Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers - PubMed (original) (raw)

Review

Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers

Bryan D White et al. Gastroenterology. 2012 Feb.

Abstract

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in gastrointestinal cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic.

Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

No conflicts of interest exist.

Figures

Figure 1

Figure 1

Schematic illustrating the Wnt/β-catenin pathway. (A) In the absence of a Wnt signal, β-catenin is bound to E-Cadherin (E-CAD) at adherens junctions or is phosphorylated by a destruction complex comprised of the core proteins AXIN, APC (adenomatous polyposis coli), GSK3 (glycogen synthase kinase), and CK1 (casein kinase 1). N-terminal phosphorylated β-catenin is targeted for ubiquitination and subsequent proteasomal degradation, maintaining low levels of cystosolic and nuclear β-catenin. Expression of Wnt/β-catenin target genes via activation of TCF/LEF (T-cell factor/lymphoid enhancer factor) transcription factors is inhibited by the transcriptional repressor Groucho. (B) Wnt ligand initiates signaling through FZD (Frizzled) receptor and LRP (low-density lipoprotein receptor-related protein) co-receptor, activating and recruiting DVL (Dishevelled) and Axin to the membrane, thereby disrupting the destruction complex. Higher cytosolic levels of β-catenin result in its translocation into the nucleus, where it binds TCF/LEF transcription factors and displaces Groucho to trans-activate Wnt/β-catenin target gene expression.

Figure 2

Figure 2

Common mechanisms by which the Wnt/β-catenin pathway is dysregulated in cancer. (A) Loss-of-function mutations in APC (adenomatous polyposis coli) lead to a breakdown of the destruction complex, accumulation of β-catenin in the cytoplasm, translocation of β-catenin into the nucleus, and constitutive expression of Wnt/β-catenin-dependent genes. (B) Gain-of-function mutations in β-catenin, often occurring in exon 3, prevent its N-terminal phosphorylation thus averting its ubiquitination and degradation. (C) Overexpression of FZD (frizzled) receptors or WNT ligands can lead to increased activation of the pathway. (D) Underexpression of secreted inhibitors of the pathway (i.e., secreted frizzled-related proteins, sFRPs) can also lead to increased sensitivity to Wnt ligands and increased pathway activation.

Figure 3

Figure 3

Additional mechanisms by which Wnt/β-catenin signaling can be modulated in cancer. (A) In hepatocytes, β-catenin can be released from an additional membrane bound pool associated with the receptor C-MET. When engaged by HGF (hepatocyte growth factor), C-MET releases β-catenin into the cytoplasm with its eventual translocation into the nucleus. (B) Membrane-bound NOTCH1 can bind activated β-catenin and cause its lysosomal destruction, thereby inhibiting Wnt/β-catenin signaling. A decrease in NOTCH1 expression may therefore potentiate Wnt/β-catenin signaling in certain types of cancer. (C) Interactions with numerous proteins can modulate Wnt/β-catenin signaling at various levels in the pathway. SULF-1 (Sulfatase-1) can increase the efficiency of Wnt ligands by modulating their interactions with heparin sulfate proteoglycans in the extracellular environment. ATDC (Ataxia telangiectasia group D-complementing) protein can potentiate pathway activation through its interaction with DVL (Dishevelled). SMO (Smoothened) can increase Wnt/β-catenin signaling by an unknown mechanism. Undoubtedly, novel mechanisms will be uncovered to explain the complex context dependency of Wnt/β-catenin signaling.

Figure 4

Figure 4

Schematic illustrating numerous small molecules and biological compounds identified in the literature that inhibit Wnt/β-catenin signaling at various points in the pathway.

Similar articles

Cited by

References

    1. Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: from flies to human disease. J Invest Dermatol. 2009;129:1614–27. - PMC - PubMed
    1. Chien AJ, Moon RT. WNTS and WNT receptors as therapeutic tools and targets in human disease processes. Front Biosci. 2007;12:448–57. - PMC - PubMed
    1. Moon RT, Kohn AD, De Ferrari GV, et al. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5:691–701. - PubMed
    1. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Developmental cell. 2009;17:9–26. - PMC - PubMed
    1. Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009;10:468–77. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources