Abstract

Simple SummaryCancer stem cells (CSCs) are cancer cells that possess traits usually attributed to stem cells. An increase in CSCs can lead to more rapid cancer progression, treatment resistance and the increased likelihood of recurrence. To promote CSC survival and associated cancer progression, cancer cells enter into reciprocal crosstalk with the surrounding tissue environment, as well as with distant metastatic sites. This mechanism of communication relies, in part, on secreted factors, of which extracellular vesicles (EVs) are thought to have a critical role. This systematic review evaluates the current knowledge of cancer communication via EVs to alter the microenvironment to increase the survival and maintenance of CSCs. A total of 16 studies spanning the EV content, pathway alterations and CSC-targeting treatments provide new insights into how EVs mediate CSC traits and identify the gaps in our understanding of how modulation of the microenvironment plays a key role.Cancer stem cells (CSCs) have increasingly been shown to be a crucial element of heterogenous tumors. Although a relatively small component of the population, they increase the resistance to treatment and the likelihood of recurrence. In recent years, it has been shown, across multiple cancer types (e.g., colorectal, breast and prostate), that reciprocal communication between cancer and the microenvironment exists, which is, in part, facilitated by extracellular vesicles (EVs). However, the mechanisms of this method of communication and its influence on CSC populations is less well-understood. Therefore, the aim of this systematic review is to determine the evidence that supports the role of EVs in the manipulation of the tumor microenvironment to promote the survival of CSCs. Embase and PubMed were used to identify all studies on the topic, which were screened using PRISMA guidelines, resulting in the inclusion of 16 studies. These 16 studies reported on the EV content, pathways altered by EVs and therapeutic targeting of CSC through EV-mediated changes to the microenvironment. In conclusion, these studies demonstrated the role of EV-facilitated communication in maintaining CSCs via manipulation of the tumor microenvironment, demonstrating the potential of creating therapeutics to target CSCs. However, further works are needed to fully understand the targetable mechanisms upon which future therapeutics can be based.

Highlights

  • Cancer is one of the leading causes of death worldwide, second to only cardiovascular disease

  • 20 articles that were in full.inThis in theinfurther removal of four of studies, four studies, as there was no inclusion of the isolation methods, leaving eligible as there was no inclusion of the extracellular vesicles (EVs) isolation methods, leaving 16 eligible studies studies to be included the review

  • Four studies determined the contents of the EVs and their effects on cancer stem cells, finding that either specific RNAs or proteins were enriched in the cargos of EVs produced by metastatic cancer cells compared to their less malignant counterparts and affected the

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Summary

Introduction

Cancer is one of the leading causes of death worldwide, second to only cardiovascular disease. 9.5 million cancer-related deaths worldwide in 2018 to 29.5 million new cases per year and the number of cancer-related deaths to 16.4 million by 2040 [1,2]. The number of cancer-related deaths to 16.4 million by 2040 [1,2]. EMT, alteration of the cell immune response, response, alteration ofdrug the surrounding microenvironment, increased plasticity and alterationproliferation/invasion of the surrounding microenvironment, increased cell plasticity increased increased (Figure 1). These CSC properties lead to anand increased caproliferation/invasion

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