Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

SIMPLE SUMMARY: Certain 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. ABSTRACT: 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.