Browse articles
REVIEW ARTICLE
J Carcinog2011,  10:5

Wnt signaling and colon carcinogenesis: Beyond APC


1 Department of Microbiology and Molecular Genetics, University of California, Irvine, USA
2 Tisch Cancer Institute, Mt. Sinai School of Medicine, New York, USA

Date of Submission25-Jan-2011
Date of Acceptance18-Feb-2011
Date of Web Publication17-Mar-2011

Correspondence Address:
Rani Najdi
Department of Microbiology and Molecular Genetics, University of California, Irvine
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1477-3163.78111

  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, colon carcinogenesis, Wnt signaling


How to cite this article:
Najdi R, Holcombe RF, Waterman ML. Wnt signaling and colon carcinogenesis: Beyond APC. J Carcinog 2011;10:5

How to cite this URL:
Najdi R, Holcombe RF, Waterman ML. Wnt signaling and colon carcinogenesis: Beyond APC. J Carcinog [serial online] 2011 [cited 2017 Oct 20];10:5. Available from: http://www.carcinogenesis.com/text.asp?2011/10/1/5/78111


  Background Top


Wnt ligands are a large family of highly conserved secreted proteins that are important for normal cell development. Wnts bind to receptors at the plasma membrane and initiate intracellular signaling cascades to control a wide variety of processes in embryonic development and adult homeostasis, including cell proliferation, cell polarity, and specification of cell fate. These effects are wide-ranging and powerful and they are also complex, there being multiple types of Wnt signals. Traditionally, Wnt signals have been classified into two types: canonical (β-catenin-dependent) and non-canonical (β-catenin-independent). This classification was based on the biological activity of Wnt overexpression in Xenopus embryos, where canonical Wnts (such as Wnts 1 and 3a) induced the formation of a secondary axis and non-canonical Wnts did not (e.g., Wnts 4, 5a, and 11). In fact, non-canonical Wnts directly suppressed the ability of canonical Wnts to induce a secondary axis. This initial characterization was functional and straight forward and it created a simple framework to classify ligands. Since then, however, the picture has become more complex. Wnt action is context dependent, there are multiple intracellular cascades that can be triggered, and some of these cascades are composed of a blend of canonical and non-canonical components. A review by van Amerongen and Nusse offers highlights of the complexities in Wnt signal transduction and discusses the limitations that come from simple classification into two linear pathways. [1] In this review we link some of these signaling complexities to a consideration of therapeutic strategies for colon cancer.

Canonical Wnts signal through the transcriptional co-activator β-catenin. In the absence of such ligands, cytoplasmic β-catenin is captured by a destruction complex composed of adenomatous polyposis coli (APC), glycogen synthase kinase 3-β (GSK-3β), Axin, and other components. Captured β-catenin is phosphorylated, ubiquitinated, and degraded, preventing its translocation to the nucleus and interaction with members of the LEF/TCF transcription factor family (LEF-1/LEF1, TCF-1/TCF7, TCF-3/TCF7L1, and TCF-4/TCF7L2). [2],[3] When canonical Wnt ligands are present, they bind to a receptor complex consisting of the seven-pass transmembrane protein Frizzled (Fz) and the single-pass LRP5/6 receptor (lipoprotein-related protein 5 or 6). Binding of these receptors recruits the scaffolding protein Dishevelled (Dvl), which leads to LRP5/6 phosphorylation and the recruitment of Axin and GSK-3β away from the destruction complex. Disruption of the destruction complex releases β-catenin and allows it to accumulate in the nucleus along with LEF/TCFs. As nuclear concentrations increase, LEF/TCFs recruit β-catenin to target genes and nucleate its associations with co-regulators Pygopus, BCL9/Legless, and transcription-activating complexes such as the CDK8 module of Mediator and TRRAP. [4],[5],[6],[7],[8],[9],[10] Therefore, the key characteristics of canonical signaling are the requirement for the LRP5/6 co-receptor to enable β-catenin accumulation and the involvement of LEF/TCF transcription factors.

Wnts that signal non-canonically eschew LRP co-receptors and β-catenin stabilization to activate intracellular kinases and regulate distinct β-catenin-independent pathways. These include the planar cell polarity (PCP) pathway and the Wnt/calcium pathway. First identified in Drosophila, the PCP pathway, which is mediated by Fz and Dvl, activates c-Jun-N-terminal kinase (JNK) and Rho-associated kinase (Rho-kinase) to control the orientation of hairs, bristles, and ommatidia in flies. Non-canonical Wnts binding to Fz can also stimulate an increase in intracellular Ca 2+ levels, thereby activating calcium-sensitive proteins such as Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC). Importantly, the Wnt/calcium pathway has been shown to antagonize β-catenin-dependent signaling and stimulate cell migration. [11],[12] Even though these pathways are very different from canonical signaling, it has been suggested that the classification of Wnt ligands as either canonical or non-canonical is too simple. Recent reports show that Wnts can signal through both types of pathways, with opposing outcomes; it all depends on the receptor context. [13] The best studied example is Wnt5a, a ligand family member traditionally considered to activate non-canonical signaling. Wnt5a inhibits β-catenin-dependent activity when its signal is mediated by the orphan tyrosine kinase Ror2. [14] But when Wnt5a signals through the co-receptors Fz4 and LRP5, it activates β-catenin-dependent signaling. More recently, Wnt5a has been shown to heterodimerize with another Wnt to direct β-catenin outcomes. Wnt5a heterodimerizes with the non-canonical Wnt11 ligand to upregulate canonical Wnt signaling in Xenopus embryos. [15] If this important discovery applies to all Wnt ligands, that is, if the entire family can engage in heterodimer formation, then signaling potential and outcomes of any one Wnt are even more influenced by the context of other Wnt ligands and receptors in cells.


  Role of Wnt Signaling in Development, Differentiation, and Carcinogenesis Top


Wnt signaling plays a critical role in embryonic development. Wnts direct programs of proliferation, stem cell self-renewal, cell fate decisions, cell polarity, and convergent extension behaviors of migrating cells. [3],[4],[11],[16] Each of these Wnt-directed outcomes are critical for proper development of the intestine.[17] For example, the now classic knockout experiments by the Clevers laboratory showed that loss of the TCF7L2 locus (TCF-4) depletes stem cell compartments in the intestines of mouse embryos because cells are unable to proliferate and repopulate crypts. [18] Stem cell self-renewal also relies on Wnt signaling. This is true in the Drosophila gut and, recently, it has been shown to be true in the mammalian gut. [19],[20] The Wnt target gene, LGR5, has been identified as the multipotent stem cell marker in crypts. Other Wnt target genes such as ASCL2, SOX9, Paneth cell defensins, and others control additional steps of differentiation from the stem cell through to the terminally differentiated phenotype. [17],[21],[22],[23]

Due to its key role in regulating early cell fate decisions and adult cell homeostasis, Wnt signaling has been extensively investigated for its involvement in cancer. [16] Many components of the β-catenin-dependent pathway are often differentially regulated between normal tissue and its cancerous counterpart. In particular, melanoma, hepatocellular carcinoma (HCC), prostate, colon, thyroid, and ovarian cancers, as well as certain subsets of breast cancers, harbor β-catenin-stabilizing mutations. [24],[25],[26] Such mutations result in high levels of β-catenin which, in turn, translate into constitutively active Wnt signaling. [26],[27],[28] While the regulation of β-catenin appears to be one of the most significant events linking Wnt signaling to cancer, modulation of other pathway components, both upstream and downstream of β-catenin, has also been shown to play a role. However, the most striking link between Wnt signaling and cancer has been the discoveries of genetic mutations in midstream signaling components (APC, β-catenin) which cause a constitutive activation of canonical signaling.

