Abstract
Simple SummaryCertain types of cancer have higher relapse rates compared to others, and cancer stem cells (CSCs) have been shown as the main drivers of cancer relapse and cancer severity. This subpopulation of cells displays stem-like characteristics which bolster tumorigenesis along with metastasis and lead to poorer prognoses. Autophagy has been studied as a mechanism by which CSCs maintain stemness and acquire resistance to chemotherapy and radiation. The aim of this review is to condense and organize what has been recently published on the connection between cancer stem cells (CSCs) and autophagy. Multiple studies on autophagy have suggested that the pathway is a double-edged sword, which can either undermine or enhance CSC characteristics depending on interactions with different pathways. Thus, future research should investigate regulation of autophagy in combination with traditional cancer therapies as a possible method to effectively eliminate CSCs and minimize cancer relapse.Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.
Highlights
Cancer stem cells (CSCs) are capable of remodeling the tumor microenvironment (TME) through the use of matrix metalloproteinases (MMP), which are calcium-dependent zinc-containing endopeptidases induced by hypoxia and extracellular acidosis [1,3,7,8,9]
TME reconstruction enhances cancer invasion and metastasis, allowing CSCs to undergo epithelial-mesenchymal transitions (EMT), where the cancer cells lose epithelial characteristics and develop mesenchymal features that allow for invasion into the local vascular network and migration to distant locations with more optimal conditions for tumor growth [10]
CSCs are shown to stem from normal stem cells that acquire CSC characteristics triggered by environmental changes which induce genetic mutations [9]
Summary
Autophagy is a mechanism of energy metabolism where intracellular components including damaged organelles, pathogens, and non-essential proteins are sequestered into vesicles and recycled during moments of environmental stress such as nutrient deprivation, oxidative stress, hypoxia, and infection in order to provide nutrients and overcome new stressors [8,46]. Protective autophagy is a major cause of survival and chemotherapy resistance in CSC populations [15] This form of autophagy promotes metastasis, allowing the cancer to spread and wreak havoc throughout the body. Initiation of autophagy begins with the formation of a non-degradative vesicle called the autophagosome This vesicle fuses with a lysosome to form the autolysosome, where intracellular materials are degraded and released into the cytoplasm for recycling [4,46]. Two main multi-protein complexes, Unc-51-like autophagy kinase (ULK) complex and vacuolar protein sorting 34-beclin 1
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