Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease

https://doi.org/10.1016/j.molmed.2005.09.008Get rights and content

Colorectal cancer is a major cause of death in the western world. Recent advances in treatment comprise variations on the classical themes of surgical resection combined with chemotherapy using cytotoxic drugs and radiation therapy. Because this therapy is only moderately successful, novel approaches to the treatment of colorectal cancer are required. Our rapidly increasing knowledge of molecular signalling pathways that are deregulated in colorectal cancer might provide a platform from which to develop new rational cancer therapies. Here, we give an update on the roles of the Wnt and Notch signalling pathways in the self renewal of the intestinal epithelium and the consequences of Wnt deregulation in colorectal cancer. We focus on the potential of recently identified small-molecule inhibitors of the Wnt pathway and γ-secretase inhibitors of the Notch pathway as novel colon cancer therapeutics.

Section snippets

Architecture and function of the gastrointestinal tract

The gastrointestinal tract, comprising the small intestine (anatomically and histologically distinguishable as duodenum, jejunum and ileum) and colon, is established during mid-to-late gestation (reviewed in [1]). It is a complex organ system in which a specialized epithelium performs its primary functions of digestion, absorption, protection and excretion. The epithelium of the small intestine is organized into finger-like villi and adjacent invaginations called crypts of Lieberkühn. These

The Wnt signalling pathway

The highly regulated Wnt signalling cascade plays a decisive role during embryonic patterning and cell-fate determination (reviewed in 3, 4, 5). The canonical Wnt pathway regulates, through a core set of evolutionarily highly conserved proteins, the ability of the multi-functional protein β-catenin to activate the transcription of specific target genes (Figure 2).

In the absence of Wnt signals, free cytoplasmic β-catenin is actively targeted for degradation. This is accomplished by two

Wnt signalling in the intestine

Current evidence indicates that the Wnt signalling pathway is the most dominant force in controlling epithelial physiology of the intestine. Several Wnts and Wnt receptors are expressed in the crypt of the intestine, as is the Tcf/Lef family member Tcf4 [21]. Moreover, nuclear β-catenin, the hallmark of active Wnt signalling, is observed in the crypts of the intestine [22]. In neonatal Tcf4 knockout mice, the entire crypt progenitor compartment is absent. This implies that the Wnt signalling

Wnt signalling in intestinal cancer

The high frequency with which gastrointestinal malignancies occur probably reflects this unprecedented rate of self-renewal. Almost invariably, intestinal tumours carry activating mutations in the Wnt pathway, which target the tumour suppressors APC or Axin2 or the oncogene β-catenin (reviewed in [29]). Allelic loss and somatic mutations of the APC tumour suppressor genes represent the most frequent molecular events in colorectal cancer (reviewed in [30]). APC was originally cloned as the gene

Intervention in the Wnt signaling pathway

The consistent presence of activating Wnt pathway mutations in colorectal cancer makes this pathway an attractive target for molecular intervention through the inhibition of β-catenin activity in the nucleus, either by preventing β-catenin accumulation or its interaction with Tcfs. The validity of this approach has been proven by in vitro studies. Disruption of the Tcf-4/β-catenin complex or deletion of the mutant β-catenin allele in colorectal cancer cell lines leads to G1 arrest regardless of

The Notch signalling pathway

Recent insights into the role of Notch signalling in intestinal development and cancer might provide a new and unexpected alternative targeted-drug strategy for the treatment of intestinal neoplastic diseases [38]. The Notch pathway plays a central role in developmental processes throughout the animal kingdom, typically controlling binary cell fate decisions (reviewed in 39, 40). The Notch genes encode single pass transmembrane receptors that interact with transmembrane ligands on adjacent

Notch signalling in the intestine

Multiple Notch pathway components are expressed in intestinal crypts 38, 49. Furthermore, several putative Notch target genes are implied in the control of intestinal homeostasis. For example, Hes1, a known Notch target gene, is expressed in intestinal crypts. Animals deficient in Hes1 die because of severe neurological abnormalities. The analysis of the developing fetal intestine of Hes1-/- mutant mice revealed a relative increase in mucosecreting and enteroendocrine cells at the expense of

