Abstract

Simple Summary Cancer is the second leading cause of death in humans, and in 2020, 9.8 million cancer-related deaths were reported worldwide. In the last 20 years, it has become apparent that small vesicles released by cancer cells, referred to as extracellular vesicles (EVs), are key players in cell-cell communication in the tumor environment, and as a consequence, research in this area has increased dramatically. This review summarizes the recent advances in our understanding of how EVs serve as mediators of communication between cancer cells and with their surroundings in order to promote the acquisition of specific characteristics that permit their aberrant behavior. In addition, we dwell on how EVs aid in the development of drug resistance, which is a frequent cause of treatment failure in chemotherapy. Finally, we discuss an exciting new area of research that envisions harnessing the unique characteristics of EVs for therapeutic and diagnostic purposes (theranostics). Taken together, the available literature suggests that advances in our understanding of EV biology in the next decades will likely be critical to achieving more effective treatments in cancer patients. Cancer remains a leading cause of death worldwide despite decades of intense efforts to understand the molecular underpinnings of the disease. To date, much of the focus in research has been on the cancer cells themselves and how they acquire specific traits during disease development and progression. However, these cells are known to secrete large numbers of extracellular vesicles (EVs), which are now becoming recognized as key players in cancer. EVs contain a large number of different molecules, including but not limited to proteins, mRNAs, and miRNAs, and they are actively secreted by many different cell types. In the last two decades, a considerable body of evidence has become available indicating that EVs play a very active role in cell communication. Cancer cells are heterogeneous, and recent evidence reveals that cancer cell-derived EV cargos can change the behavior of target cells. For instance, more aggressive cancer cells can transfer their "traits" to less aggressive cancer cells and convert them into more malignant tumor cells or, alternatively, eliminate those cells in a process referred to as "cell competition". This review discusses how EVs participate in the multistep acquisition of specific traits developed by tumor cells, which are referred to as "the hallmarks of cancer" defined by Hanahan and Weinberg. Moreover, as will be discussed, EVs play an important role in drug resistance, and these more recent advances may explain, at least in part, why pharmacological therapies are often ineffective. Finally, we discuss literature proposing the use of EVs for therapeutic and prognostic purposes in cancer.