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

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.

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“…Exosomes and microvesicles (EMV) are associated with tumor spread and chemotherapy resistance, through expelling drugs outside the cancer cells (Liu and Wang 2023 ). Their inhibition will enhance the accumulation of chemotherapy drugs inside the cancer cells and produce the same efficacy with the lower dose, accordingly potentiate the apoptosis in the cancer cells (Liguori and Kralj-Iglič 2023 ).…”

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“…GB cells have been shown to invade normal brain tissues, penetrating the brain parenchyma and the perivascular space by degrading the extracellular matrix through the release of proteolytic factors and by forming membrane-derived extensions known as invadopodia, which are involved in cell migration [64,65]. The patterns, directionality, and mechanisms responsible for this invasive behavior involve the extracellular matrix (ECM) and cytoskeletal remodeling, cell-to-cell and cell-to-ECM adhesion mechanisms, and the overall features of epithelial-mesenchymal transition (EMT).…”

“…Several strategies have been identified that are based on targeting EVs on route (i.e., hemodialysis) or inhibiting EV release and uptake, including the use of natural substances (i.e., the antifungal agent ketoconazole or the alkaloid berberine extracted from herbal plants), as well as based on repurposed drugs such as heparin and reserpine, which are already used as anticoagulant and anti-hypertensive drugs, respectively [64,[90][91][92]. Alone, berberine, an efficient sensitizer used in PDT, can also suppress cancer cell proliferation by reducing the synthesis of fatty acids and inhibiting the formation and secretion of extracellular vesicles in cancer cells [91].…”

“…MSCs are a well-studied source of EVs that have been utilized in several clinical trials, both in their native form or after engineering, to target a wide range of pathologies, including tumors [64,117]. MSCs can communicate with different cell types, including GB cells, through direct contact via gap junctions and/or contact-independent pathways mboxciteB102-cells-2802205,B118-cells-2802205.…”

“…Tumor-derived EVs (TDEVs) can be also used as natural carriers for the delivery of antioncogenic molecules [64], thanks to their high tumor targeting and permeability, making them a technological Trojan horse, as evoked by Simionescu and coauthors [100]. EVs isolated from engineered patient-derived GSCs and carrying the miR-302-367 cluster are rapidly internalized by neighboring GB cells, and are able to inhibit GB cell proliferation, stemness, and invasion through the repression of the Cyclin A, Cyclin D1, E2F1, and CXCR4 pathways [122].…”