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Importance of the Niche: Wnt Signaling and Stem Cell Plasticity in Intestinal Homeostasis and Disease

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Molecular Pathogenesis of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer deaths in the Western world. Its molecular pathology is well characterized and has taught us much about the normal physiology of the tissue that lines the gut lumen and gives rise to tumours. Central to our understanding of what drives cancer in this tissue was the discovery that mutations in the adenomatous polyposis coli gene (APC) are common to most tumours and that both familial and sporadic cancers in gut tissue are driven by mutations in APC (Su et al. 1992; Moser et al. 1992). A key function that explained the high penetrance of APC mutations in this tissue is its role in mediating signalling by Wnt (Polakis 1999). Specifically important is the ability of APC to act as a scaffold in assembling a protein complex that regulates the availability of β-catenin, which in turn regulates the activity of transcription factors that drive the expression of genes important for proliferation and differentiation (Rubinfeld et al. 1996; Polakis 2007). Signalling by Wnt has emerged not only as a key factor in driving the initiation of CRC but is also as a crucial regulator of normal tissue maintenance in the gut epithelium (Polakis 2007; Bejsovec 1999; Muncan et al. 2006). In particular, it plays an important role in specifying cell fate in this highly dynamic tissue. The APC protein is involved in many other functions that include regulation of cytoskeletal proteins to affect migration (Näthke et al. 1996; Kroboth et al. 2007), contribution to apoptosis (Steigerwald et al. 2005; Brocardo et al. 2008), nuclear import (Murawala et al. 2009), and mitotic spindles and related checkpoints (Dikovskaya et al. 2004, 2007; Draviam et al. 2006). In the background of the increased proliferation and decreased differentiation that accompanies mutations of APC, loss of the normal execution of these additional functions renders cells particularly prone to accumulate additional mutations that confer a significant survival advantage to APC mutant cells in gut epithelial tissue (McCartney and Näthke 2008).

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Authors and Affiliations

  1. Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK

    Owen J. Sansom

  2. Division of Cell and Developmental Biology, University of Dundee, Dow Street, Dundee, DD1 5EH, UK

    Inke Näthke

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Correspondence to Owen J. Sansom or Inke Näthke .

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  1. Molecular Pathology Unit, Harvard Medical School, Charlestown, Massachusetts, USA

    Kevin M. Haigis, Ph.D.

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Sansom, O.J., Näthke, I. (2013). Importance of the Niche: Wnt Signaling and Stem Cell Plasticity in Intestinal Homeostasis and Disease. In: Haigis, Ph.D., K. (eds) Molecular Pathogenesis of Colorectal Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8412-7_4

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