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Review
. 2015 Jan 1;4(1):97-108.
doi: 10.1089/biores.2014.0035. eCollection 2015.

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

Rani Ojha  1 , Shalmoli Bhattacharyya  2 , Shrawan K Singh  1
Affiliations
Review

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

Rani Ojha et al. Biores Open Access. .

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.

Keywords: apoptosis; autophagy; cancer; cancer stem cells; resistance.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Conventional and proposed chemotherapeutic strategies in cancer treatment: Tumor cells are heterogeneous and include cancer stem cell (CSC) populations. Chemotherapy can reduce tumor burden by eliminating the highly proliferative cells, and relatively dormant cells or CSCs are spared. These chemotherapy-resistant cells can seed a new cancer by promoting tumor growth and metastasis. Thus, chemotherapy that also targets CSCs might be beneficial for preventing or inhibiting tumor regrowth or recurrence.
<b>FIG. 2.</b>
FIG. 2.
Schematic diagram of biogenesis of an autophagosome. Autophagy involves the degradation of cytosolic proteins and organelles in the lysosomes via double-membraned structures called autophagosomes which are formed from pre-autophagosomal structures (PASs) or isolated membrane. The membrane source involved in autophagosome biogenesis may involve contributions from endoplasmic reticulum, mitochondria, and plasma membrane. Atg13-ULK1 and Beclin-Vps34 complexes regulate the initiation of PAS formation. Two ubiquitin-like conjugation systems [Atg5–Atg12 conjugation and LC3–phosphatidyl ethanolamine (PE) conjugation] are involved in the elongation of PAS. The Atg5–Atg12 conjugation involves Atg7 (E1-like ubiquitin ligase) and Atg10 (E2-like ubiquitin ligase), while Atg7 and Atg3 act as the E1-like and E2-like, respectively, in LC3-PE conjugation. The Atg12–Atg5 is noncovalently conjugated to Atg16L1 (Atg12–Atg5.Atg16L1), resulting in an 800-kDa complex containing Atg12–Atg5. The Atg12–Atg5.Atg16L1 complex exhibits an E3-like ubiquitin ligase activity toward LC3–PE conjugation. Rab-GTPase and LAMP2 complex is involved in the fusion step of autophagy. After formation of autophagolysosomes, cytoplasmic material is degraded and transported to the cytosol wherein degraded biomolecules are used for the maintenance of cellular homeostasis.
<b>FIG. 3.</b>
FIG. 3.
Proposed model for the role of autophagy in cancer stem cells. Tumor consists of a heterogeneous cell population composed of clones from dividing tumor cells and a few tumor initiating cells or cancer stem cells (CSCs). Conventional therapies like radiotherapy and cytotoxic chemotherapy kill the dividing cells, but the tumor-initiating CSCs remain unaffected via autophagy-mediated cell survival mechanism. Therefore, targeting autophagy in CSCs may help to overcome the resistance and relapse of tumor.
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