Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition

Figures & data

Figure 1 Schematic representation of Notch receptors (A) and Notch ligands (B) in mammals.

Notes: Mammals contain four Notch receptors (Notch-1–4) and five ligands (Jagged-1/2, homologous to Serrata in Drosophila) and DLL 1, 3, and 4 (homologous to Delta in Drosophila).
Abbreviations: ANK, ankyrin repeats; CR, cysteine-rich domain; DLL, Delta-like; DOS, Delta and OSM-11-like protein domain; DSL, Delta, Serrata, and LAG-2 domain; EGF, epidermal growth factor; LNR, cysteine-rich Lin 12-Notch repeats; P, PEST domain; R, RAM domain; TAD, transactivation domain; N^IC, Notch intracellular domain; N^EC, Notch extracellular domain; N™, Notch transmembrane domain.

Figure 2 Schematic representation of the activation of Notch in mammal cells.

Notes: The Notch receptor is activated by binding to a ligand presented by a neighboring cell. Endocytosis and membrane trafficking regulate ligand and receptor availability at the cell surface. Ligand endocytosis is also thought to generate mechanical force to promote a conformational change in the bound Notch receptor. This conformational change exposes the site in Notch for cleavage by ADAM metalloproteases. This Notch cleavage generates the membrane-anchored Notch extracellular truncation fragment, a substrate for the γ-secretase complex. γ-secretase then cleaves the Notch transmembrane domain to release the N^IC. γ-secretase cleavage can occur at the cell surface or in endosomal compartments, but cleavage at the membrane favors the production of a more stable form of N^IC. N^IC then enters the nucleus where it associates with the DNA-binding protein CSL. In the absence of N^IC, CSL may associate with ubiquitous corepressor proteins and histone to repress transcription of some target genes. Upon N^IC binding, allosteric changes may occur in CSL that facilitate displacement of transcriptional repressors. The transcriptional coactivator Mastermind-like protein 1 (MAML1) then recognizes the N^IC/CSL interface, and this triprotein complex recruits additional coactivators to activate transcription.
Abbreviations: ADAM, A disintegrin and metalloprotease; CSL, CBF-1-Suppressor of Hairless/Lag1 (also known as RBP-jκ); N^IC, Notch intracellular domain.

Figure 3 Role of Notch in tumor metastasis as an inducer of EMT.

Notes: Epithelial cells can undergo EMT with activation of embryonic programs of epithelial plasticity, including Notch. Aberrant expression of EMT markers N-cadherin, vimentin, platelet-derived growth factor-D, NF-κB, Notch-1, and ZEB 1 has been observed in metastatic lesions, together with high Notch receptor and ligand expression. Notch signaling is often and aberrantly activated by hypoxia that induces EMT during tumor progression. Thus, the hypoxic niche promotes EMT and self-renewal of breast CSCs, suggesting a critical role of Notch-induced EMT in tumor progression and metastasis.
Abbreviations: CSC, cancer stem-like cell; EMT, epithelial-to-mesenchymal transition; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ZEB, zinc finger E-box-binding homeobox; N^IC, Notch intracellular domain; MAML1, Mastermind-like protein 1; CSL, CBF-1-Suppressor of Hairless/Lag1 (also known as RBP-jκ).

Figure 4 Intercellular interaction between mesenchymal stem cells and breast cancer cells through Notch can activate EMT through N^IC, Hey, HES, and other activators. Mesenchymal stem cells modified with miR-126 release proangiogenic factors and induce expression of proangiogenic Notch ligand DLL 1, 3, 4 and Jagged-1/2 enhancing angiogenesis. Moreover, Notch signaling regulates the expression of CXCR4 in mesenchymal stem cells, modulating their migration.

Abbreviations: DLL, Delta-like; EMT, epithelial-to-mesenchymal transition; Notch-1^IC, Notch-1 intracellular domain; Jag, Jagged; HES, Hairy/Enhancer of Split; Hey, Hairy/enhancer-of-split related with YRPW motif-like protein.

Figure 5 Proposed model for the growth of breast cancer stem cells in the brain.

Notes: Interleukin (IL)-1β secreted from metastatic cancer stem cells upregulates Jagged-1 on the reactivated astrocytes, which in turn promote self-renewal of cancer stem cells through the Jagged-1–Notch axis. Metastatic breast tumor cells in the brain highly express IL-1β, which then activates surrounding astrocytes. This activation significantly augments the expression of Jagged-1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem cells significantly stimulated Notch signaling in cancer stem cells.