Autophagy in Cancer Stem Cells: A Potential Link Between Chemoresistance, Recurrence, and Metastasis

Abstract

Cancer cells require an uninterrupted nutritional supply for maintaining their proliferative needs and this high demand in concurrence with inadequate supply of blood and nutrition induces stress in these cells. These cells utilize various strategies like high glycolytic flux, redox signaling, and modulation of autophagy to avoid cell death and overcome nutritional deficiency. Autophagy allows the cell to generate ATP and other essential biochemical building blocks necessary under such adverse conditions. It is emerging as a decisive process in the development and progression of pathophysiological conditions that are associated with increased cancer risk. However, the precise role of autophagy in tumorigenesis is still debatable. Autophagy is a novel cytoprotective process to augment tumor cell survival under nutrient or growth factor starvation, metabolic stress, and hypoxia. The tumor hypoxic environment may provide site for the enrichment/expansion of the cancer stem cells (CSCs) and successive rapid tumor progression. CSCs are characteristically resistant to conventional anticancer therapy, which may contribute to treatment failure and tumor relapse. CSCs have the potential to regenerate for an indefinite period, which can impel tumor metastatic invasion. From last decade, preclinical research has focused on the diversity in CSC content within tumors that could affect their chemo- or radio-sensitivity by impeding with mechanisms of DNA repair and cell cycle progression. The aim of this review is predominantly directed on the recent developments in the CSCs during cancer treatment, role of autophagy in maintenance of CSC populations and their implications in the development of promising new cancer treatment options in future.

MicroRNA-140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy

“…Furthermore, mounting evidences had suggested that activation of autophagy promoted chemoresistance 8, 36, 37 . On the other hand, we found that siRNA knocking down of BECN-1 or ATG5 could reduce the chemoresistance and reversed the effect of miR-140-5p, suggesting an important role of autophagy on chemoresistance and miR-140-5p increased the chemoresistance through miR-140-5p/HMGN5/autophagy regulatory loop.…”

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

“…It is hypothesized that the increased autophagy within HSC is necessary for lipid breakdown to provide the necessary energy source to undergo activation through the process of lipophagy (30). Such dichotomous findings are noted in cancer literature, where autophagy has been reported as both promotional and inhibitory for tumor growth (31)(32)(33)(34)(35). These divergent findings likely reflect the complexity of the role of autophagy in vivo.…”

Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

“…BCSCs have also been observed in vitro and in vivo to accumulate less DNA breaks after radiation [56]. Therefore, it is hypothesized that the traditional cancer therapies reduce tumor bulk, but the inability to completely eradicate BCSCs results in the failure of complete remission [54,56,57]. …”

“…Although numerous factors contribute to the characteristics of BCSCs, autophagy has been linked to BCSCs survival and resistance to therapy [57]. Previously, breast tumors injected with serum-deprived mesenchymal stem cells have demonstrated higher cellularity and decreased apoptosis, with increased levels of autophagic activity in the surrounding areas [59].…”