fig1

Figure 1. Mechanisms related to CSC and EMT involved in drug resistance in cancer described in this review. The CSC phenotype is a plastic state and can be adopted by most cancer cells. CSCs are slow-cycling or quiescent, and circumvent therapies targeting rapidly-dividing cells. CSCs exhibit increased activities of detoxifying proteins including ALDH and ABC transporters (P-gp, BCRP). CSCs maintain low levels of ROS by metabolic reprogramming and/or auto/mitophagy to protect from radio- and chemo-therapies. Hypoxia and Hifα are crucial regulators of metabolic reprogramming primarily by increasing flux to glycolysis and antioxidant production (e.g., GSH) and inducing autophagy. Hypoxia and Hifα are also emerging inducers of EMT/CSC phenotype, one of the mechanisms is via NF-κB signaling pathway activation (not shown in the figure). EMT is a crucial regulator of and tightly interconnected with CSC, their involvement in drug resistance may represent different manifestations of the EMT/CSC phenotype. Activation of diverse signaling pathways are involved in the induction of EMT/CSC phenotype, including developmental pathways (e.g., Wnt/β-catenin, Hh/Gli1, Notch), cell survival pathways (e.g., GFR), and EMT-related pathways (e.g., TGF-β/SMAD signaling). The above pathways act independently or cross talk with each other to induce EMT/CSC phenotypes, leading to elevated drug resistance by various mechanisms: (1) The activation of these pathways allows the maintenance of CSC properties, including enhanced drug resistance. (2) These pathways converge on EMT-TFs (e.g., Snail, Slug, Zeb, Twist, FOX, etc.) to alter the expression of EMT markers (e.g., increase in N-cadherin, vimentin; decrease in E-cadherin) and induce EMT; the downstream transcription factor of the above pathways, as well as EMT-TFs, can upregulate ABC transporters, leading to enhanced drug efflux. EMT-TFs also enhance stemness and anti-apoptotic signaling. (3) The activation of these pathways is associated with enhanced anti-apoptotic machinery and thereby promotes tumor cell survival. (4) Certain pathways and EMT-TFs like Zeb1 can enhance ATM and CHK1/2-mediated DNA-damage repair and promote resistance to genotoxic therapies. (5) Non-cancer cells such as CAFs and TAMs in the TME can also activate these signaling pathways by secreted proteins and thus promote drug resistance. CSC: Cancer stem cell; EMT: epithelial-mesenchymal transition; ALDH: aldehyde dehydrogenase; ABC transporters: ATP-binding cassette (ABC) transporters; P-gp: P-glycoprotein; BCRP: breast cancer resistance protein; ROS: reactive oxygen species; Hifα: hypoxia-inducible factors α; GSH: glutathione; NF-κB: nuclear factor-κB; Hh: Hedgehog; GFR: growth factor receptor; TGF-β: transforming growth factor-β; EMT-TFs: EMT-inducing transcriptional factors; Zeb: zinc finger E-box binding homeobox; FOX: forkhead box; ATM: ataxia telangiectasia mutated; CHK: checkpoint kinase; CAF: cancer-associated fibroblasts; TAM: tumor-associated macrophages; TME: tumor microenvironment.