Role of Wnt signaling in colon carcinonesis

Activation of the Wnt pathway has been linked to colon cancer since the recognition that abnormalities of chromosome 5q were early events in the carcinogenic process for sporadic and hereditary (familial adenomatous polyposis, FAP) tumors, and the discovery that the FAP locus resides at this chromosomal location. [29],[30],[31] Encoded at 5q is the APC gene, the protein product of which is a key component of the β-catenin destruction complex. [27],[30],[32],[33],[34] About 90% of sporadic colon cancers harbor activating mutations within the Wnt pathway; most of these mutations destroy APC function. [35] Truncating mutations in APC prevent effective phosphorylation of β-catenin, resulting in its accumulation. Ultimately, β-catenin translocates to the nucleus, driving LEF/TCF-mediated gene transcription. [36] The same outcome can arise through mutations in β-catenin and Axin2, though these are significantly less frequent than mutations in APC. [28],[37]

Activation of the Wnt pathway by these mechanisms does not, by itself, cause cancer, though it is important in initiating the carcinogenic process. Inherited mutations in APC, as in FAP, lead to the development of noninvasive colonic adenomas (polyps), often thousands of them in an individual patient.Presumably, this is caused directly by the overexpression of growth-promoting genes driven by β-catenin-LEF/TCFs through canonical Wnt signaling. Mouse models of FAP, such as the Apc min/+ mouse, are characterized by innumerable intestinal (in this case, primarily small bowel) tumors, but these are typically noninvasive and most analogous to human colonic adenomas. [38] Similarly, somatic mutations in APC are an early event in sporadic adenoma formation.While Wnt pathway activation is clearly a driving force in the development of adenomas, activation of additional signaling pathways, such as those mediated through the proto-oncogene K-ras, are required for optimal nuclear localization of β-catenin to the nucleus and activation of the carcinoma program. [39] Additional mutations (TGFBRII, SMAD4, and TP53) may be necessary before frank carcinoma develops. [29] Because of the central role of APC/β-catenin in controlling mucosal proliferation and in the development of precancerous adenomas, almost all of the focus on the Wnt pathway in colon cancer has been on the linear path of canonical signaling. It is only recently that there has been recognition of the potential importance of non-mutational modulation of the Wnt signal (i.e., via cell surface receptor and ligand interactions) and of non-canonical components of the pathway. This review highlights two types of modulators: LEF/TCFs in the nucleus and extracellular signals from the tumor microenvironment.

Modulation of Wnt signaling in colon cancer

LEF/TCFs

LEF/TCF transcription factors are expressed in various tissues during embryonic development, where they mediate proper Wnt signaling. [40] After birth, they continue to mediate Wnt signaling, especially in tissues that derive from stem cell populations. LEF/TCFs also play important roles in colon cancer and in this regard the collective pattern of expression is important to consider because it changes in ways that maximize canonical Wnt signaling in cancer. Canonical signaling depends on the recruitment of β-catenin to target genes through a β-catenin-binding domain at the N-terminus of LEF/TCFs. The HMG box, a sequence-specific DNA binding/bending domain near the C-terminus of LEF/TCFs, allows the β-catenin-LEF/TCF complex to recognize Wnt response elements in target genes. Both of these functional domains are highly conserved and present in all LEF/TCFs, leading one to expect that LEF/TCF proteins are functionally redundant. However, this is not the case, because different LEF/TCF loci can produce differently acting protein isoforms through the use of alternative promoters and/or alternative splicing. [2],[40] For example, an alternative splicing event in the TCF7 (produces TCF-1) and TCF7L2 (produces TCF-4) genes leads to the inclusion of a carboxy-terminal domain called the E-tail. This tail contains a highly conserved second DNA-binding domain called the C-clamp. [41],[42] The C-Clamp has sequence selectivity and enables access to a set of Wnt target genes that are important for cell proliferation in colon cancer cells. [41] In addition to differences in DNA binding, alternative promoters in TCF7 and LEF1 produce dominant negative forms that are missing the β-catenin-binding domain (dnTCF-1 and dnLEF-1).These truncated isoforms act as dominant negative versions and negatively regulate Wnt signaling. [43],[44]

The expression pattern of LEF/TCF loci and isoforms is different in normal human colon as compared to colon cancer. In the normal colon, family members TCF-1 and TCF-4 are expressed and LEF-1 and TCF-3 loci are silent.[43],[45],[46] The TCF7L2 locus produces a full-length form of TCF-4 that contains the C-clamp auxiliary DNA-binding domain (TCF-4E), but the predominant isoform produced from the TCF7 locus is a dominant negative isoform of TCF-1, also with a C-clamp domain (dnTCF-1E). [47] That the TCF7L2 gene produces a Wnt-promoting form of TCF-4 that is important for proliferation and stem cell self-renewal is borne out in the Clevers' knockout mouse model, where loss of TCF-4 depletes stem cells and eliminates cell proliferation in the intestine. [18] That TCF-1 might be functioning as a homeostatic counterbalance to TCF-4 through its expression as a dnTCF-1E isoform is also borne out in mouse knockout studies, where loss of TCF-1 leads to adenoma formation in this tissue. [46][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).

Click here to view


The situation is quite different in colon cancer. While TCF-4 continues to be expressed as a full-length form with two DNA-binding domains, TCF-1 expression changes dramatically to a full-length Wnt-promoting isoform (TCF-1B). [47] Also, because LEF1 is a Wnt target gene, it is activated by the developing oncogenic Wnt signal, and full-length β-catenin-binding forms of LEF-1 are produced. A dnLEF-1 is not produced because its promoter is actively silenced through repressor action. [48],[49] Collectively, then, only full-length Wnt-promoting forms of LEF/TCFs are produced in cancer cells, a pattern that emerges for maximum β-catenin interaction and oncogenic Wnt signaling. [43],[50] Therapeutic strategies that restore normal levels and patterns of LEF/TCF expression or those that counter their recruitment of β-catenin and its co-activators Pygopus, BCL9, or CDK8 could bypass the effects of the loss of the destruction complex and the stabilization of β-catenin.

Wnt ligands and Wnt inhibitors in the tumor microenvironment

While loss of heterozygosity (LOH) at the APC locus or stabilizing mutations in β-catenin create a constitutive canonical Wnt signal, extracellular signals from the tumor microenvironment can influence oncogenic actions of the pathway, either by enhancing or repressing actions. Notably, there are changes in expression of Wnt ligands and secreted inhibitors that hint at the signaling potential of upstream components beyond the role of APC and β-catenin, an idea first noted in a study of autocrine Wnt signaling in cancer cells. [51] For example, Wnt2 and Wnt5a expression is elevated in colon cancer compared to normal colon and during the progression from adenoma to carcinoma. [52],[53],[54] In contrast, the expression of other Wnts, including Wnts 2b, 4, 7b, and 10b, does not change, as they remain strongly expressed in both normal colon and colon cancer. [55] In addition to Wnts, several Fz receptors (Fz-1 and Fz-2) are upregulated in poorly differentiated tumors, and expression of the scaffolding protein Dvl1 is increased in IBD (inflammatory bowel disease)-related colon cancer.[52],[56] The differential expression of upstream Wnt components is not exclusive to Wnt ligands. Genes encoding secreted soluble inhibitors of Wnt signaling such as DKK-1, SFRPs (secreted Fz-related protein), and WIF-1 (Wnt inhibitory factor) are hypermethylated and therefore silenced in colon cancer. Reintroduction of SFRP and DKK-1 into colon cancer cells causes a loss of cancer phenotypes, such as tumor growth and colony formation in soft agar, and this is true even in colon cancer cells where the APC locus has suffered LOH and where oncogenic Wnt signaling is presumably constitutive.[55],[57],[58],[59] These findings hint that colon cancers with a mutated pathway and stabilized β-catenin might still derive growth advantages from autocrine/paracrine Wnt signaling at the Fz-receptor level.

