Abstract
Within tumors, Cancer Stem Cell (CSC) subpopulation has an important role in maintaining growth and dissemination while preserving high resistance against current treatments. It has been shown that, when CSCs are eliminated, the surrounding Differentiated Cancer Cells (DCCs) may reverse their phenotype and gain CSC-like features to preserve tumor progression and ensure tumor survival. This strongly suggests the existence of paracrine communication within tumor cells. It is evidenced that the molecular crosstalk is at least partly mediated by Extracellular Vesicles (EVs), which are cell-derived membranous nanoparticles that contain and transport complex molecules that can affect and modify the biological behavior of distal cells and their molecular background. This ability of directional transport of small molecules prospects EVs as natural Drug Delivery Systems (DDS). EVs present inherent homing abilities and are less immunogenic than synthetic nanoparticles, in general. Currently, strong efforts are focused into the development and improvement of EV-based DDS. Even though EV-DDS have already reached early phases in clinical trials, their clinical application is still far from commercialization since protocols for EVs loading, modification and isolation need to be standardized for large-scale production. Here, we summarized recent knowledge regarding the use of EVs as natural DDS against CSCs and cancer resistance.
Highlights
Despite achieving great advances in oncology in the past few years, in terms of treatment and patient survival, cancer still represents the second cause of death worldwide
Extracellular Vesicles (EVs) produced in cancer cells express tumor-specific antigens on their membrane, which could help in the generation of the anti-tumor immune response, which has been recently confirmed using a mouse model [34,58]
The results showed that the global quantity of tumor cells and the incidence of Cancer Stem Cell (CSC) was reduced drastically, while treatment with free cisplatin did not show any beneficial effects for the patients [34,64]
Summary
Despite achieving great advances in oncology in the past few years, in terms of treatment and patient survival, cancer still represents the second cause of death worldwide. Strong efforts have been invested over the past decade, in the identification of CSCs within the tumor in order to target treatments against them [10] This hierarchical model cannot explain the dynamic behavior seen in the CSC subpopulation, as the concepts of DCC and CSC were not conceived within the same cell [16]. A new stochastic model has been recently postulated (Figure 1B) [16,22,23] According to this model, a tumor is composed by different cell populations that maintain a stable communication among them. They can “sense” if one specific subpopulation of the tumor cells is redundant, absent or has been depleted In this model, the amount of CSCs seems to remain constant, to maintain the mentioned equilibrium within the TME [4,6,17]. TThhiiss tutummooraral lninchicehceomcopmonpeonntesnctasncan simsuilmtaunletoaunseloyurselgyurleagteutlahteertehqeuirreeqdueirqeudileibqruiuilmibroifuCmSCofsCanSCd sthaenpdrothceespsroofcceeslsluolfarceplllausltairciptylaasntidciatyreand requairreedrefqourirthede mfoaritnhteenmanaicneteonf athneceCoSfCthpeoCpuSClatpioonpu(Flaigtiuorne (2Fbi)gu[1r0e,122B,)17[1,207,1].2,17,27]
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