), Agencia Estatal de Investigacion, Spain. Not applicable. The authors declare no conflict of interest. * [PERSON] et al. (2018) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway. _Cell Death Dis._**2018**, \(9\), 513. [CrossRef] [PubMed]
* [PERSON] et al. (2018) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; et al. Hypoxia-Induced Matrix Metalloproteininase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases. _Cell Death Dis._**2018**, \(9\), 382. [CrossRef] [PubMed]
* [PERSON] et al. (2015) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON] [PERSON]; [PERSON] [PERSON]; [PERSON]; et al. Tumour exosome integrins determine organotropic metastasis. _Nature_**2015**, _527_, 329-335. [CrossRef]
* [PERSON] et al. (2017) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. _Nat. Commun._**2017**, \(8\), 15016. [CrossRef] [PubMed]
* [PERSON] et al. (2021) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON] Landscape of extracellular vesicles in the tumour microenvironment: Interactions with stromal cells and with non-cell components, and impacts on metabolic reprogramming, horizontal transfer of neoplastic traits, and the emergence of therapeutic resistance. _Semic. Cancer Biol._**2021**, _74_, 24-44. [CrossRef]
* [PERSON] et al. (2018) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON] Exosomes, Their Biogenesis and Role in Inter-Cellular Communication, Tumor Microenvironment and Cancer Immunotherapy. _Vaccites_**2018**, \(6\), 69. [CrossRef]
* [PERSON] et al. (2013) [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON]; [PERSON] [PERSON]; [PERSON]; [PERSON] [PERSON]; [PERSON] [PERSON]; [PERSON]; et al. Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling. _J. Biol. Chem._**2013**, _288_, 36691-36702. [CrossRef]
* [PERSON] et al. (2017) [PERSON]; [PERSON]; [PERSON] [PERSON]; [PERSON]; [PERSON]; [PERSON] [PERSON]; [PERSON] Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis. _Mol. Cancer Res._**2017**, _15_, 93-105. [CrossRef] [PubMed]
* [PERSON] et al. (2017) [PERSON]; [PERSON]; [PERSON]; [PERSON] Exosomal TGF-\(\beta\)1 is correlated with lymphatic metastasis of gastric cancers. _Am.