Even though colon cancers might progress by altering expression of Wnt ligands and secreted inhibitors to maximize oncogenic Wnt signaling, other extracellular Wnt signals can arise that inhibit the pathway. Interestingly, such signals are linked to the actions of the non-canonical class of Wnt ligands. Much of what is known about inhibitory Wnt signals comes from studies using Wnt5a as the extracellular ligand and, notably, several studies of colon cancer report significant changes in Wnt5a expression. One study of Wnt5a in Dukes' B-stage cancer found its expression decreased in 50% of the tumors, but either normal or increased in the other half. [60] Other comparative studies observed more consistent increases in Wnt5a expression. [53],[56] Differences in the reports are likely due to differences in methods used to detect Wnt5a; the first study examined protein and the second set of studies used methods to detect mRNA. It is possible that Wnt5a translation is regulated and mRNA and protein patterns are not always congruent. Nevertheless, Wnt5a expression shows upregulation in a significant cohort of tumors and this expression has been observed in both the epithelial and stromal compartment, which includes infiltrating macrophages. This is important because there is compelling evidence that Wnt5a can circumvent the constitutive oncogenic signaling in cells with defective, mutated APC. For example, β-catenin-dependent Wnt signaling in APC-negative colon cancer cells can be inhibited through the combined actions of Wnt5a/calcium signaling and RORa, a nuclear hormone receptor. [61] Likewise, Macleod et al. report that calcium-induced secretion of Wnt5a causes an autocrine inhibition of β-catenin signaling in APC-defective colon cancer cells. This signal requires the ROR2 receptor for Wnt5a. [62] Other groups find that Wnt5a treatment of APC-defective colon cancer lines reduces cancer behaviors such as cell migration and growth in soft agar (although the molecular basis for these effects was not explored). [60],[63]

There is another type of inhibitory Wnt signal that develops in colon cancer. This signal reduces β-catenin-dependent signaling by triggering the nuclear export of TCF-1 and, in doing so, reduces the concentration of LEF/TCFs in the nucleus. [47] This activity was discovered in primary human colon tumors where TCF-1 staining experiments showed dramatic shifts in localization to the cytoplasm. [47] TCF-1 export is activated by autocrine, paracrine actions of Wnts and these actions can be inhibited by DKK-1 and SFRPs.DKK-1 sensitivity implicates β-catenin and a canonical-type signal since this inhibitor works by blocking LRP5/6 action. However, the calcium-activated CaMKII/TAK1/NLK kinase cascade is also involved, and this pathway is activated by Wnt5a and other non-canonical-type ligands.[64],[65] The requirement for both canonical and non-canonical components attests to the complexity of Wnt signaling and the cross-talk between its different arms. The Wnt/CaMKII signal antagonizes β-catenin-dependent canonical signaling in APC-defective colon cancer cells because the form of TCF-1 exported from the nuclei is a full-length TCF-1 with oncogenic potential. A Wnt5a/CaMKII signal can also negatively affect the DNA-binding activities of LEF-1 and TCF-4 in 293 cells. [47] Whether this specific action occurs in colon cancer is unknown, but LEF-1 and TCF-4 do not export and their expression levels do not change. [47] Therefore, at a minimum, even though LEF-1, TCF-4, and β-catenin remain in the nucleus, TCF-1 export reduces the overall concentration of LEF/TCFs enough to affect canonical signaling. These data imply that LEF/TCF activities can be limiting for canonical signaling in colon cancer.

Are the actions of Wnt5a and calcium/CaMKII signals relevant to colon cancer? As mentioned above, Wnt5a expression can be elevated in colon cancer either through expression in the transformed epithelial cell compartment or through expression in stromal and inflammatory compartments such as infiltrating macrophages. [52],[53],[60] Sporadic colon cancer is not thought to have an overriding inflammatory component, but inflammation can occur and, interestingly, an inflammatory signature correlates with a good prognosis. [66],[67],[68],[69] A direct correlation between Wnt5a expression and prognosis is a more complicated issue, especially when all types of cancer are considered together. However, in the case of sporadic-type colon cancer, Wnt5a expression correlates with a better prognosis. [60],[70] If Wnt5a is truly a positive prognostic indicator, then the various Wnt5a-type signals summarized here might be the main reason for better outcome, as they can bypass APC and repress oncogenic Wnt signaling.

Cross-talking signals in the tumor microenvironment

In contrast to Wnts that oppose oncogenic Wnt signaling, there are important examples of extracellular growth factorsand cross-talk interactions that enhance β-catenin actions. For example, many sporadic colon cancers contain activating mutations in the GTPase K-RAS (40%). [71],[72] EGF (epidermal growth factor) and VEGF (vascular endothelial growth factor) signaling activates Rac/K-RAS pathways, which enhance canonical Wnt signaling by increasing the residence time and concentration of β-catenin in the nucleus. [39],[73] Adenomas from mouse models of intestinal cancer have increased levels of EGF receptor activity in the tumors.[74],[75] Moreover, inhibition of EGFR signaling in humans via blocking antibodies has proved to be an effective therapeutic intervention for patients with wild-type K-RAS. [76] Also important to consider are the effects of HGF (hepatocyte growth factor/scatter factor), a factor recently shown to promote stable β-catenin accumulation in nuclei.[77] HGF signals through the c-Met receptor and, although the signal transduction pathway is complex, there is a strong Ras component. HGF greatly enhances β-catenin signaling in experimental models of human colon cancer stem cells.[77] Indeed, disruption of HGF cross-talk might have real potential intherapy since Met inhibitor treatment of mice injected with gastric carcinoma cells induces regression of metastases. [78] Thus, there appears to be a strong synergy between K-RAS-dependent signals and oncogenic Wnt signals. Finally, signals from cell surface integrin-extracellular matrix interaction sengage non-canonical signaling to Rac/JNK, which in turn triggers the formation of the AP-1 transcription factor. [79] AP-1 action can synergize with Wnt signals to influence the activation of a subset of target genes. [80] The interesting connection to Wnt target genes is important. Two separate studies identify AP-1 binding sites as one of the most frequent DNA regulatory elements that co-segregate with Wnt response elements (WRE). [81],[82] The functional consequence of this co-segregation is that LEF/TCF/β-catenin complexes and AP-1 factors co-occupy and synergize for transcriptional regulation. [79],[83],[84] Synergy between Wnt and integrin-triggered AP-1 suggests that non-canonical signaling is highly sensitive to extracellular matrix connections.

Given the variety of extracellular signals that can modify Wnt signaling in colon cancer, one might presume that the level of oncogenic potential in individual patient tumors, and even within regions of a single tumor, lies along a continuum of strong to weak Wnt signaling. Indeed, if nuclear β-catenin levels are any measure of the strength of Wnt signaling, it would seem that the invasion front of a tumor, i.e., the cells with the greatest exposure to stroma and the tumor environment, should have the highest concentrations of nuclear β-catenin. This is certainly the case. [77],[85],[86] These examples of synergy and cross-talk imply that signals that enhance the canonical Wnt pathway could be bonafide targets for therapy, whereas missing signals that can counter Wnt action could be re-introduced as treatments.


