Section 3.2.6: TGF/SMAD signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)

Navigation

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
https://doi.org/10.1038/s41392-020-0110-5

Section 3.2.6: TGF/SMAD signaling pathway in CSCs

The TGF-beta signaling pathway is involved in many cellular processes associated with organism and embryo development, including cell proliferation, differentiation, apoptosis, and homeostasis. Although the TGF-beta signaling pathway regulates a wide range of cellular processes, its structure is relatively simple. TGF-beta superfamily ligands bind to a type II receptor, which recruits a type I receptor and phosphorylates it. This type I receptor phosphorylates receptor-regulated Smads (R-Smads), which bind to common pathway Smad (co-Smad). The R-Smad/co-Smad complex acts as a transcription factor and accumulates in the nucleus to regulate the expression of target genes. TGF-beta superfamily ligands include BMPs, growth and differentiation factors (GDFs), anti-Mullerian hormone (AMH), activin Nodal, and TGF-beta. These ligands can be divided into two groups, TGF-beta/activin and BMP/GDF. The TGF-beta/activin group includes TGF-beta, activin, and Nodal, and the BMP/GDF group includes BMP, GDF, and AMH ligands. Based on Smad structure and functions, Smad proteins can be divided into three subfamilies: receptor-activated or pathway-restricted Smad (R-Smads), Co-Smad, and inhibitory Smad (I-Smads), which includes at least nine Smad proteins. R-Smads are activated by type I receptors and form transient complexes with these receptors. There are two types of Smad complexes: AR-Smads are activated by activin TGF-beta, including Smad2 and Smad3, and BR-Smads are activated by BMP, including Smad1, Smad5, Smad8, and Smad9. Co-Smad, including Smad4, is a common medium in various TGF-beta signal transduction processes. I-Smads, including Smad6 and Smad7, bind to activated type I receptors and inhibit or regulate signal transduction of the TGF-beta family.

Many studies have shown that activation of TGF/Smad signaling also occurs in human cancers. Dkk-3, a secreted protein, inhibits TGF-beta-induced expression of matrix metallopeptidase 9 (MMP9) and MMP13 to prevent migration and invasion of prostate cancer. Cancer upregulated gene 2 promotes cellular transformation and stemness, which is mediated by nuclear NPM1 protein and TGF-beta signaling in lung cancer. TGF/Smad also plays an important role in the cell proliferation of CSCs. Cyclin D1 interacts with and activates Smad2/3 and Smad4, promoting cyclin D1-Smad2/3-Smad4 signaling to regulate self-renewal of liver CSCs. CD51 binds to TGF-beta receptors to upregulate TGF-beta/Smad signaling in colorectal CSCs. Upregulation of TGF-beta1 induces the expression of smad4, p-Smad2/3, and CD133 in liver CSCs. TGF-beta1 also upregulates the expression of PFKFB3 through activation of the p38 MAPK and PI3K/Akt signaling pathways to regulate glycolysis in glioma stem cells. Furthermore, silencing ShcA expression also induces activation of STAT4 in breast CSCs. Moreover, miR-148a inhibits the TGF-beta/Smad2 signaling pathway in HCC stem cells. Smad7, a newly discovered target gene of miR-106b, is an inhibitor of TGF-beta/Smad signaling, which inhibits sphere formation of gastric cancer stem-like cells. Although there are few studies on the TGF/Smad signaling pathway in CSCs, this pathway still plays a very important role.