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. 2011 Mar 17:10:5.
doi: 10.4103/1477-3163.78111.

Wnt signaling and colon carcinogenesis: beyond APC

Rani Najdi  1 , Randall F Holcombe, Marian L Waterman
Affiliations

Wnt signaling and colon carcinogenesis: beyond APC

Rani Najdi et al. J Carcinog. .

Abstract

Activation of the Wnt signaling pathway via mutation of the adenomatous polyposis coli gene (APC) is a critical event in the development of colon cancer. For colon carcinogenesis, however, constitutive signaling through the canonical Wnt pathway is not a singular event. Here we review how canonical Wnt signaling is modulated by intracellular LEF/TCF composition and location, the action of different Wnt ligands, and the secretion of Wnt inhibitory molecules. We also review the contributions of non-canonical Wnt signaling and other distinct pathways in the tumor micro environment that cross-talk to the canonical Wnt pathway and thereby influence colon cancer progression. These 'non-APC' aspects of Wnt signaling are considered in relation to the development of potential agents for the treatment of patients with colon cancer. Regulatory pathways that influence Wnt signaling highlight how it might be possible to design therapies that target a network of signals beyond that of APC and β-catenin.

Keywords: Adenomatous polyposis coli gene; Wnt signaling; colon carcinogenesis.

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Figures

Figure 1
Figure 1
Pathways that modulate canonical Wnt signaling. Canonical Wnt signaling requires Frizzled (Fz) receptors and a LRP5/6 co-receptor. This signal induces stabilization of β-catenin through Dishevelled (Dvl)-mediated inhibition of the destruction complex. Stabilized β-cateninaccumulates in the nucleus where TCFs recruits it and associated co-regulators BCL9 and Pygopus (Pygo) to Wnt target genes for regulation. Tankyrase is an enzyme recently discovered to inactivate the destruction complex through ADP PARsylation of Axin. Secreted inhibitors such as DKK-1, DKK-2, and DKK-3 prevent canonical signaling through negative actions on LRP5/6. Secreted inhibitors such as the SFRPs inhibit all types of Wnt signaling by direct binding to Wnt ligands (WIF and others not shown). Wnt ligands are present in the tumor microenvironment through production by cancer cells and infiltrating lymphocytes and macrophages (green cells),which release Wnt 5a. Non-canonical types of Wnt signaling do not involve LRP5/6 co-receptors, and they trigger multiple kinase cascades, including those that involve calcium/calmodulin-dependent kinase II (CaMKII), protein kinase C (PKC), and others (c-Jun-N-terminal kinase and the planar cell polarity pathway not shown). Activation of these signals can inhibit the actions of LEF/TCFs, including the nuclear export of TCF-1, even in colon cancer cells where the destruction complex is nonfunctional and high levels of β-catenin are constitutively available. Other signals released in the tumor microenvironment (i.e.,stromal fibroblasts, brown cells) activate pathways that enhance Wnt target gene regulation. Pathways relevant to colon cancer include signaling through receptor tyrosine kinases (RTK) for epidermal growth factor (EGF) and hepatocyte growth factor/scatter factor (HGF), or through integrin receptors to growth factor receptor-bound protein-2 (Grb2). RTK and integrin signaling activates K-RAS, a GTPase often detected as a mutation-activated oncogene in colon tumors and a pathway that stimulates the formation of the transcription factor activator protein-1 (AP-1).
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