Wnt signaling in stem and cancer stem cells

doi:10.1016/j.ceb.2013.01.004

Current Opinion in Cell Biology

Volume 25, Issue 2, April 2013, Pages 254-264

https://doi.org/10.1016/j.ceb.2013.01.004 Get rights and content

The functional versatility of Wnt/β-catenin signaling can be seen by its ability to act in stem cells of the embryo and of the adult as well as in cancer stem cells. During embryogenesis, stem cells demonstrate a requirement for β-catenin in mediating the response to Wnt signaling for their maintenance and transition from a pluripotent state. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to specification of different tissues. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signaling in stem and progenitor cells is subverted in cancer cells to allow malignant progression. Intensive work is currently being performed to resolve how intrinsic and extrinsic factors that regulate Wnt/β-catenin signaling coordinate the stem and cancer stem cell states.

Section snippets

Introduction to the biology of canonical Wnt signaling: stem cell issues

Wnt signaling controls, in cooperation with half a dozen other signaling systems, embryonic development and tissue homeostasis in adult organisms. After Nusse and Varmus’ identification of the proto-oncogene integration-1 in 1982, int-1 turned out to be the mammalian homolog of the segment polarity gene in Drosophila, wingless (wg). ‘Wnt’ is thus a fusion of the terms ‘wg’ and ‘int’. In the 1990s, the basic components of Wnt signaling were discovered, and epistasis experiments placed them into

Wnt, new ligands and receptors: R-spondins and Lgrs

In 2011, the surprising finding was made that R-spondin growth factors bind to Leucine-rich repeat-containing G-protein-coupled receptors (Lgr) 4–6, a group of stem cell-associated cell surface receptors of fundamental importance, which control progenitor and stem cell maintenance (Figure 1a, upper part; [5••, 6••]). R-spondin/Lgr complexes and Wnt ligands directly interact with Frizzled (Fzd)-LRP-receptor complexes on target cells to activate downstream signaling. In 2012, the X-ray structure

The β-catenin destruction complex: new targets for cancer therapy

This complex plays a key role in the stability and transcriptional activity of β-catenin, which controls stem and cancer stem cells (Figure 1, middle, [1, 2]). Recently, it has been shown: (i) that the membrane-bound destruction complex is sequestered inside multi-vesicular bodies in a GSK3-dependent manner [12], and (ii) that stabilization of β-catenin results from of Wnt-mediated inhibition of ubiquitination [13], see also [14]. Tankyrase was introduced as an important new target for the

Wnt/β-catenin controls transcription: pluripotency genes and self-renewal

The way β-catenin fulfills stem cell-associated functions depends on its ability to interact with molecules that control nuclear translocation, co-activation, epigenetic modification, Lef/Tcf-dependent transcription and chromatin modifications (Figure 1; reviewed in [18]). Basler and colleagues generated knock-in mice, in which β-catenin was replaced by mutant forms that lack binding sites for co-factors, not impairing cell adhesion [19]. Using β-catenin double-mutant mice (one allele lacked

Modulation by ubiquitination and sumoylation: control of Wnt at all levels

Expression of the genes encoding the transmembrane E3 ubiquitin ligases ZNRF3 and RNF43, which induce endocytosis of Wnt receptors in stem cells in an R-spondin-sensitive manner and enhance Wnt signaling, is regulated by β-catenin [32, 33]. The stability of Axins is controlled by tankyrase-dependent poly-ADP-ribosylation and subsequent ubiquitination by the E3 ubiquitin ligase RNF146 [34••, 35••]. Moreover, sumoylation, phosphorylation or ubiquitin-specific proteases like USP34 oppose

Wnt and stemness in the embryonic system: an early snapshot into Wnt mechanisms

Nusse and colleagues have shown in mouse ESCs (mESCs) containing LIF that Wnt promotes self-renewal [38^••]. Inhibition of Wnt using soluble Frizzled (Fz8CRD) or the inhibitor IWP2, which interferes with Porcupine (Figure 1a, upper left), inhibits expansion of ESCs. ESCs lacking Porcupine fail to activate Wnt reporter activity [39]. Recently, groups have derived ESCs from β-catenin-floxed mouse embryos and induced gene ablation in culture [40••, 41••]. Smith and colleagues found that β-catenin

