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Current models predict that beta-catenin (beta-cat) functions in Wnt signaling via activation of Tcf/Lef target genes and that its abundance is regulated by the adenomatous polyposis coli (APC) and glycogen synthase kinase 3beta (GSK3beta) proteins. In colon and other cancers, mutations in APC or presumptive GSK3beta phosphorylation sites of beta-cat are associated with constitutive activation of Tcf/Lef transcription. In spite of assumptions about its oncogenic potential, prior efforts to demonstrate that mutated beta-cat will induce neoplastic transformation have yielded equivocal results. We report here that mutated, but not wild-type, beta-cat proteins induced neoplastic transformation of RK3E, an adenovirus E1A-immortalized epithelial cell line. Analysis of the properties of mutant beta-cat proteins and studies with a dominant negative Tcf-4 mutant indicated that the ability of beta-cat to bind and activate Tcf/Lef factors is crucial for transformation. c-myc has recently been implicated as a critical Tcf-regulated target gene. However, c-myc was not consistently activated in beta-cat-transformed RK3E cells, and a dominant negative c-Myc mutant protein failed to inhibit beta-cat transformation. Our findings underscore the role of beta-cat mutations and Tcf/Lef activation in cancer and illustrate a useful system for defining critical factors in beta-cat transformation.

Background and aims: This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). Methods: Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. Results: 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p,0.001). Conclusions: High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps .5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.Colorectal cancer is one of the major public health issues in industrialised countries. Most colorectal cancers are thought to originate from benign adenomatous polyps that develop over a period of many years.1 Early detection followed by removal of adenomas has been shown to reduce incidence and colorectal cancer-related mortality.2 3Therefore, screening of the asymptomatic and average risk population is recommended by many organisations and expert panels, and is reimbursed by insurance companies in several countries. 4-7Next to colonoscopy, flexible sigmoidoscopy (FS) and guaiac-based faecal occult blood test (FOBT) are widely applied screening procedures which have been compared prospectively with each other. Colonoscopy has been found to be the screening test with the highest sensitivity and outperforms FS and FOBT which miss a significant number of relevant adenomas. 8 Colonoscopy, however, is not a perfect test in itself, and misses 6-12% of large adenomas. 9-11CT colonography (CTC), also known as virtual colonoscopy, and faecal immunochemical tests (FITs) have been proposed as screening tests for colonic neoplasia.12-14 They have at present not been integrated into screening programmes. Based on recent research, CTC shows heterogeneous results in the detection of colonic polyps: some studies demonstrated high sen...

Cancers of the gastrointestinal tract, including the liver, bile ducts, and pancreas, constitute the largest group of malignant tumors. Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of cancer-related deaths. Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like p53. Identification of the interaction of APC with the proto-oncogene β-catenin has linked colorectal carcinogenesis to the Wnt-signal transduction pathway. The main function of APC is thought to be the regulation of free β-catenin in concert with the glycogen synthase kinase 3β (GSK-3β) and Axin proteins. Loss of APC function, inactivation of Axin or activating β-catenin mutations result in the cellular accumulation of β-catenin. Upon translocation to the nucleus β-catenin serves as an activator of T-cell factor (Tcf)-dependent transcription leading to an increased expression of several specific target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations are almost exclusively found in colorectal cancers, deregulation of Wnt/β-catenin/Tcf signaling is also common in other gastrointestinal and extra-gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the Wnt pathway is deregulated by inactivation of Axin or stabilizing mutations of β-catenin. The majority of hepatoblastomas and a group of gastric cancers also carry β-catenin mutations. Clearly, this pathway harbors great potential for future applications in cancer diagnostics, staging, and therapy.

Wnts have key roles in many developmental processes, including hair follicle growth and differentiation. Stabilization of ␤-catenin is essential in the canonical Wnt signaling pathway. We developed transgenic mice expressing a regulated form of ␤-catenin in the skin. Chronic activation of ␤-catenin in resting (telogen) hair follicles resulted in changes consistent with induction of an exaggerated, aberrant growth phase (anagen). Transient activation of ␤-catenin produced a normal anagen. Our data lend strong support to the notion that a Wnt/ ␤-catenin signal operating on hair follicle precursor cells serves as a crucial proximal signal for the telogen-anagen transition. Wnt family proteins function in short-range signaling. They regulate cell fate, adhesion, differentiation, proliferation, and motility, and many studies have demonstrated their critical roles in development (for review, see Peifer and Polakis 2000). Mutational defects in Wnt signaling have a major contributing role in a broad spectrum of cancers (Polakis 2000). At present, it appears many Wnts exert their effects, at least in part, through a "canonical" signaling pathway in which stabilization of the ␤-catenin protein is essential. Much of the ␤-catenin protein in the cell is associated with the cell membrane, where ␤-catenin binds to and links E-cadherin to the cytoskeleton through ␤-catenin's binding to ␣-catenin. A fraction of the ␤-catenin is free in the cytoplasm and/or nucleus. Normally, in the absence of Wnt signals, ␤-catenin is bound and negatively regulated by a protein complex that includes the adenomatous polyposis coli (APC) and axin tumor suppressor proteins as well as glycogen synthase kinase-3␤ (GSK-3␤; for review, see Peifer and Polakis 2000). This complex promotes phosphorylation of ␤-catenin at a number of N-terminal serine and threonine residues, and the phosphorylated ␤-catenin is ubiquitinated and subsequently degraded by the proteasome.Binding of Wnts to their cognate frizzled and low-density lipoprotein receptor-related protein receptor complexes on the cell surface leads to inhibition of GSK-3␤ activity and increased levels of free ␤-catenin in the cell (Peifer and Polakis 2000). In cancers, inactivating mutations in the APC or axin proteins or activating mutations affecting N-terminal phosphorylation sites in ␤-catenin lead to stabilization of ␤-catenin (Polakis 2000). Regardless of whether Wnt signals or mutational defects stabilize ␤-catenin, following its accumulation in the cell, ␤-catenin can complex in the nucleus with T cell factor/ lymphoid enhancer factor (TCF/LEF) transcription regulators, leading to activation of TCF-regulated genes (a list of candidate TCF target genes is provided at: http:// www.stanford.edu/∼rnusse/wntwindow.html).Wnt/␤-catenin signaling has been proposed to function in hair follicle morphogenesis and differentiation (Kishimoto et al. 2000;Fuchs et al. 2001;Millar 2002). Hair follicle morphogenesis is characterized by the downward growth of epithelial hair follicle precursor cells into the ...