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: 41.46). 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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    • "Despite controversial results being reported (McQueen et al 2011), our previous studies, conducted on osteosarcoma tissue sections and bulk cell lines, demonstrated that the Wnt/β-catenin signaling is generally inactivated in osteosarcoma (Cai et al 2010). However, here we report that the Wnt/β-catenin pathway is specifically activated in the subset of osteosarcoma CSCs and not in their parental cells, suggesting that it can play an important role on the self-renewal of stem-like cell populations, as previously reported (Mao et al 2014; Malanchi et al 2008). The discrepancy between nuclear β-catenin, TCF/LEF activity and AXIN2 expression observed in SJSA-1 spheres maybe be explained by the fact that this cell line showed the highest constitutive expression of Sox2 (Fig. 2B). "
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    ABSTRACT: Osteosarcoma is a bone tumor displaying significant cellular and histological heterogeneity and a complex genetic phenotype. Although multiple studies strongly suggest the presence of cancer stem cells in osteosarcoma a consensus on their characterization is still missing. We used a combination of functional assays (sphere-forming, Aldefluor and side-population) for identification of cancer stem cell populations in osteosarcoma cell lines. Expression of stemness-related transcription factors, quiescent nature, in vivo tumorigenicity and Wnt/β-catenin activation were evaluated. We show that different cancer stem cell populations may co-exist in osteosarcoma cell lines exhibiting distinct functional properties. Osteosarcoma spheres are slowly-proliferating populations, overexpress SOX2 and KLF4 stemness-related genes and have enhanced tumorigenic potential. Additionally, spheres show specific activation of Wnt/β-catenin signaling as evidenced by increased nuclear β-catenin, TCF/LEF activity and AXIN2 expression, in a subset of the cell lines. Aldefluor-positive populations were detected in all osteosarcoma cell lines and overexpress SOX2, but not KLF4. The side-population phenotype is correlated with ABCG2 drug-efflux transporter expression. Distinct functional methods seem to identify cancer stem cells with dissimilar characteristics. Intrinsic heterogeneity may exist within osteosarcoma cancer stem cells and can have implications on the design of targeted therapies aiming to eradicate these cells within tumors.
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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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    ABSTRACT: The Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission of the Deutsche Forschungsgemeinschaft) evaluates chemical substances using scientific criteria to prevent adverse effects on health at the work place. As part of this task there is a need to evaluate tumor promoting activity of chemicals (enhancement of formation of squamous cell carcinomas via premalignant papillomas) obtained from two-stage initiation/promotion experiments using the mouse skin model. In the present communication we address this issue by comparing responses seen in mouse skin with those in humans. We conclude that tumor promotional effects seen in such animal models be carefully analyzed on a case by case basis. Substances that elicit a rather non-specific effect that is restricted to the high dose range are considered to be irrelevant to humans and thus do not require classification as carcinogens. In contrast, substances that might have both a mode of action and a potency similar to the specific effects seen with TPA (12-O-tetradecanoylphorbol-13-acetate), the prototype tumor promoter in mouse skin, which triggers receptor-mediated signal cascades in the very low dose range, have to be classified in a category for carcinogens. Copyright © 2015. Published by Elsevier Inc.
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    • "Insights into the identity, behavior, and needs of cancer cells that have the capacity to initiate metastasis are coming from three fronts. First, the existence of CSCs originally described in tumors of hematopoietic origin (Bonnet and Dick, 1997; Lapidot et al., 1994) has now been established in many solid tumors including those arising in the brain (Chen et al., 2012; Singh et al., 2004), colon (Dalerba et al., 2007; Merlos-Suá rez et al., 2011; O'Brien et al., 2007; Ricci-Vitiani et al., 2007; Schepers et al., 2012), breast (Al-Hajj et al., 2003; Mani et al., 2008; Pece et al., 2010), skin (Driessens et al., 2012; Malanchi et al., 2008), prostate (Wang et al., 2009), and pancreas (Hermann et al., 2007; Li et al., 2007a). These findings have pushed the debate on the nature of cancer stem cells from conjecture to more concretion, though many questions remain. "
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