Stem and cancer stem cells in the nervous system: congenital disorders and neoplasms

Wnt/β-catenin signaling is fundamental to the development and function of the nervous system, and aberrations in the pathway lead to congenital disease or result in neural malignancies [47]. Wnt/β-catenin signaling maintains self-renewal of neural stem cells in the ventricular zones of the developing nervous system and in the neurogenic areas of the adult mammalian brain. Shh is required upstream of Wnt to control neural progenitor proliferation during development, and in the absence of Shh

Stem and cancer stem cells in the hematopoietic system: Wnt functions at many levels of the hierarchy

Hematopoietic stem cells undergo self-renewal as well as differentiating into mature cells of the myeloid and lymphoid lineages. The impact of Wnt/β-catenin signaling in HSCs is complex, since the levels of activation alter according to the developmental stage, Wnt protein dosage and the profile of factors in the local microenvironment [56]. Overall, Wnt/β-catenin signaling clearly plays a more essential role in HSC development rather than in the maintenance of fully developed HSCs. In mice

Wnt in stem cells of the skin: the Lgrs and cooperation with the mesenchyme

Mouse genetics and lineage tracing have emphasized the crucial role of Wnt/β-catenin in skin stem cells that form hair (reviewed in [61], [62]). Lgr5⁺/CD34⁻ proliferating stem cells isolated from the lower part of the hair follicles, when transplanted with fibroblasts into the back skin of mice, leads to their regeneration [63]. Lgr6⁺ cells that reside above the bulge area were characterized to represent the most primitive stem cells capable of generating all cell lineages of the skin (Table 1,

Wnt in the intestine: inter-convertible stem cells and stem cell therapy

All intestinal cell types are continuously renewed by stem cells, which in the small intestine are located in the lower parts of the crypts, the stem cell niches [68]. Two stem cell types have been identified in the crypts: (i) fast-cycling columnar-based stem cells (CBCs), which express the Wnt-controlled stem cell marker Lgr5 and are intercalated between the paneth cells at the bottom of the crypts, and (ii) quiescent stem cells, which express the stem cell marker Bmi1 located at position +4.

Stem and cancer stem cells in the mammary gland: Wnt acts at all stages of development and tumor formation

The mammary gland undergoes development postnatally, giving rise to ductal, basal/myoepithelial and alveolar components. Wnt signaling has been implicated in influencing mammary gland stem cell (MaSC) maintenance at different stages of development [3]. Wnt3a accelerates the formation of mammary gland placodes during embryogenesis, which depends on Lef1. Lrp5^−/− mice display aberrations in branching morphology, and Wnt4 plays an essential role in alveolar development during early pregnancy [79].

Wnt in stem and cancer stem cells in many other organs: reconstruction of development and disease with iPSCs

The specification of pluripotent embryonic cells into mesodermal progenitors and distinct cell types of the heart involves spatiotemporal control of epigenetic and transcriptional networks [85]. In the mouse, cardiac regeneration has been achieved through reprogramming fibroblasts residing in the heart with cardiogenic transcription factors: Gata4, Hand2, Mef2c and Tbx5 are sufficient to generate cardiac-like myocytes [86]. Canonical Wnt signaling controls the self-renewal of second heart field

Conclusions

In the last two years, new components of Wnt/β-catenin signaling have been linked to stem cell functions, for instance R-spondins, which activate Lgr5 stem cell receptors. Wnt signaling has been found to be important for driving self-renewal and differentiation, which are important mechanisms in many types of stem and cancer stem cells. Wnt signaling can also couple stem cells of the skin with their niches, basement membranes and mesenchymal stem cells. Remarkably, human intestinal stem cells

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We would like to thank Liang Fang, MDC Berlin, for generating pictures of X-ray structures. We would like to mention that owing to space constraints, we were not able to include all the relevant papers from the report period. WB is supported by grants from the Deutsche Krebshilfe (Mildred-Scheel-Stiftung) and the Deutsche Forschungs-Gemeinschaft (DFG). ANG is supported by a grant from the German Federal Ministry for Education and Research (National Genome Research Network, NGFNplus).

