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Review
. 2002 Feb;160(2):389-401.
doi: 10.1016/s0002-9440(10)64856-0.

Beta-catenin--a linchpin in colorectal carcinogenesis?

Newton Alexander Chiang Shuek Wong  1 , Massimo Pignatelli
Affiliations
Review

Beta-catenin--a linchpin in colorectal carcinogenesis?

Newton Alexander Chiang Shuek Wong et al. Am J Pathol. 2002 Feb.

Abstract

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.

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Figures

Figure 1.
Figure 1.
Summary of established β-catenin pathways. β-catenin may exist: 1) as part of the cell membrane-bound adherens complex with E-cadherin and α-catenin; 2) in the cytosol where binding with GSK-3β, APC, and AXIN promotes; 3) ubiquitination and, hence, degradation; or 4) in the nucleus where binding with a TCF leads to promotion of gene transcription. *, Recent data suggest an alternative pathway (involving Siah-1 protein) via which β-catenin may be _targeted for ubiquitination without GSK-3β-mediated phosphorylation. Molecules that bind to β-catenin are shown in bold. The Wnt-Frz-Dvl regulatory pathway is shown in italics. Black broken arrows represent the potential subcellular movements of β-catenin. Dvl, disheveled protein.
Figure 2.
Figure 2.
Sections of nonneoplastic colorectal mucosa (a and b) and colorectal carcinoma (c to f) immunostained for β-catenin (a, c, and e) and cyclin D1 (b, d, and f). The colorectal epithelial cells show strong membranous expression of β-catenin (a) and no detectable expression of cyclin D1 (b). The invasive edge of the carcinoma shows particularly prominent cytoplasmic and nuclear expression of β-catenin (c) and nuclear overexpression of cyclin D1 (d, arrows). Higher power views of the carcinoma show diffuse but heterogeneous nuclear expression of both proteins (e and f). The carcinoma cells also show prominent cytoplasmic β-catenin expression and loss of membranous expression (e). Scale bars: 150 μm (a and b); 600 μm (c and d); 75 μm (e and f).
Figure 3.
Figure 3.
Summary of regulators, effectors, and genetic aberrations of components of β-catenin pathways, which relate to colorectal carcinogenesis. Those preceded by “?” represent pathways or changes that have yet to be unequivocally demonstrated in colorectal carcinoma. HGF, hepatocyte growth factor; PKC-βΙΙ, protein kinase C-βΙΙ; TFF-3, trefoil factor 3.
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