Review
Wnt signaling in stem and cancer stem cells

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Abstract

Canonical Wnt signaling supports the formation and maintenance of stem and cancer stem cells. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment how embryonic and tissue stem cells are generated and maintained, and how Wnt signaling might be involved. The core of this review highlights the roles of Wnt signaling in stem and cancer stem cells of tissues such as skin, intestine and mammary gland. Lastly, we refer to the characterization of novel and powerful inhibitors of canonical Wnt signaling and describe attempts to bring these compounds into preclinical and clinical studies.

Introduction

Stem cells have the unique capacity to either self-renew or to differentiate. Embryonic stem cells (ESC) are pluripotent and can form each of the cell lineages of our body [1]. Once differentiated, cells can recreate ESC by overexpression of four transcription factors: Oct4, Sox2, Klf4 and c-myc [2]. Adult tissue stem cells are termed multipotent since they can give rise to several cell types. For instance, Lgr6-expressing stem cells of the skin can form all lineages of the skin including epidermis, hair and glands [3]. Tissue stem cells are considered rare and are associated with particular stem cell niches [4]. Tumors also contain stem cells, the so-called cancer stem cells (CSC) or cancer-initiating cells. These may represent a fraction of the malignant tissue and have the potential to reconstitute the whole heterogeneity of the tumor following transplantation [5]. However, many reports are still contradictory, and for instance reach varying conclusions in regards to the proportion of CSC in tumors or the correlation between clinical outcome and stem cells status. Different researchers use different protocols to identify CSC, and some argue that CSC may not necessarily be rare, but that we still lack the appropriate tools to probe their capacities [6].

Over the last decade transcriptional programs of ‘stemness’ were identified. Based on several studies, module maps of genes whose expression was characteristic of particular stem cell types were generated [7]. An overlap in the gene expression program of human and mouse ESC, neural stem cells (NSC), fetal hematopoietic stem cells (HSC) and retinal stem cells was identified. This created a ‘signature’, including for instance the transcriptional regulators Sox2, c-myc, Dnmt1, or Hdac1. It was also possible to identify a cluster of genes expressed in bone marrow HSC, different NSC, as well as neural crest, hair bulge and mammary gland stem cells, yielding a signature that includes essential transcriptional regulators of differentiation including Hox, GATA, forkhead transcription factors or MLL histone methyltransferases. Apparently, two distinct classes of signatures exist, one of ESC-like and another of adult stem cells. Remarkably, the ESC-like gene expression signature is also reactivated in large collections of human cancers, e.g., breast and lung cancers [8]. It is striking that in keratinocytes, c-myc is capable of activating the ESC-module when it is transforming the cells into malignant tumor cells [7]. Moreover, the ESC-like signature was associated with poor tumor differentiation, with progress to metastasis and short survival of patients. In contrast, the adult tissue stem cell signature was repressed in the tumors.

Section snippets

Biology of canonical Wnt signaling

Wnt signaling is an ancient and highly conserved system that controls, together with half a dozen of other signaling pathways, embryonic development and tissue homeostasis [9], [10]. Most components of Wnt signaling and the mechanisms of signal transduction have been elucidated through genetic and biochemical experiments in model organisms and cell culture. After Nusse and Varmus’ identification of the proto-oncogene integration-1 [11], int-1 turned out to be the mammalian homolog of the

Insights into the interplay between Wnt/β-catenin signaling, epigenetic regulation and stemness

Activated Wnt/β-catenin signaling is a key feature of epithelial cancers and is perceived as critical for metastasis and epithelial–mesenchymal transitions (EMT). Since tumor cells that undergo EMT share characteristics with ESC [15], there is no surprise that activated Wnt signaling can be linked to stemness. The pertinent question is, how does Wnt/β-catenin signaling increase stemness? Since ESC follow an innate transcriptional program, the activity of various signaling systems and the

Stem and cancer stem cells in the skin

The epidermis forms the outermost layer of the mammalian skin. Within the basal layer of the epidermis reside the progenitor cells that constantly proliferate ensuring the renewal of the epithelium. In addition to these epidermal progenitors, the bulge that is attached to the hair follicles is an important niche for skin stem cells, which contributes to all epithelial cell types of the skin appendages, e.g., hair follicles and glands. Bulge stem cells express the stem cell marker CD34 and

Stem and cancer stem cells in the intestine

The intestine of vertebrates is essentially a tube with a luminal surface composed of a single cell-layered epithelium, which constitutes the most rapidly self-renewing adult tissue. Morphologically, the small intestinal epithelium is ordered into villi and crypts of Lieberkuehn. The latter represent the intestinal stem cell niche that ensures self-renewal through the maintenance of stem cells and transit amplifying cells, which give rise to all differentiated cell types, i.e. enterocytes,

Stem and cancer stem cells in the mammary gland

The mammary gland represents a complex secretory organ, which unlike other appendage in the body undergoes the major part of its development postnatally. The remarkable regenerative capacity and extensive tissue remodeling that occurs during development and reproductive estrous cycles authenticates the existence of mammary stem cells (MaSC). Transplantation assays demonstrated the existence of rare MaSC that can reconstitute an entire mammary gland [65]. The stem cell niche of the mammary gland

Inhibition of Wnt/β-catenin signaling and therapeutic perspectives

Mutations of the Wnt/β-catenin cascade provoke the development of cancer and other disease [10]. Therefore, targeting this signaling pathway harbors enormous therapeutic potential. A broad spectrum of compounds seems useful to specifically modulate Wnt/β-catenin signals at different levels, i.e. at the cell membrane, in the cytoplasm or in the nucleus (Fig. 1). Such drugs may also help to eliminate drug-resistant CSC, which are thought to be responsible for tumor relapse and metastasis [83].

A

Acknowledgements

P.W. was funded in part by the German Cancer Aid (Deutsche Krebshilfe). J.D.H. is funded in part by the 7th Framework Programme of the European Commission. U.Z. is funded by a Marie Curie Excellence Grant of the European Commission.

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