Cutaneous cancer stem cell maintenance is dependent on β-catenin signaling

Ecole Polytechnique Fédérale de Lausanne/ISREC (Swiss Institute for Experimental Cancer Research) and National Center of Competence in Research Molecular Oncology, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Nature (Impact Factor: 42.35). 05/2008; 452(7187):650-3. DOI: 10.1038/nature06835
Source: PubMed

ABSTRACT Continuous turnover of epithelia is ensured by the extensive self-renewal capacity of tissue-specific stem cells. Similarly, epithelial tumour maintenance relies on cancer stem cells (CSCs), which co-opt stem cell properties. For most tumours, the cellular origin of these CSCs and regulatory pathways essential for sustaining stemness have not been identified. In murine skin, follicular morphogenesis is driven by bulge stem cells that specifically express CD34. Here we identify a population of cells in early epidermal tumours characterized by phenotypic and functional similarities to normal bulge skin stem cells. This population contains CSCs, which are the only cells with tumour initiation properties. Transplants derived from these CSCs preserve the hierarchical organization of the primary tumour. We describe beta-catenin signalling as being essential in sustaining the CSC phenotype. Ablation of the beta-catenin gene results in the loss of CSCs and complete tumour regression. In addition, we provide evidence for the involvement of increased beta-catenin signalling in malignant human squamous cell carcinomas. Because Wnt/beta-catenin signalling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate CSCs and consequently eradicate squamous cell carcinomas.

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Available from: Marcel Huber, Aug 20, 2015
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    • "In addition to the Ras/MAP kinase pathway, the Wnt/b-catenindependent signaling pathway plays an essential role in the development of skin papillomas in mice. The keratinocyte-specific (conditional) knockout of the Ctnnb1 b-catenin gene almost completely prevents papilloma development induced by DMBA/TPA, and the de-activation of the Wnt/b-catenin signaling pathway in pre-existing tumors leads to their complete regression (Malanchi et al., 2008). The same authors demonstrated that human squamous cell carcinomas often contain nuclearly localized b-catenin. "
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    • "Here, we report that mice with increased Wnt/b-catenin and attenuated Bmp signalling in Keratin 14-expressing tissues rapidly develop salivary gland SCC, from which we can enrich tumour propagating cells by FACS. The importance of canonical Wnt signalling in tumour propagating cells is known (Malanchi et al, 2008; Barker et al, 2009; Wend et al, 2010). We provide evidence that b-catenin activation leads to an induction and stabilization of MLL, and that b-catenin, CBP and MLL are required to trigger H3K4 tri-methylation at promoters of self-renewal genes in tumour propagating cells (summary scheme in Figure 7A). "
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    • "The cell proliferation marker, Ki67, was frequently expressed in the skin cancer cells, but the HA/Ptch positive cells (78–100%) were largely negative for Ki67 expression (Figure 6b), indicating that these cells are likely non-proliferative. We also performed co-staining of the known skin stem cell markers, Sox2, Pax6, or Cd34, with the HA/Ptch tag (Takahashi, 2008; Li, 2005; Malanchi et al., 2008). Some HA/Ptch positive cells showed co-staining with Sox2 and Pax6, but the pattern was essentially random (Figure 6c), and these cells were largely negative for Cd34 (Figure 6c). "
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