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Journal ArticleDOI

Wnt signalling in stem cells and cancer

14 Apr 2005-Nature (Nature Publishing Group)-Vol. 434, Iss: 7035, pp 843-850
TL;DR: Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
Abstract: The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
Citations
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Journal ArticleDOI
Hans Clevers1
03 Nov 2006-Cell
TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.

5,042 citations


Cites background from "Wnt signalling in stem cells and ca..."

  • ...(Right) Wnt signaling in hair follicles activates bulge stem cells, promotes entry into the hair lineage, and recruits the cells to the transit-amplifying matrix compartment. within the same structure, such as the hair follicle or the intestinal crypt (Reya and Clevers, 2005)....

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  • ...Loss-of-function mutations in Axin have also been found in hepatocellular carcinomas, whereas oncogenic β-catenin mutations occur in a wide variety of solid tumors (reviewed in Reya and Clevers, 2005)....

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  • ...A popular view equates Wnt signaling with maintenance or activation of stem cells (Reya and Clevers, 2005)....

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  • ...Inhibition of Wnt signaling by the transgenic expression of Dkk-1 in adult mice induces the complete loss of crypts, identifying Wnt as the dominant mitogen for crypt progenitor cells throughout life (reviewed in Reya and Clevers, 2005)....

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  • ...Committed progenitors arrest their cell cycle and differentiate when they reach the crypt-villus junction (reviewed in Reya and Clevers, 2005)....

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Journal ArticleDOI
25 Oct 2007-Nature
TL;DR: The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers, suggesting that it represents the stem cell of the small intestine and colon.
Abstract: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.

4,918 citations

Journal ArticleDOI
08 Jun 2012-Cell
TL;DR: An update of the core Wnt/β-catenin signaling pathway is provided, how its various components contribute to disease, and outstanding questions to be addressed in the future are discussed.

4,561 citations


Cites background from "Wnt signalling in stem cells and ca..."

  • ...Loss-of-function mutations in Axin have also been found in hepatocellular carcinomas, whereas oncogenic b-catenin mutations, first described in colon cancer and melanoma (Rubinfeld et al., 1997), occur in a wide variety of solid tumors (reviewed in Reya and Clevers, 2005)....

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Journal ArticleDOI
TL;DR: The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours.
Abstract: Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

3,289 citations

Journal ArticleDOI
01 Mar 2017-Oncogene
TL;DR: Current insights into novel components of Wnt pathways are reviewed and how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control are described.
Abstract: Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.

1,698 citations

References
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Journal ArticleDOI
01 Nov 2001-Nature
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Abstract: Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.

8,999 citations


"Wnt signalling in stem cells and ca..." refers background in this paper

  • ...There is growing evidence that signals such as Notch, Hedgehog and Wnt—pathways that control many developmental processes and are dysregulated in cancer—might regulate self-renewal of haematopoietic progenitors and stem cell...

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Journal ArticleDOI
18 Oct 1996-Cell
TL;DR: The authors are grateful to the members of their laboratories for their contributions to the reviewed studies and to F. Giardiello and S. Hamilton for photographs of colorectal lesions.

4,959 citations


"Wnt signalling in stem cells and ca..." refers background in this paper

  • ...Loss of APC also occurs in most sporadic colorectal cancer...

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Journal ArticleDOI
04 Sep 1998-Science
TL;DR: The c-MYC oncogene is identified as a target gene in this signaling pathway and shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c- MYC promoter.
Abstract: The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.

4,686 citations

Journal ArticleDOI
TL;DR: Counts of macroscopic splenic colonies were used to obtain an estimate of the radiation sensitivity of normal mouse bone marrow progenitor cells.
Abstract: Counts of macroscopic splenic colonies were used to obtain an estimate of the radiation sensitivity of normal mouse bone marrow progenitor cells. Reproduced from Radiation Research 1961(Feb); 14(2): 213-222 by copyright permission of the Radiation Research Society (www.radres.org).

4,451 citations

Journal ArticleDOI
21 Mar 1997-Science
TL;DR: Results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β- catenin.
Abstract: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.

3,859 citations