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Review
. 2020 Feb 7;5(1):8.
doi: 10.1038/s41392-020-0110-5.

Targeting cancer stem cell pathways for cancer therapy

Liqun Yang #  1   2 , Pengfei Shi #  1   2 , Gaichao Zhao  1   2 , Jie Xu  1   2 , Wen Peng  1   2 , Jiayi Zhang  1   2 , Guanghui Zhang  1   2 , Xiaowen Wang  1   2 , Zhen Dong  1   2 , Fei Chen  3 , Hongjuan Cui  4   5
Affiliations
Review

Targeting cancer stem cell pathways for cancer therapy

Liqun Yang et al. Signal Transduct Target Ther. .

Abstract

Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Wnt/β-catenin pathway in cancer stem cells. The canonical Wnt/β-catenin pathway regulates the pluripotency of CSCs and determines the differentiation fate of CSCs. In the absence of Wnt signaling, β-catenin is bound to the Axin complex, which contains APC and GSK3β, and is phosphorylated, leading to ubiquitination and proteasomal degradation through the β-Trcp pathway. However, the complex (TAZ/YAP), the long noncoding RNA TIC1 and proteins (TRAP1 and TIAM1) regulate the β-Trcp pathway. In the presence of Wnt signaling, the binding of LRP5/6 and Fzd inhibits the activity of the Axin complex and the phosphorylation of β-catenin, which makes β-catenin enter the nucleus, and then bind to TEF/TCF to form a complex, which then recruits cofactors to initiate downstream gene expression. Some proteins (DKK2 (Dickkopf-related protein 2), DACT1, CDH11, GECG, PKM2, EZH2, CD44v6, MYC, and TERT), microRNAs (miR-1246, miR-9, miR-92a, miR-544a, and miR-483-5p), and long noncoding RNAs (lncR-β-catm and lncR-TCF7) regulate the activation of the Wnt/β-catenin pathway in CSCs
Fig. 2
Fig. 2
Hedgehog signaling pathway in cancer stem cells. The Hedgehog pathway plays a key role in stem maintenance, self-renewal, and regeneration of CSCs. The secreted Hh protein acts in a concentration- and time-dependent manner to initiate a series of cell responses, such as cell survival, proliferation, and differentiation. After receiving the Shh signal, the transmembrane protein receptor PTCH relieves the inhibition of the transmembrane protein SMO, which induces Gli1/2 to detach from SUFU and enter the nucleus to regulate downstream gene transcription. During activation of the Hh pathway, some proteins (IL-6, IL-27, Fbxl17 (F-box and leucine-rich repeat protein 17), PPKCI, RARα2, RUXN3, SCUBE2, HDAC6 (histone deacetylase 6), USP48, CK2α, WIP1, GALNT1, VASH2 (Vasohibin 2), BCL6, FOXC1 (forkhead box C1), and p65), microRNAs (miR-324-5p, miR-122, and miR-326), and the long noncoding RNA HDAC2 are involved in the Hedgehog pathway to affect CSC growth
Fig. 3
Fig. 3
NF-κB signaling pathway in cancer stem cells NF-κB proteins are involved in the dimerization of transcription factors, regulate gene expression, and affect various CSC biological processes, including inflammation, stress responses, growth, and development of CSCs. The main physiological function of NF-κB is the p50-p65 dimer. The active p50-p65 dimer is further activated by post-translational modification (phosphorylation, acetylation, or glycosylation) and transported into the nucleus, which induces the expression of target genes in combination with other transcription factors. Some proteins (CD44, CD146, TNFRSF19, Bmi-1, FOXP3, and SDF-1) and microRNAs (miR-221 and miR-222) directly regulate the NF-κB pathway. In addition, some proteins (PGE2, GIT-1 (G protein-coupled receptor kinase-interacting protein 1), C-C chemokine receptor 7 (CCR7), and TGF-β) and miR-491 indirectly affect the NF-κB pathway via the ERK and MAPK pathways in CSCs
Fig. 4
Fig. 4
The microenvironment of cancer stem cells. Proliferation, self-renewal, differentiation, metastasis, and tumorigenesis of CSCs in the CSC microenvironment. The CSC microenvironment is mainly composed of vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, and extracellular matrix. These cells in response to hypoxic stress and matrix induce growth factors and cytokines (such as IL-6 and VEGF) to regulate the growth of CSCs via Wnt, Notch, and other signaling pathways
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