  Considerations for Wnt-Focused Clinical Therapeutics of Colon Cancer Top


Given the pivotal role of Wnt signaling in the development of colon cancer and many other malignancies, it would seem an ideal target for new cancer drugs. Several cancer drugs have been approved or are in late-stage clinical trials that effectively target the EGFR, the AKT, and the Hedgehog signaling pathways. [87],[88],[89] However, clinically useful agents to inhibit Wnt signaling pathways have, despite significant investment by several pharmaceutical and biotech companies, remained elusive. A lack of Wnt agents might reflect the difficulty in identifying 'druggable' targets in the pathway, enzymes amenable to small-molecule inhibition. But the surprising lack of new drugs might also be due to the perception that a downstream mutation in APC or CTNNB1 (β-catenin) would make the manipulation of upstream components therapeutically ineffective. [90] The recognition that the colon cancer phenotype can be suppressed by secreted inhibitors of Fz/LRP5/6 (DKK-1) or Wnt ligands (SFRP) argues that 'druggable' targets upstream of APC are worth considering.[51],[91],[92] Indeed, as described above, abrogation of autocrine signaling through epigenetic silencing of the inhibitory soluble Fz-related proteins (SFRPs) appears to be a naturally occurring mechanism in many types of cancer.[55],[93],[94],[95],[96],[97] These tumors may possess a growth advantage via blockage of natural Wnt inhibitory feedback loops. Blocking Wnt signaling by introduction of SFRP-like molecules suppresses tumor cell growth and proliferation in in vivo models in tumor cells which carry an activated form of β-catenin. [98] The presence of methylation, which silences SFRP1 in breast cancer, is associated with an unfavorable prognosis, emphasizing the clinical significance of cell surface components as they relate to modulation of Wnt signal throughput. [99]

Many potential Wnt modulating drugs are being investigated, but there are few currently in clinical trials. [100],[101],[102],[103],[104] A study supported by Momotaro-Gene Inc. (NCT01197209) delivers DKK-3, an inhibitor of the Fz-LRP cell surface complex, via a viral vector in a neoadjuvant fashion for prostate cancer. No results from this phase I trial are yet available. More advanced is the use of a Novartis compound, BHQ880, for the treatment of bone disease in multiple myeloma (NCT00741377). In myeloma, decreased activity of osteoblasts contributes to the development of lytic bone lesions. [105] Osteoblasts are inhibited by the production of DKK-1 by myeloma cells.BHQ880 is an anti-DKK-1 neutralizing antibody. Thus, for this 'cancer' indication, the approach is to block inhibition of the Wnt pathway in osteoblasts in order to prevent a cancer-related complication.

Additional clinical research has focused on inhibition of Wnt signaling through dietary manipulations (NCT00256334, NCT00578396, and NCT01214681) as a colon cancer chemoprevention approach. These studies are based in part on the observation that certain naturally occurring compounds may inhibit Wnt signaling in vitro. [106],[107] However, while this approach may be applicable in a general sense for cancer prevention, it is nonspecific and unlikely to be clinically efficacious in the setting of frank malignancy. Another interesting compound is the pyrvinium, which potentiates casein kinase 1-alpha activity and is utilized clinically as an anthelminthic for the treatment of pinworms. [108],[109] Pyrvinium treatment of APC-defective colon cancer cells degrades Pygopus and decreases oncogenic Wnt signaling in colon cancer cells. Interestingly, increases in Pygopus1 and Pygopus2 mRNA have been detected in villous adenomas, the relatively more aggressive precursor to colon carcinoma.[110] Finally, a chemical genetic screen has identified XAV939, a small molecule that selectively inhibits β-catenin-mediated transcription by targeting the poly-ADP-ribosylating enzyme Tankyrase. Tankyrase inhibition stabilizes the Axin scaffold of the destruction complex and forces β-catenin degradation in colon cancer cells. [111]

Overall, the targeting of the Wnt pathway for cancer treatment and prevention remains in its infancy. Initial approaches have focused on inhibiting critical downstream events such as β-catenin/TCF interactions or small molecules that disrupt the interaction of β-catenin with co-activators such as CREB-binding protein (CBP). [112,113] Targeting upstream events via antibodies to Wnt ligands, SFRPs or SFRP-like molecules, is a more recent approach. [114],[115] Antagonizing Fz-Dvl interactions with small molecules or peptide inhibitors may also prove useful. [116],[117] Recently, inhibitors of porcupine, a membrane-bound acetyltransferase that is essential for the production of Wnt proteins and that interrupts the autocrine Wnt feedback loop, have been identified. [118] These represent an exciting class of molecules that may preferentially target cells with activated Wnt signaling, such as tumor cells. All of these approaches primarily target canonical Wnt signaling. Nonetheless, inhibition of upstream events may also inhibit non-canonical signaling and this may not be beneficial. It may be preferable to augment, or at a minimum, not inhibit signaling induced by some Wnt ligands, such as Wnt5a. Further understanding of both canonical and non-canonical signaling pathways, other signaling pathways that cross-talk with the Wnt pathway, and factors that may modify signals despite mutation-associated activation, will be essential to guide the development of a new class of therapeutic interventions.


  Acknowledgments Top


We would like to thank Dr. Xing Dai (University of California, Irvine) and Dr. Christopher C.W. Hughes (University of California, Irvine) for helpful suggestions. M.L.W. and R.N. are supported by RO1 CA096878 and RO1 CA108697, and R.F.H. is supported by K24CA82450. Dr. Waterman and Dr. Holcombe contributed equally as senior authors for this publication

 
  References Top

1.van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development 2009;136:3205-14.  Back to cited text no. 1
    
2.Waterman ML. Lymphoid enhancer factor/T cell factor expression in colorectal cancer. Cancer Metastasis Rev 2004;23:41-52.  Back to cited text no. 2
    
3.Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005;434:843-50.  Back to cited text no. 3
    
4.MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17:9-26.  Back to cited text no. 4
    
5.Belenkaya TY, Han C, Standley HJ, Lin X, Houston DW, Heasman J, et al. Pygopus Encodes a nuclear protein essential for wingless/Wnt signaling. Development 2002;129:4089-101.  Back to cited text no. 5
    
6.Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 2002;109:47-60.  Back to cited text no. 6
    
7.Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, et al. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 2008;455:547-51.  Back to cited text no. 7
    
8.Sierra J, Yoshida T, Joazeiro CA, Jones KA. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev 2006;20:586-600.  Back to cited text no. 8
    
9.Parker DS, Jemison J, Cadigan KM. Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development 2002;129:2565-76.  Back to cited text no. 9
    
10.Townsley FM, Thompson B, Bienz M. Pygopus residues required for its binding to Legless are critical for transcription and development. J BiolChem 2004;279:5177-83.  Back to cited text no. 10
    
11.Kohn AD, Moon RT. Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 2005;38:439-46.  Back to cited text no. 11
    
12.Widelitz R. Wnt signaling through canonical and non-canonical pathways: recent progress. Growth Factors 2005;23:111-6.  Back to cited text no. 12
    
13.Mikels AJ, Nusse R. Wnts as ligands: processing, secretion and reception.Oncogene 2006;25:7461-8.  Back to cited text no. 13
    
14.Mikels AJ, Nusse R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoSBiol 2006;4:e115.  Back to cited text no. 14
    
