Section 3.2.9: Interactions between signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)

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Article	Targeting cancer stem cell pathways for cancer therapy (DOI: 10.1038/s41392-020-0110-5)
Sections in this Publication
Section	Section 1: Introduction (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 2: The concept of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 2.1: Biological characteristics of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 2.2: Isolation and identification of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3: Factors regulating CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.1: Major transcription factors in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2: Major signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.1: Wnt signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.2: Notch signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.3: Hh signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.4: NF-kappaB signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.5: JAK-STAT signaling pathway (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.6: TGF/SMAD signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.7PI3K/AKT/mTOR signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.8: PPAR signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.9: Interactions between signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3: The microenvironment of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.1: Vascular niche microenvironments and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.2: The hypoxia microenvironment and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.3: Tumor-associated macrophages and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.4: Cancer-associated fibroblasts and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.5: Cancer-associated MSCs and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.6: Extracellular matrix and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.7: Exosomes in the TME and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4: Therapeutic targeting of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.1: Agents targeting CSC-associated surface biomarkers in clinical trials (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.2: Agents targeting CSC-associated signaling pathways in clinical trials (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.3: Targeting the CSC microenvironment (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.4: CSC-directed immunotherapy (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 5: Conclusions and perspectives (from DOI: 10.1038/s41392-020-0110-5)
Section	Competing interests (from DOI: 10.1038/s41392-020-0110-5)
Section	Bibliography (from DOI: 10.1038/s41392-020-0110-5)
Named Entities in this Section

From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5

Section 3.2.9: Interactions between signaling pathways in CSCs

As mentioned previously, these complex signal transduction pathways are not linear. In some cases, crosstalk between and among various pathways occurs to regulate CSCs. Wnt/beta-catenin and NF-kappaB signaling work together to promote cell survival and proliferation of CSCs. TNFRSF19, a member of the TNF receptor superfamily, is regulated in a beta-catenin-dependent manner, but its receptor molecules activate NF-kappaB signaling to regulate the development of colorectal cancer. Knockdown of CD146 results in inhibition of NF-kappaB/p65-initiated GSK3beta expression, which promotes nuclear translocation and activation of beta-catenin. In addition, there is negative regulation between Wnt/beta-catenin and NF-kappaB signaling. Studies have revealed a negative effect of beta-catenin on NF-kappaB activity in liver, breast, and colon cancer cells. Leucine zipper tumor suppressor 2 (LZTS2) is a putative tumor suppressor, and NF-kappaB activation inhibits beta-catenin/TCF activity through upregulation of LZTS2 in liver, colon, and breast cancer cells. Wnt/beta-catenin and Hh signaling have important functions in embryogenesis, stem cell maintenance, and tumorigenesis. Wnt/beta-catenin signaling induces the expression of CRD-BP, an RNA-binding protein, which results in the binding and stabilization of Gli1 mRNA, leading to an increase in Gli1 expression and transcriptional activity, which promotes the survival and proliferation of colorectal CSCs. However, a report showed that noncanonical Hh signaling is a positive regulator of Wnt signaling in colon CSCs.

In addition, crosstalk between pathways promotes cell growth and metastasis through maintenance of the CSC population. Downregulation of Notch1 and IKKalpha enhances NF-kappaB activation to promote the CD133+ cell population in melanoma CSCs. IL-6/JAK/STAT3 and TGF-beta/Smad signaling induce the proliferation and metastasis of lung CSCs. IL-17E binding to IL-17RB activates the NF-kappaB and JAK/STAT3 pathways to promote proliferation and sustain self-renewal of CSCs in HCC. TGF-beta1 silencing decreases the expression of Smad2/3, beta-catenin, and cleaved-Notch1 to inhibit the activation of Wnt and Notch signaling in liver CSCs. Activation of TGF-beta1 induces lncRNA NKILA expression to block NF-kappaB signaling, which inhibits metastasis of breast CSCs. TGF-beta also directly regulates the expression of Wnt5a in breast CSCs to limit the stem cell population. Furthermore, Notch, IKK/NF-kappaB, and other pathways together regulate the proliferation and metastasis of CD133+ cutaneous SCC stem cells. PI3K/mTOR signaling upregulates the expression of STAT3 to promote the survival and proliferation of breast CSCs. Inhibition of TORC1/2 increases FGF1 and Notch1 expression. The PI3K/AKT/mTOR and Sonic Hh pathways cooperate to inhibit the growth of pancreatic CSCs. Increasing evidence shows that crosstalk regulates the survival, self-renewal, and metastasis of CSCs.