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.
The mechanisms that underlie tumor formation and progression have not been elucidated in detail in cancer biology. Recently, the identification of a tumor cell subset defined as cancer stem cells (CSCs), which is enriched for tumor initiating capacity, has engendered new perspectives towards selective targeting of tumors. In this study, we isolated the side population (SP) cells which share characteristics of CSCs from bladder cancer cell lines, T24 and UM-UC-3 by fluorescence activated cell sorting. The cells were cultured in serum free medium and expression profile of stem cell like markers (SOX-2, NANOG, KLF-4 and OCT-4), drug resistant genes (ABCG2 and MDR1) and spheroid forming capability were examined in SP, non-side population (NSP) and bulk T24 and UM-UC-3 cells. We observed that SP cells possessed a higher mRNA expression of SOX-2, NANOG, KLF-4, OCT-4, ABCG2, and MDR1 as well as a higher spheroid forming ability as compared to other bulk cells or NSP cells. The SP cells had low ROS levels and high GSH/GSSG ratio which may contribute to radio-resistance. The SP cells also showed substantial resistance to gemcitabine, mitomycin and cisplatin compared with the NSP counterpart. A high autophagic flux was observed in the SP cells. Both pharmacological and siRNA mediated inhibition of autophagy potentiated the chemotherapeutic effects of gemcitabine, mitomycin and cisplatin in these cells. We concluded that the ABCG2 expressing SP cells show autophagy associated cell survival and may be a potent target for developing more effective treatment in bladder carcinoma to enhance patient survival.
Dental tissue is emerging as a promising source of stem cells especially in nerve regeneration mainly due to their neural origin and ease of harvest. We isolated dental stem cells from three sources, namely, dental pulp (DPSCs), dental follicle (DFSCs), and apical papilla (SCAP), and explored the efficacy of each towards neural differentiation in comparison to bone marrow-derived stem cells. The neural differentiation potential was assessed by expression of various neural markers and neurosphere assay. We observed that DPSCs were inherently predisposed towards neural lineage. To further delineate the paracrine cues responsible for the differences in neural differentiation potential, we harvested the conditioned secretome from each of the stem cell population and observed their effect on colony formation, neurite extension, and neural gene expression of IMR-32, a pre-neuroblastic cell line. We found that neural differentiation was significantly enhanced when IMR-32 cells were treated with secretome derived from DMSCs as compared to the same from BMSCs. Th1/Th2/Th17 cytokine array revealed DPSC secretome had higher expression of the cytokines like GCSF, IFNγ, and TGFβ that promote neural differentiation. Thus, we concluded that DPSCs may be the preferred source of cells for obtaining neural lineage among the four sources of stem cells. Our results also indicate that the DPSC-secreted factors may be responsible for their propensity towards neural differentiation. This study suggests that DPSCs and their secretomes can be a potentially lucrative source for cell-based and "cell-free" (secretome) therapy for neural disorders and injury.
Autophagy is related to urothelial carcinoma grade and regulated via the AMPK pathway for tumor cell survival. Autophagy inhibition leads to cancer cell death through an intrinsic apoptotic pathway. The potential application of autophagy inhibitors as an adjunct to chemotherapy for urothelial carcinoma must be explored.
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