15.Cha SW, Tadjuidje E, White J, Wells J, Mayhew C, Wylie C, et al. Wnt11/5a complex formation caused by tyrosine sulfation increases canonical signaling activity. CurrBiol 2009;19:1573-80.  Back to cited text no. 15
    
16.Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387-98.  Back to cited text no. 16
    
17.van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009;71:241-60.  Back to cited text no. 17
    
18.Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998;19:379-83.  Back to cited text no. 18
    
19.Lin G, Xu N, Xi R. Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature 2008;455:1119-23.  Back to cited text no. 19
    
20.Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature 2007;449:1003-7.  Back to cited text no. 20
    
21.van der Flier LG, van Gijn ME, Hatzis P, Kujala P, Haegebarth A, Stange DE, et al. Transcription factor achaetescute-like 2 controls intestinal stem cell fate.Cell 2009;136:903-12.  Back to cited text no. 21
    
22.Blache P, van de Wetering M, Duluc I, Domon C, Berta P, Freund JN, et al. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 2004;166:37-47.  Back to cited text no. 22
    
23.vanEs JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 2005;7:381-6.  Back to cited text no. 23
    
24.Polakis P. Wnt signaling and cancer.Genes Dev 2000;14:1837-51.  Back to cited text no. 24
    
25.Brown AM. Wnt signaling in breast cancer: have we come full circle? Breast Cancer Res 2001;3:351-5.  Back to cited text no. 25
    
26.Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997;275:1790-2.  Back to cited text no. 26
    
27.Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 1997;275:1784-7.  Back to cited text no. 27
    
28.Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275:1787-90.  Back to cited text no. 28
    
29.Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.  Back to cited text no. 29
    
30.Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, et al. Identification of FAP locus genes from chromosome 5q21. Science 1991;253:661-5.  Back to cited text no. 30
    
31.Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253:665-9.  Back to cited text no. 31
    
32.Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66:589-600.  Back to cited text no. 32
    
33.Okamoto M, Sato C, Kohno Y, Mori T, Iwama T, Tonomura A, et al. Molecular nature of chromosome 5q loss in colorectal tumors and desmoids from patients with familial adenomatous polyposis. Hum Genet 1990;85:595-9.  Back to cited text no. 33
    
34.Rubinfeld B, Souza B, Albert I, Müller O, Chamberlain SH, Masiarz FR, et al. Association of the APC gene product with beta-catenin. Science 1993;262:1731-4.  Back to cited text no. 34
    
35.Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 1994;54:3011-20.  Back to cited text no. 35
    
36.Polakis P. The oncogenic activation of beta-catenin. Curr Opin Genet Dev 1999;9:15-21.  Back to cited text no. 36
    
37.Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet 2000;26:146-7.  Back to cited text no. 37
    
38.Merritt AJ, Gould KA, Dove WF. Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant loss of Apc+ from all tumor lineages.Proc Natl Acad Sci USA 1997;94:13927-31.  Back to cited text no. 38
    
39.Phelps RA, Chidester S, Dehghanizadeh S, Phelps J, Sandoval IT, Rai K, et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 2009;137:623-34.  Back to cited text no. 39
    
40.Arce L, Yokoyama NN, Waterman ML. Diversity of LEF/TCF action in development and disease. Oncogene 2006;25:7492-504.  Back to cited text no. 40
    
41.Atcha FA, Syed A, Wu B, Hoverter NP, Yokoyama NN, Ting JH, et al. A unique DNA binding domain converts T-cell factors into strong Wnt effectors. Mol Cell Biol 2007;27:8352-63.  Back to cited text no. 41
    
42.Chang MV, Chang JL, Gangopadhyay A, Shearer A, Cadigan KM. Activation of wingless targets requires bipartite recognition of DNA by TCF. CurrBiol 2008;18:1877-81.  Back to cited text no. 42
    
43.Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Lawrence Marsh J, et al. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet 2001;28:53-7.  Back to cited text no. 43
    
44.van de Wetering M, Oosterwegel M, Dooijes D, Clevers H. Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. EMBO J 1991;10:123-32.  Back to cited text no. 44
    
45.Korinek V, Barker N, Willert K, Molenaar M, Roose J, Wagenaar G, et al. Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse. Mol Cell Biol 1998;18:1248-56.  Back to cited text no. 45
    
46.Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, et al. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 1999;285:1923-6.  Back to cited text no. 46
    
47.Najdi R, Syed A, Arce L, Theisen H, Ting JH, Atcha F,et al. A Wnt kinase network alters nuclear localization of TCF-1 in colon cancer. Oncogene 2009;28:4133-46.  Back to cited text no. 47
    
48.Li TW, Ting JH, Yokoyama NN, Bernstein A, van de Wetering M, Waterman ML. Wnt activation and alternative promoter repression of LEF1 in colon cancer. Mol Cell Biol 2006;26:5284-99.  Back to cited text no. 48
    
49.Yokoyama NN, Pate KT, Sprowl S, Waterman ML. A role for YY1 in repression of dominant negative LEF-1 expression in colon cancer. Nucleic Acids Res 2010;38:6375-88.  Back to cited text no. 49
    
50.Kaiser S, Park YK, Franklin JL, Halberg RB, Yu M, Jessen WJ, et al. Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biol 2007;8:R131.  Back to cited text no. 50
    
51.Bafico A, Liu G, Goldin L, Harris V, Aaronson SA. An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004;6:497-506.  Back to cited text no. 51
    
52.Holcombe RF, Marsh JL, Waterman ML, Lin F, Milovanovic T, Truong T. Expression of Wnt ligands and Frizzled receptors in colonic mucosa and in colon carcinoma. Mol Pathol 2002;55:220-6.  Back to cited text no. 52
    
53.Smith K, Bui TD, Poulsom R, Kaklamanis L, Williams G, Harris AL. Up-regulation of macrophage Wnt gene expression in adenoma-carcinoma progression of human colorectal cancer. Br J Cancer 1999;81:496-502.  Back to cited text no. 53
    
54.Park JK, Song JH, He TC, Nam SW, Lee JY, Park WS. Overexpression of Wnt-2 in colorectal cancers. Neoplasma 2009;56:119-23.  Back to cited text no. 54
    
55.Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive Wnt signaling in colorectal cancer. Nat Genet 2004;36:417-22.  Back to cited text no. 55
    
56.You XJ, Bryant PJ, Jurnak F, Holcombe RF. Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease. Oncol Rep 2007;18:691-4.  Back to cited text no. 56
    
57.González-Sancho JM, Aguilera O, García JM, Pendás-Franco N, Peña C, Cal S, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene 2005;24:1098-103.  Back to cited text no. 57
    
58.Caldwell GM, Jones C, Gensberg K, Jan S, Hardy RG, Byrd P, et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res 2004;64:883-8.  Back to cited text no. 58
    
59.Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 2006;25:4116-21.  Back to cited text no. 59
    
60.Dejmek J, Dejmek A, Säfholm A, Sjölander A, Andersson T. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res 2005;65:9142-6.  Back to cited text no. 60
    
61.Lee JM, Kim IS, Kim H, Lee JS, Kim K, Yim HY, et al. ROR alpha attenuates Wnt/beta-catenin signaling by PKC alpha-dependent phosphorylation in colon cancer. Mol Cell. 2010;37:183-95.  Back to cited text no. 61
    
62.MacLeod RJ, Hayes M, Pacheco I. Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells. Am J Physiol Gastrointest Liver Physiol 2007;293:G403-11.  Back to cited text no. 62
    
63.Ying J, Li H, Yu J, Ng KM, Poon FF, Wong SC, et al. Wnt5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res 2008;14:55-61.  Back to cited text no. 63
    
