Pathological and Therapeutic Significance of Tumor-Derived Extracellular Vesicles in Cancer Cell Migration and Metastasis

Simple Summary Cancer metastasis accounts for almost 90% of cancer deaths worldwide. The efficiency of current surgical, radiotherapeutic, and chemotherapeutic approaches is limited, and new, more powerful therapeutic strategies are urgently needed. Tumor metastasis as well as primary tumor invasiveness strongly rely on the ability of cancer cells to migrate at distant sites or locally in the surrounding tissue. Here, we give an overview of the underlying mechanisms, with special emphasis on the role of extracellular vesicles (EVs). EVs are nanoparticles released by cells implied in cell-cell communication. They can travel in the bloodstream and in other body fluids, thus transporting molecules to specific cells and inducing specific responses. Based on the recent literature, we discuss the role of vesicles in cancer cell migration and metastasis as well as their anti-cancer therapeutic significance, focusing on tumor-derived EVs. Moreover, we propose EV encapsulation as an alternative route with specific effects on target cells.Abstract The infiltration of primary tumors and metastasis formation at distant sites strongly impact the prognosis and the quality of life of cancer patients. Current therapies including surgery, radiotherapy, and chemotherapy are limited in targeting the complex cell migration mechanisms responsible for cancer cell invasiveness and metastasis. A better understanding of these mechanisms and the development of new therapies are urgently needed. Extracellular vesicles (EVs) are lipid-enveloped particles involved in inter-tissue and inter-cell communication. This review article focuses on the impact of EVs released by tumor cells, specifically on cancer cell migration and metastasis. We first introduce cell migration processes and EV subtypes, and we give an overview of how tumor-derived EVs (TDEVs) may impact cancer cell migration. Then, we discuss ongoing EV-based cancer therapeutic approaches, including the inhibition of general EV-related mechanisms as well as the use of EVs for anti-cancer drug delivery, focusing on the harnessing of TDEVs. We propose a protein-EV shuttle as a route alternative to secretion or cell membrane binding, influencing downstream signaling and the final effect on target cells, with strong implications in tumorigenesis. Finally, we highlight the pitfalls and limitations of therapeutic EV exploitation that must be overcome to realize the promise of EVs for cancer therapy.