Extracellular Vesicle-DNA: The Next Liquid Biopsy Biomarker for Early Cancer Diagnosis?

Simple Summary Each human cancer is a specific disease, but all cancers share the necessity of an early diagnosis for providing the optimal outcome for the patient. Liquid biopsy in blood, as a substitute to invasive tissue biopsies, brought the first important breakthrough for cancer diagnosis. The race for efficient cancer biomarkers was first focused on the few circulating tumor cells released in the bloodstream, then on circulating cell-free tumor DNAs in plasma and serum. The last decade's discovery of the ubiquitous cell-derived extracellular vesicles (EVs) brought a new "treasure chest" for the worldwide search of cancer biomarkers among the many tumor EVs-associated biological components. The aim of this review is to follow the different steps-mostly in vitro and preclinical liquid biopsies-which focused the current interest on tumor EVs-associated DNA as a promising cancer biomarker that still has many challenges yet to be solved before reaching the clinic. After a short introduction about the history of liquid biopsy, aimed to noninvasively replace the common tissue biopsy as a help for cancer diagnosis, this review is focused on extracellular vesicles (EVs), as the main third component, which is now coming into the light of liquid biopsy. Cell-derived EV release is a recently discovered general cellular property, and EVs harbor many cellular components reflecting their cell of origin. This is also the case for tumoral cells, and their cargoes might therefore be a "treasure chest" for cancer biomarkers. This has been extensively explored for a decade, but the EV-DNA content escaped this worldwide query until recently. The aim of this review is to gather the pilot studies focused on the DNA content of circulating cell-derived EVs, and the following five years of studies about the circulating tumor EV-DNA. The recent preclinical studies about the circulating tEV-derived gDNA as a potential cancer biomarker developed into a puzzling controversy about the presence of DNA into exosomes, coupled with an increased unexpected non vesicular complexity of the extracellular environment. This is discussed in the present review, together with the challenges that need to be solved before any efficient clinical transfer of EV-DNA as a quite promising cancer diagnosis biomarker.