64.Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, et al. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 1999;399:798-802.  Back to cited text no. 64
    
65.Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, et al. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol Cell Biol 2003;23:131-9.  Back to cited text no. 65
    
66.Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960-4.  Back to cited text no. 66
    
67.Zlobec I, Minoo P, Baumhoer D, Baker K, Terracciano L, Jass JR, et al. Multimarker phenotype predicts adverse survival in patients with lymph node-negative colorectal cancer. Cancer 2008;112:495-502.  Back to cited text no. 67
    
68.Lugli A, Karamitopoulou E, Panayiotides I, Karakitsos P, Rallis G, Peros G, et al. CD8+ lymphocytes/ tumour-budding index: an independent prognostic factor representing a 'pro-/anti-tumour' approach to tumour host interaction in colorectal cancer. Br J Cancer 2009;101:1382-92.  Back to cited text no. 68
    
69.Camus M, Tosolini M, Mlecnik B, Pagès F, Kirilovsky A, Berger A, et al. Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 2009;69:2685-93.  Back to cited text no. 69
    
70.McDonald SL, Silver A. The opposing roles of Wnt-5a in cancer. Br J Cancer 2009;101:209-14.  Back to cited text no. 70
    
71.Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987;327:293-7.  Back to cited text no. 71
    
72.Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 1987;327:298-303.  Back to cited text no. 72
    
73.Wu X, Tu X, Joeng KS, Hilton MJ, Williams DA, Long F. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell 2008;133:340-53.  Back to cited text no. 73
    
74.Moran AE, Hunt DH, Javid SH, Redston M, Carothers AM, Bertagnolli MM. Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. J BiolChem 2004;279:43261-72.  Back to cited text no. 74
    
75.Hu T, Li C. Convergence between Wnt-â-catenin and EGFR signaling in cancer.Mol Cancer 2010;9:236.  Back to cited text no. 75
    
76.Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J ClinOncol 2009;27:2091-6.  Back to cited text no. 76
    
77.Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010;12:468-76.  Back to cited text no. 77
    
78.Corso S, Migliore C, Ghiso E, De Rosa G, Comoglio PM, Giordano S. Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene 2008;27:684-93.  Back to cited text no. 78
    
79.Crampton SP, Wu B, Park EJ, Kim JH, Solomon C, Waterman ML, et al. Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. PLoS One 2009;4:e7841.  Back to cited text no. 79
    
80.Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R, et al. Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc Natl Acad Sci USA 1998;95:4374-9.  Back to cited text no. 80
    
81.Hatzis P, van der Flier LG, van Driel MA, Guryev V, Nielsen F, Denissov S, et al. Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells. Mol Cell Biol 2008;28:2732-44.  Back to cited text no. 81
    
82.Bottomly D, Kyler SL, McWeeney SK, Yochum GS. Identification of {beta}-catenin binding regions in colon cancer cells using ChIP-Seq. Nucleic Acids Res 2010;38:5735-45.  Back to cited text no. 82
    
83.Nateri AS, Spencer-Dene B, Behrens A. Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 2005;437:281-5.  Back to cited text no. 83
    
84.Toualbi K, Güller MC, Mauriz JL, Labalette C, Buendia MA, Mauviel A, et al. Physical and functional cooperation between AP-1 and beta-catenin for the regulation of TCF-dependent genes. Oncogene 2007;26:3492-502.  Back to cited text no. 84
    
85.Kirchner T, Brabletz T. Patterning and nuclear beta-catenin expression in the colonic adenoma-carcinoma sequence. Analogies with embryonic gastrulation. Am J Pathol 2000;157:1113-21.  Back to cited text no. 85
    
86.Brabletz T, Jung A, Kirchner T. Beta-catenin and the morphogenesis of colorectal cancer. Virchows Arch 2002;441:1-11.  Back to cited text no. 86
    
87.Vivanco I, Mellinghoff IK. Epidermal growth factor receptor inhibitors in oncology. CurrOpinOncol 2010;22:573-8.  Back to cited text no. 87
    
88.Ou SH, Bazhenova L, Camidge DR, Solomon BJ, Herman J, Kain T, et al. Rapid and dramatic radiographic and clinical response to an ALK inhibitor (crizotinib, PF02341066) in an ALK translocation-positive patient with non-small cell lung cancer. J Thorac Oncol 2010;5:2044-6.  Back to cited text no. 88
    
89.Garber K. Hedgehog drugs begin to show results. J Natl Cancer Inst 2008;100:692-7.  Back to cited text no. 89
    
90.Garber K. Drugging the Wnt pathway: problems and progress. J Natl Cancer Inst 2009;101:548-50.  Back to cited text no. 90
    
91.Schlange T, Matsuda Y, Lienhard S, Huber A, Hynes NE. Autocrine Wnt signaling contributes to breast cancer cell proliferation via the canonical Wnt pathway and EGFR transactivation. Breast Cancer Res 2007;9:R63.  Back to cited text no. 91
    
92.Taketo MM. Shutting down Wnt signal-activated cancer. Nat Genet 2004;36:320-2.  Back to cited text no. 92
    
93.Suzuki H, Toyota M, Carraway H, Gabrielson E, Ohmura T, Fujikane T, et al. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer.Br J Cancer 2008;98:1147-56.  Back to cited text no. 93
    
94.Bu XM, Zhao CH, Zhang N, Gao F, Lin S, Dai XW. Hypermethylation and aberrant expression of secreted frizzled-related protein genes in pancreatic cancer. World J Gastroenterol 2008;14:3421-4.  Back to cited text no. 94
    
95.Takagi H, Sasaki S, Suzuki H, Toyota M, Maruyama R, Nojima M, et al. Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J Gastroenterol 2008;43:378-89.  Back to cited text no. 95
    
96.Hirata H, Hinoda Y, Ueno K, Majid S, Saini S, Dahiya R. Role of secreted frizzled-related protein 3 in human renal cell carcinoma. Cancer Res 2010;70:1896-905.  Back to cited text no. 96
    
97.Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, et al. Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. Oncogene 2007;26:4699-713.  Back to cited text no. 97
    
98.Lavergne E, Hendaoui I, Coulouarn C, Ribault C, Leseur J, Eliat PA, et al. In vivo blocking Wnt signaling by SFRP-like molecules inhibits cell proliferation and tumor growth in cells carrying active beta-catenin. Oncogene 2010;30:423-33.  Back to cited text no. 98
    
99.Veeck J, Niederacher D, An H, Klopocki E, Wiesmann F, Betz B, et al. Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene 2006;25:3479-88.100.   Back to cited text no. 99
    
100.Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006;5:997-1014.  Back to cited text no. 100
    
101.Chen W, Chen M, Barak LS. Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach. Am J Physiol Gastrointest Liver Physiol 2010;299:G293-300.  Back to cited text no. 101
    
102.Camilli TC, Weeraratna AT. Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression. BiochemPharmacol 2010;80:702-11.  Back to cited text no. 102
    
103.Hood JG, Hu Y, Jiang Y, Pedraza M, Situ E, Sunil KC. Discovery of small molecule Wnt pathway modulators. In: editor name missing Proc Keystone Conference: New Paradigms in Cancer Therapeutics; 2010.  Back to cited text no. 103
    
104.Curtin JC. Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget 2010;1:563-6.  Back to cited text no. 104
    
105.Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009;114:371-9.  Back to cited text no. 105
    
106.Hope C, Planutis K, Planutiene M, Moyer MP, Johal KS, Woo J, et al. Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention. Mol Nutr Food Res 2008;52:S52-61.  Back to cited text no. 106
    
