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论文范文
1. Introduction Cancer stem cells (CSCs) are a small subset of cancer cells with the capability of self-renewal and differentiation into heterogeneous tumor cells, and they have been believed to be responsible for tumor initiation, growth, and recurrence. The first population of CSCs was identified in human acute myeloid leukemia (AML), where they displayed strong tumorigenic ability in an in vivo mouse model [1, 2]. Subsequently, many laboratories across the globe have been able to capture and propagate CSCs from a variety of human tumors including brain cancer, melanoma and breast cancer, liver cancer, pancreatic cancer, colon cancer, and prostate cancer [3–9]. As CSCs can survive traditional cancer therapies and result in tumor recurrence and drug resistance [10–12], eradication of CSCs in tumors may represent an effective anticancer therapeutic strategy. Towards this goal, significant efforts have been made to explore the signaling mechanisms underlying CSCs’ self-renewal and differentiation, as well as development of regimens targeting the CSCs. In this review, we focus on three key evolutionarily conserved CSC signaling pathways (Wnt, Hedgehog, and Notch pathways) and therapeutic strategies disrupting CSCs’ stemness and functions by modulating these pathways. 2. Signaling Pathways in CSCs In the past, multiple CSC models have been proposed for tumor heterogeneity including the classical CSC unidirectional differentiation model and the plastic CSC bidirectional dedifferentiation model [13, 14] (Figure 1). In the classical CSC unidirectional differentiation model, CSCs differentiate to non-CSC tumor cells that are unable to move back up the hierarchy to acquire CSC-like activity; however, in the plastic CSC bidirectional dedifferentiation model, non-CSC tumor cells can undergo a dedifferentiation process and acquire CSC-like properties, presumably through epithelial-mesenchymal transition (EMT) in carcinoma [15–19]. Nevertheless, in either CSC model, Wnt, Hedgehog, and Notch pathways are considered important CSCs’ regulators. 2.1. Canonical Wnt Signaling Pathway Canonical Wnt pathway, in which Wnt ligands signal through β-catenin for their biological functions, is a critical evolutionarily conserved pathway in embryonic development and tissue homeostasis [20]. In the absence of Wnt ligands, the cytoplasmic β-catenin is phosphorylated for proteasome-dependent degradation by a “destruction complex” consisting of axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and casein kinase Iα (CKIα) [21]. However, in the presence of the Wnt ligands, the signaling is activated through the ligands binding to the seven-transmembrane receptor Frizzled (FZD) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6). FZD then recruits the intracellular protein dishevelled (Dvl), which subsequently sequesters Axin and GSK3β from the cytoplasm to the cellular membrane resulting in decomposition of the “destruction complex” [22]. Consequently, the active unphosphorylated β-catenin accumulates and translocates into the nucleus to regulate target gene expression (Figure 2(a)). 
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