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. 2012 Apr 9:4:7.
doi: 10.1186/2045-824X-4-7.

Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy

Jian-Wei Gu  1 , Paola Rizzo, Antonio Pannuti, Todd Golde, Barbara Osborne, Lucio Miele
Affiliations

Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy

Jian-Wei Gu et al. Vasc Cell. .

Abstract

Anti-angiogenesis agents and the identification of cancer stem-like cells (CSC) are opening new avenues for targeted cancer therapy. Recent evidence indicates that angiogenesis regulatory pathways and developmental pathways that control CSC fate are intimately connected, and that endothelial cells are a key component of the CSC niche. Numerous anti-angiogenic therapies developed so far target the VEGF pathway. However, VEGF-targeted therapy is hindered by clinical resistance and side effects, and new approaches are needed. One such approach may be direct targeting of tumor endothelial cell fate determination. Interfering with tumor endothelial cells growth and survival could inhibit not only angiogenesis but also the self-replication of CSC, which relies on signals from surrounding endothelial cells in the tumor microenvironment. The Notch pathway is central to controlling cell fate both during angiogenesis and in CSC from several tumors. A number of investigational Notch inhibitors are being developed. Understanding how Notch interacts with other factors that control endothelial cell functions and angiogenesis in cancers could pave the way to innovative therapeutic strategies that simultaneously target angiogenesis and CSC.

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Figures

Figure 1
Figure 1
A simplified diagram of canonical Notch signaling: A: membrane and cytoplasmic events. In ligand expressing cells, ligands are ubiquitinated (UQ) by E3 ligases Mindbomb and Neuralized, endocytosed and "activated". "Active" ligands bind Notch receptors, dissociating NEC from N™. The complex ligand- NEC is trans-endocytosed into the ligand-expressing cell, perhaps providing mechanical energy to separate NEC from N™. Some ligands expressed in cis can bind Notch on the same cell, causing cis-inhibition. Ligand-induced NEC separation unmasks the ADAM cleavage site (red), which is cleaved by ADAM10 or ADAM17, producing NEXT and a short peptide which is released. NEXT is cleaved by γ-secretase, at the membrane or during endocytosis, generating NIC. This process is facilitated by adaptor-associated kinase AAK1 [101] and may require mono-ubiquitination. The release of NIC from endosomes (or the selection of cleavage site by γ-secretase) may require endosome acidification (H+) by aquaporin Bib. The stability of NIC is regulated by factors such as Pin-1 prolyl isomerase and NLK kinase. Endocytosis can lead to ligand-independent Notch activation catalyzed by γ-secretase. In the absence of non-visual β-arrestin Kurz, Deltex may lead to Notch endocytosis and activation. The amount of Notch available at the membrane is controlled by many endocytosis-recycling mechanisms. Several E3 ligases (Itch, CBL, Nedd4, the Deltex-Kurz complex) can target Notch for degradation. The ESCRT complex and lgd in Drosophila (and presumably their homologues in mammals) control Notch degradation, and their loss causes accumulation of Notch in endosomes and ligand-independent activation. In actively dividing cells, Numb/ACBD3 asymmetrically partitions to one daughter cell, causing selective Notch degradation in it. GSI, monoclonal antibodies (mAbs) to Notch receptors and ligands and Notch decoy molecules have been used effectively in vivo to inhibit Notch signaling. B: nuclear events. NIC is transported to the nucleus, where it causes the dissociation of the co-repressor complex including SHARP, SKIP and several other proteins (CoR) from CSL. Notch, CSL and MAML form a tertiary complex which in turn recruites p300 and other coactivators (CoA) to the chromatin and forming the NTC that activates transcription. The NTC can form heterodimers on the chromatin with other NTCs or supramolecular complexes with other transcription factors, modulating the choice of genes regulated by Notch. Dominant negative (DN) MAML constructs or peptidomimetic agents have been used in vivo to inhibit Notch-mediated transcriptional activation (see reference 5 for review).
Figure 2
Figure 2
Selected cellular interactions within the CSC niche: Endothelial cells (EC) specialize into "tip" EC, which respond to VEGF-A signals by expressing DLL4 and activating Notch in "stalk" EC, where Notch prevents further branching. Notch-ligand interactions are represented by intercellular receptor-ligand pairs (see inset). Notch-ligand interactions can occur between tip EC and stalk EC, between CC and EC, between CSC and EC. Blood and lymphatic EC contribute to the CSC niche by providing trophic factors and ligand-Notch interactions. Non-stem cancer cells (CC) produce VEGF-A as well as numerous cytokines, including IL-8, IL-6, TNFα, MCP-1, TGF-β and RANTES. VEGF-A activates angiogenesis and has autocrine effects on cancer cells. Some cytokines (e.g., IL-8) act on EC directly, while others (e.g., IL-6, MCP-1) recruit pro-inflammatory Th17 cells. These are stimulated by IL-23 and produce IL-17, which stimulates angiogenesis. TAM produce cytokines (not shown) and VEGF-C. The latter activates VEGFR-3 in EC, stimulating Notch activity and inhibiting further branching in the context of lymphangiogenesis. Additional cells not shown in this diagram include fibroblasts, osteoclasts (in bone metastastases), bone marrow stromal cells, NK cells and others.
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