107.Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C, et al. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res 2009;1:25-37.  Back to cited text no. 107
    
108.Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1a. Nat Chem Biol 2010;6:829-36.  Back to cited text no. 108
    
109.Turner JA, Johnson PE, Jr.: Pyrviniumpamoate in the treatment of pinworm infection (enterobiasis) in the home. J Pediatr 1962;60:243-51.  Back to cited text no. 109
    
110.Nguyen AV, Albers CG, Holcombe RF. Differentiation of tubular and villous adenomas based on Wnt pathway-related gene expression profiles. Int J Mol Med 2010;26:121-5.  Back to cited text no. 110
    
111.Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009;461:614-20.  Back to cited text no. 111
    
112.Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004;5:91-102.  Back to cited text no. 112
    
113.Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 2004;101:12682-7.  Back to cited text no. 113
    
114.He B, Reguart N, You L, Mazieres J, Xu Z, Lee AY, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene 2005;24:3054-8.  Back to cited text no. 114
    
115.DeAlmeida VI, Miao L, Ernst JA, Koeppen H, Polakis P, Rubinfeld B. In vivo the soluble Wnt receptor Frizzled 8CRD-hFc inhibits the growth of teratocarcinomas. Cancer Res 2007;67:5371-9.  Back to cited text no. 115
    
116.Shan J, Shi DL, Wang J, Zheng J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 2005;44:15495-503.  Back to cited text no. 116
    
117.Zhang Y, Appleton BA, Wiesmann C, Lau T, Costa M, Hannoush RN, et al. Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nat Chem Biol 2009;5:217-9.  Back to cited text no. 117
    
118.Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 2009;5:100-7.  Back to cited text no. 118
    

 
  Authors Top

Dr. Rani Najdi, Department of Microbiology and Molecular Genetics, University of California, Irvine.
Dr. Marian L Waterman, Department of Microbiology and Molecular Genetics, University of California, Irvine
Dr. Randall F Holcombe, Tisch Cancer Institute, Mt. Sinai School of Medicine, New York, NY


    Figures

  [Figure 1]