Intervention in the Notch signalling pathway

Indirect support for the control of intestinal cell fate by the Notch signaling pathway also stems from the use of γ-secretase inhibitors. These γ-secretase inhibitors have been developed in an attempt to block the production of β-amyloid peptides and subsequent plaque formation in Alzheimer's disease patients (reviewed in [56]). Many γ-secretase inhibitors have been shown to inhibit Notch processing. Rodent (toxicological) studies with these inhibitors have revealed a dramatic increase in the

Concluding remarks and perspective

A wealth of evidence implicates the Wnt cascade as the major driving force behind the proliferative potential of adenomas and adenocarcinomas of the intestine. The consistent presence of activating mutations in the Wnt signalling pathway in colorectal cancer makes this pathway an attractive target for molecular intervention. Various different approaches have been tested, however, with limited success to date. Recent data indicate that active Notch signalling might play an equally important role

Acknowledgements

The authors thank Nick Barker, Marc Vooijs and Marielle van Gijn for critically reading this manuscript. We apologize to authors whose relevant work we did not refer to directly.

References (60)

  • M. Baron

    An overview of the Notch signalling pathway

    Semin. Cell Dev. Biol.

    (2003)
  • C.M. Blaumueller

    Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane

    Cell

    (1997)
  • T. Okajima

    Modulation of notch-ligand binding by protein O-Fucosyltransferase 1 and fringe

    J. Biol. Chem.

    (2003)
  • C. Brou

    A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE

    Mol. Cell

    (2000)
  • N. Schroder et al.

    Expression of Notch pathway components in fetal and adult mouse small intestine

    Gene Expr. Patterns

    (2002)
  • G.T. Wong

    Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation

    J. Biol. Chem.

    (2004)
  • G.H. Searfoss

    Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor

    J. Biol. Chem.

    (2003)
  • D.J. Roberts

    Molecular mechanisms of development of the gastrointestinal tract

    Dev. Dyn.

    (2000)
  • E. Batlle

    Signaling pathways in intestinal development and cancer

    Annu. Rev. Cell Dev. Biol.

    (2004)
  • C.Y. Logan et al.

    The Wnt signaling pathway in development and disease

    Annu. Rev. Cell Dev. Biol.

    (2004)
  • J. Behrens et al.

    The Wnt connection to tumorigenesis

    Int. J. Dev. Biol.

    (2004)
  • S. Amit

    Axin-mediated CKI phosphorylation of β-catenin at Ser 45: A molecular switch for the Wnt pathway

    Genes Dev.

    (2002)
  • M. Kitagawa

    An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin

    EMBO J.

    (1999)
  • J.T. Winston

    The SCF β-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro

    Genes Dev.

    (1999)
  • R.A. Cavallo

    Drosophila Tcf and Groucho interact to repress Wingless signalling activity

    Nature

    (1998)
  • J. Roose

    The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors

    Nature

    (1998)
  • K. Willert

    Wnt proteins are lipid-modified and can act as stem cell growth factors

    Nature

    (2003)
  • J. Behrens

    Functional interaction of β-catenin with the transcription factor LEF-1

    Nature

    (1996)
  • K.I. Takemaru et al.

    The transcriptional coactivator CBP interacts with β-catenin to activate gene expression

    J. Cell Biol.

    (2000)
  • N. Barker

    The chromatin remodelling factor Brg-1 interacts with β-catenin to promote target gene activation

    EMBO J.

    (2001)

    • Cited by (125)

    • Complex role of time delay in dynamical coordination of neural progenitor fate decisions mediated by Notch pathway

      2024, Chaos, Solitons and Fractals

    • Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression

      2024, International Review of Cell and Molecular Biology

    • The cross-talk of NOTCH and GSK-3 signaling in colon and other cancers

      2020, Biochimica et Biophysica Acta - Molecular Cell Research

    • Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells

      2017, Food and Chemical Toxicology

    • Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

      2017, Biochimica et Biophysica Acta - Molecular Cell Research

    • The Identifications and Clinical Implications of Cancer Stem Cells in Colorectal Cancer

      2017, Clinical Colorectal Cancer
    View all citing articles on Scopus
    View full text
    Copyright © 2005 Elsevier Ltd. All rights reserved.