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Wnt signaling in stem and cancer stem cells

Section snippets

Introduction to the biology of canonical Wnt signaling: stem cell issues

Wnt, new ligands and receptors: R-spondins and Lgrs

The β-catenin destruction complex: new targets for cancer therapy

Wnt/β-catenin controls transcription: pluripotency genes and self-renewal

Modulation by ubiquitination and sumoylation: control of Wnt at all levels

Wnt and stemness in the embryonic system: an early snapshot into Wnt mechanisms

Stem and cancer stem cells in the nervous system: congenital disorders and neoplasms

Stem and cancer stem cells in the hematopoietic system: Wnt functions at many levels of the hierarchy

Wnt in stem cells of the skin: the Lgrs and cooperation with the mesenchyme

Wnt in the intestine: inter-convertible stem cells and stem cell therapy

Stem and cancer stem cells in the mammary gland: Wnt acts at all stages of development and tumor formation

Wnt in stem and cancer stem cells in many other organs: reconstruction of development and disease with iPSCs

Conclusions

References and recommended reading

Acknowledgements

Cell

Semin Cell Dev Biol

Science

Cell

Cancer Res

Proc Natl Acad Sci USA

Dev Cell

EMBO Rep

Gastroenterology

Cell Stem Cell

Cell Stem Cell

Nature

Nat Neurosci

Science

Nat Cell Biol

EMBO J

Nat Cell Biol

Nature

Nat Cell Biol

Breast Cancer Res

Nature

Nat Rev Urol

Nat Struct Biol

Nat Struct Biol

Wnt signalling and its impact on development and cancer

Nat Rev Cancer

Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling

Nature

R-spondins function as ligands of the orphan receptors lgr4 and lgr5 to regulate wnt/beta-catenin signaling

Proc Natl Acad Sci USA

Lgr5 homologues associate with wnt receptors and mediate r-spondin signalling

Nature

Structural basis of wnt recognition by frizzled

Science

Tiki1 is required for head formation via wnt cleavage-oxidation and inactivation

Cell

Crystal structures of the extracellular domain of lrp6 and its complex with dkk1

Nat Struct Mol Biol

Structural architecture and functional evolution of wnts

Dev Cell

Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes

Cell

Dishevelled interacts with the dix domain polymerization interface of axin to interfere with its function in down-regulating beta-catenin

Proc Natl Acad Sci USA

Phosphorylated beta-catenin localizes to centrosomes of neuronal progenitors and is required for cell polarity and neurogenesis in developing midbrain

Dev Biol

Beta-catenin hits chromatin: regulation of wnt target gene activation

Nat Rev Mol Cell Biol

Probing transcription-specific outputs of beta-catenin in vivo

Genes Dev

Foxm1 promotes beta-catenin nuclear localization and controls wnt target-gene expression and glioma tumorigenesis

Cancer Cell

Kindlin 2 forms a transcriptional complex with beta-catenin and tcf4 to enhance wnt signalling

EMBO Rep

An intrinsically labile alpha-helix abutting the bcl9-binding site of beta-catenin is required for its inhibition by carnosic acid

Nat Commun

Targeted disruption of the bcl9/beta-catenin complex inhibits oncogenic wnt signaling

Sci Transl Med

Pygo2 associates with mll2 histone methyltransferase and gcn5 histone acetyltransferase complexes to augment wnt target gene expression and breast cancer stem-like cell expansion

Mol Cell Biol

Histone h4 lys 20 monomethylation by histone methylase set8 mediates wnt target gene activation

Proc Natl Acad Sci USA

Linking h3k79 trimethylation to wnt signaling through a novel dot1-containing complex (dotcom)