This article has been cited by
1 New insights into the regulation of Axin function in canonical Wnt signaling pathway
Xiaomin Song,Sheng Wang,Lin Li
Protein & Cell. 2014;
[Pubmed] | [DOI]
2 Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction
Yves Lecarpentier,Victor Claes,Guillaume Duthoit,Jean-Louis H├ębert
Frontiers in Physiology. 2014; 5
[Pubmed] | [DOI]
3 Functional and genetic analysis of the colon cancer network
Frank Emmert-Streib,Ricardo de Matos Simoes,Galina Glazko,Simon McDade,Benjamin Haibe-Kains,Andreas Holzinger,Matthias Dehmer,Frederick Campbell
BMC Bioinformatics. 2014; 15(Suppl 6): S6
[Pubmed] | [DOI]
4 Nutrient-induced intestinal adaption and its effect in obesity
Megan J. Dailey
Physiology & Behavior. 2014;
[Pubmed] | [DOI]
5 CD58, aánovel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer
S Xu,Z Wen,Q Jiang,L Zhu,S Feng,Y Zhao,J Wu,Q Dong,J Mao,Y Zhu
Oncogene. 2014;
[Pubmed] | [DOI]
6 The APC Network Regulates the Removal of Mutated Cells from Colonic Crypts
Je-Hoon Song,DavidáJ. Huels,RacheláA. Ridgway,OwenáJ. Sansom,BorisáN. Kholodenko,Walter Kolch,Kwang-Hyun Cho
Cell Reports. 2014; 7(1): 94
[Pubmed] | [DOI]
7 RSPO fusion transcripts in colorectal cancer in Japanese population
Kazuya Shinmura,Tomoaki Kahyo,Hisami Kato,Hisaki Igarashi,Shun Matsuura,Satoki Nakamura,Kiyotaka Kurachi,Toshio Nakamura,Hiroshi Ogawa,Kazuhito Funai,Masayuki Tanahashi,Hiroshi Niwa,Haruhiko Sugimura
Molecular Biology Reports. 2014;
[Pubmed] | [DOI]
8 Nuclear expression of Glycogen synthase kinase-3▀ and lack of membranous ▀-catenin is correlated with poor survival in colon cancer
Tavga Salim,Anita Sj÷lander,Janna Sand-Dejmek
International Journal of Cancer. 2013; 133(4): 807
[Pubmed] | [DOI]
9 Pharmacophore modeling, 3D-QSAR and DFT studies of IWR small-molecule inhibitors of Wnt response
Palani Kirubakaran,Muthusamy Karthikeyan
Journal of Receptors and Signal Transduction. 2013; 33(5): 276
[Pubmed] | [DOI]
10 Wnt5a promotes human colon cancer cell migration and invasion but does not augment intestinal tumorigenesis in Apc1638N mice
E. R. M. Bakker,A. M. Das,W. Helvensteijn,P. F. Franken,S. Swagemakers,M. A. van der Valk,T. L. M. ten Hagen,E. J. Kuipers,W. van Veelen,R. Smits
Carcinogenesis. 2013; 34(11): 2629
[Pubmed] | [DOI]
11 Calcium sensing receptor signalling in physiology and cancer
Sarah C. Brennan,Ursula Thiem,Susanne Roth,Abhishek Aggarwal,Irfete Sh. Fetahu,Samawansha Tennakoon,Ana Rita Gomes,Maria Luisa Brandi,Frank Bruggeman,Romuald Mentaverri,Daniela Riccardi,Enik÷ Kallay
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2013; 1833(7): 1732
[Pubmed] | [DOI]
12 Wnt signaling inhibits CTL memory programming
Zhengguo Xiao,Zhifeng Sun,Kendra Smyth,Lei Li
Molecular Immunology. 2013; 56(4): 423
[Pubmed] | [DOI]
13 Ellagic acid coordinately attenuates Wnt/▀-catenin and NF-?B signaling pathways to induce intrinsic apoptosis in an animal model of oral oncogenesis
Prabukumar Anitha,Ramamurthi Vidya Priyadarsini,Krishnamurthy Kavitha,Paranthaman Thiyagarajan,Siddavaram Nagini
European Journal of Nutrition. 2013; 52(1): 75
[Pubmed] | [DOI]
14 Colon cancer stem cells ľ From basic to clinical application
Galina Botchkina
Cancer Letters. 2013; 338(1): 127
[Pubmed] | [DOI]
15 Improving outcomes in colorectal cancer: Where do we go from here?
Eric Van Cutsem,Josep Maria BorrÓs,Antoni Castells,Fortunato Ciardiello,Michel Ducreux,Asif Haq,Hans-Joachim Schmoll,Josep Tabernero
European Journal of Cancer. 2013; 49(11): 2476
[Pubmed] | [DOI]
16 Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment
Kestutis Planutis,Marina Planutiene,Anthony V Nguyen,Mary Pat Moyer,Randall F Holcombe
Journal of Translational Medicine. 2013; 11(1): 50
[Pubmed] | [DOI]
17 Nuclear expression of Glycogen synthase kinase-3╬▓ and lack of membranous ╬▓-catenin is correlated with poor survival in colon cancer
Salim, T. and Sj├Âlander, A. and Sand-Dejmek, J.
International Journal of Cancer. 2013; 133(4): 807-815
[Pubmed]
18 Improving outcomes in colorectal cancer: Where do we go from here?
Van Cutsem, E. and Borràs, J.M. and Castells, A. and Ciardiello, F. and Ducreux, M. and Haq, A. and Schmoll, H.-J. and Tabernero, J.
European Journal of Cancer. 2013; 49(11): 2476-2485
[Pubmed]
19 Calcium sensing receptor signalling in physiology and cancer
Brennan, S.C. and Thiem, U. and Roth, S. and Aggarwal, A. and Fetahu, I.S. and Tennakoon, S. and Gomes, A.R. and Brandi, M.L. and Bruggeman, F. and Mentaverri, R. and Riccardi, D. and Kallay, E.
Biochimica et Biophysica Acta - Molecular Cell Research. 2013; 1833(7): 1732-1744
[Pubmed]
20 Wnt modulating agents inhibit human cytomegalovirus replication
Kapoor, A. and He, R. and Venkatadri, R. and Forman, M. and Arav-Boger, R.
Antimicrobial Agents and Chemotherapy. 2013; 57(6): 2761-2767
[Pubmed]
21 Combination of Selenium and Green Tea Improves the Efficacy of Chemoprevention in a Rat Colorectal Cancer Model by Modulating Genetic and Epigenetic Biomarkers
Hu, Y. and McIntosh, G.H. and Le Leu, R.K. and Nyskohus, L.S. and Woodman, R.J. and Young, G.P.
PLoS ONE. 2013; 8(5)
[Pubmed]
22 Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment
Planutis, K. and Planutiene, M. and Nguyen, A.V. and Moyer, M.P. and Holcombe, R.F.
Journal of Translational Medicine. 2013; 11(1)
[Pubmed]
23 Ellagic acid coordinately attenuates Wnt/╬▓-catenin and NF-╬║B signaling pathways to induce intrinsic apoptosis in an animal model of oral oncogenesis
Anitha, P. and Priyadarsini, R.V. and Kavitha, K. and Thiyagarajan, P. and Nagini, S.
European Journal of Nutrition. 2013; 52(1): 75-84
[Pubmed]
24 Metabolic trajectory of cellular differentiation in small intestine by Phasor Fluorescence Lifetime Microscopy of NADH
Stringari, C. and Edwards, R.A. and Pate, K.T. and Waterman, M.L. and Donovan, P.J. and Gratton, E.
Scientific Reports. 2012; 2(568)
[Pubmed]
25 Colorectal cancer and canonical Wnt signalling pathway [Kolorekt├íln├ş karcinom a kanonick├í Wnt signalizace]
Moravec, M.
Casopis Lekaru Ceskych. 2012; 151(7): 335-342
[Pubmed]
26 A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities
Najdi, R. and Proffitt, K. and Sprowl, S. and Kaur, S. and Yu, J. and Covey, T.M. and Virshup, D.M. and Waterman, M.L.
Differentiation. 2012; 84(2): 203-213
[Pubmed]
27 Multispecies model of cell lineages and feedback control in solid tumors
Youssefpour, H. and Li, X. and Lander, A.D. and Lowengrub, J.S.
Journal of Theoretical Biology. 2012; 304: 39-59
[Pubmed]
28 The many faces and functions of Î 2-catenin
Valenta, T. and Hausmann, G. and Basler, K.
EMBO Journal. 2012; 31(12): 2714-2736
[Pubmed]
29 A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice
Waaler, J. and Machon, O. and Tumova, L. and Dinh, H. and Korinek, V. and Wilson, S.R. and Paulsen, J.E. and Pedersen, N.M. and Eide, T.J. and Machonova, O. and Gradl, D. and Voronkov, A. and Von Kries, J.P. and Krauss, S.
Cancer Research. 2012; 72(11): 2822-2832
[Pubmed]
30 Wnt signaling from membrane to nucleus: ╬▓-catenin caught in a loop
Jamieson, C. and Sharma, M. and Henderson, B.R.
International Journal of Biochemistry and Cell Biology. 2012; 44(6): 847-850
[Pubmed]
31 Impact of mutant ╬▓-catenin on ABCB1 expression and therapy response in colon cancer cells
Stein, U. and Fleuter, C. and Siegel, F. and Smith, J. and Kopacek, A. and Scudiero, D.A. and Hite, K.M. and Schlag, P.M. and Shoemaker, R.H. and Walther, W.
British Journal of Cancer. 2012; 106(8): 1395-1405
[Pubmed]
32 Specific Armadillo repeat sequences facilitate ╬▓-catenin nuclear transport in live cells via direct binding to nucleoporins Nup62, Nup153, and RanBP2/Nup358
Sharma, M. and Jamieson, C. and Johnson, M. and Molloy, M.P. and Henderson, B.R.
Journal of Biological Chemistry. 2012; 287(2): 819-831
[Pubmed]
33 A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities
Rani Najdi,Kyle Proffitt,Stephanie Sprowl,Simran Kaur,Jia Yu,Tracy M. Covey,David M. Virshup,Marian L. Waterman
Differentiation. 2012; 84(2): 203
[Pubmed] | [DOI]
34 Our evolving view of Wnt signaling in C. elegans
Scott M. Robertson,Rueyling Lin
Worm. 2012; 1(1): 82
[Pubmed] | [DOI]
35 The many faces and functions of ▀-catenin
Tomas Valenta,George Hausmann,Konrad Basler
The EMBO Journal. 2012; 31(12): 2714
[Pubmed] | [DOI]
36 Impact of mutant ▀-catenin on ABCB1 expression and therapy response in colon cancer cells
U Stein,C Fleuter,F Siegel,J Smith,A Kopacek,D A Scudiero,K M Hite,P M Schlag,R H Shoemaker,W Walther
British Journal of Cancer. 2012; 106(8): 1395
[Pubmed] | [DOI]
37 Wnt signaling from membrane to nucleus: ▀-catenin caught in a loop
Cara Jamieson,Manisha Sharma,Beric R. Henderson
The International Journal of Biochemistry & Cell Biology. 2012; 44(6): 847
[Pubmed] | [DOI]
38 Chlorophyllin abrogates canonical Wnt/▀-catenin signaling and angiogenesis to inhibit the development of DMBA-induced hamster cheek pouch carcinomas
Nagini Siddavaram,Vidya Priyadarsini Ramamurthi,Veeravarmal Veeran,Rajakishore Mishra
Cellular Oncology. 2012; 35(5): 385
[Pubmed] | [DOI]
39 Multispecies model of cell lineages and feedback control in solid tumors
H. Youssefpour,X. Li,A.D. Lander,J.S. Lowengrub
Journal of Theoretical Biology. 2012; 304: 39
[Pubmed] | [DOI]
40 Differential proteomics identifies pdia3 as a novel chemoprevention target in human colon cancer cells
Antoine MÚnoret,David A. Drew,Shingo Miyamoto,Masako Nakanishi,Anthony T. Vella,Daniel W. Rosenberg
Molecular Carcinogenesis. 2012; : n/a
[Pubmed] | [DOI]
41 Probing transcription-specific outputs of ╬▓-catenin in vivo
Valenta, T. and Gay, M. and Steiner, S. and Draganova, K. and Zemke, M. and Hoffmans, R. and Cinelli, P. and Aguet, M. and Sommer, L. and Basler, K.
Genes and Development. 2011; 25(24): 2631-2643
[Pubmed]



 

Top
Previous article  Next article
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Background
Role of Wnt Sign...
Considerations f...
Acknowledgments
References
Authors
Article Figures

 Article Access Statistics
    Viewed19948    
    Printed572    
    Emailed8    
    PDF Downloaded206    
    Comments [Add]    
    Cited by others 41    

Recommend this journal