Autophagy, cancer stem cells and drug resistance

Abstract

Autophagy is a cellular survival mechanism that is induced by cancer therapy, among other stresses, and frequently contributes to cancer cell survival during long periods of dormancy and the eventual outgrowth of metastatic disease. Autophagy degrades large cellular structures that, once broken down, contribute to cellular survival through the recycling of their constituent metabolites. However, the extent to which this fuel function of autophagy is key to its role in promoting stemness, dormancy and drug resistance remains to be determined. Other roles for autophagy in determining cell fate more directly through targeted degradation of key transcription factors, such as p53 and FoxO3A, or by enforcing a reversible quiescent growth arrest, are discussed in this review. This review also highlights the need to parse out the roles of different forms of selective autophagy in stemness, CD44 expression and dormancy that, for example, are increasingly being attributed explicitly to mitophagy. The clinical relevance of this work and how an increased understanding of functions of autophagy in stemness, dormancy and drug resistance could be manipulated for increased therapeutic benefit, including eliminating minimal residual disease and preventing metastasis, are discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: CD44; FoxO3A; autophagy; dormancy; drug resistance; mitochondria; quiescence; stem cells.

Figure 1.

Multifaceted roles of autophagy in cancer. Autophagy is a catabolic process by which cells degrade large cellular cargoes, such as organelles, ribosomes and intracellular pathogens that are captured inside double-membraned autophagosomes before fusing with the lysosome and resultant constituent metabolites (amino acids, nucleotides, fatty acids) released to the cytsosol for reuse in biosynthetic processes and cell growth. This fuel function of autophagy is important in terms of promoting tumor cell survival at many stages in tumorigenesis. Autophagy also performs an organelle quality control function as part of cellular homeostasis that is important in both normal and tumor cells. As cells progress to becoming invasive, autophagy plays a role in promoting cell migration through focal adhesion disassembly and secretion of pro-migratory cytokines, such as IL-6. Autophagy also plays a role in the tumor microenvironment in modulating recruitment and response of T cells to the tumor and providing tumor cells with nutrients via amino acid transfer from cancer-associated fibroblasts to the tumor. Finally, emerging data have identified a role for autophagy in maintaining CSCs and tumor dormancy, both of which may play into drug resistance of cancers, minimal residual disease and metastatic latency.

Figure 2.

Autophagy in CSCs. (A) Autophagy plays an important role in maintaining both normal tissue stem cells and CSCs. The survival and quiescence of normal tissue stem cells appears dependent on autophagy and autophagy has also been reported to promote pluripotency. In CSCs, autophagy promotes expression of stem cell markers such as CD44 as well as expression of mesenchymal markers such as vimentin. Autophagy also promotes spheroid formation, in vivo tumorigenesis and drug resistance consistent with a critical role in maintaining CSCs. Inhibition of autophagy limits tumor dormancy and promotes outgrowth of metastases. (B) Key transcription factors have been linked to the induction of autophagy and the stem cell state, including FOXO3A, which induces expression of autophagy genes in stem cells and is itself turned over by autophagy. Also, SOX2 and STAT3 have been shown to modulate autophagy genes and to determine the stemness of CSCs.

Figure 3.

Mitophagy promotes stemness. Mitophagy is a selective form of autophagy in which mitochondria are specifically targeted for degradation at the autophagosome. Recently, mitophagy has been specifically implicated in maintaining the stem cell state by promoting turnover of mitochondria and limiting the capacity of the stem cell for oxidative phosphorylation and making stem cells more dependent on glycolysis for energy demands. This has also been proposed to contribute to the quiescent state of stem cells. Inhibition of mitophagy suppressed CD44 expression and also promoted translocation of p53 to the nucleus, where it has been reported to antagonize expression of stem cell genes.

Figure 4.

Autophagy promotes cancer drug resistance. (A) Autophagy is induced in tumors by many different cancer therapeutic approaches, including irradiation, inhibition of PI3K, AKT or mTOR, as well as other conventional and targeted therapies. As a result of autophagy induction, tumor cells are more resistant to apoptosis, with an interesting mechanism revealed recently showing targeted turnover of FOXO3A by autophagy to prevent FOXO3A-dependent induction of Puma, a BH3-only pro-apoptotic protein [119]. Autophagy may also promote drug resistance by promoting selection for a CSC phenotype, as has been suggested by work in breast cancer [117] and glioblastoma [118]. (B) CQ and its derivatives are the mainstay of efforts to inhibit autophagy in a clinical setting and this has seen some efficacy in combination with conventional therapies for some cancers and drug combinations. Clinical trials with the combination of CQ and mTOR inhibitors are ongoing and there is particular interest in testing DQ661, which has the dual activity of inhibiting autophagy and mTOR at the lysosome. New generation autophagy inhibitors include small molecules targeted at catalytic components of autophagosome biogenesis, including ULK1, VPS34 and ATG4B.