γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer.

PURPOSE: γ-Catenin is a protein closely related to ß-catenin. While the overexpression of ß-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells. METHODS: γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. RESULTS: γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule ß-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo. CONCLUSIONS: This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.

Addition of local hepatic therapy to sorafenib in patients with advanced hepatocellular carcinoma (stage BCLC C).

BACKGROUND/AIMS: For most patients with hepatocellular carcinoma (HCC), diagnosis is invariably done only in the advanced stages of the disease. For advanced, non-metastatic stage, standard therapy is transarterial chemoembolization (TACE). For metastatic disease, the recommended therapy is systemic treatment with sorafenib. In this study, we evaluated the benefit of an additional local hepatic treatment for patients with advanced metastatic disease. METHODS: In a retrospective study, we assessed the overall survival (OS), time to progression (TTP), and disease control rate (DCR) in 37 patients with metastasized HCC treated with sorafenib. Sixteen patients received additional local therapy, while 21 patients received only sorafenib. RESULTS: Median OS of patients with combined therapy was significantly higher with 25 months (95% CI: 13.7-36.3 months) as compared to 11 months (95% CI: 6.2-15.8 months) in patients treated with sorafenib alone. TTP was 7 months (95% CI: 5.3-8.7 months) compared to 5 months (95% CI: 3-7 months) and DCR was 87 versus 72% after 3 months and 31 versus 22% after 9 months. CONCLUSION: These data suggest that control of the liver tumor burden by local therapy in combination with sorafenib might prove beneficial for metastasized HCC. Randomised studies are needed to confirm this exploratory finding.

Risk factors for advanced neoplasia within subcentimetric polyps: implications for diagnostic imaging.

OBJECTIVE: Diagnostic imaging by CT colonography and capsule endoscopy is used to detect colonic lesions. Controversy exists regarding the work-up of subcentimetric lesions. The aim of this study was to identify risk indicators for advanced neoplasia (AN) in subcentimetric polyps. DESIGN: Colonoscopies were classified on the basis of the largest lesion found. AN was defined as high-grade dysplasia, villous histology, or cancer. Logistic regression models were developed to identify risk factors for AN, and validated on separate datasets. A risk index based on the logistic regression was generated, and the number needed to screen (NNS) to detect AN was determined. RESULTS: 1,077,956 colonoscopies identified 106,270 intermediate (5-9 mm) and 198,954 diminutive (≤ 4 mm) lesions; 13% of intermediate and 3.7% of diminutive lesions contained AN. The risk of AN was higher in intermediate than in diminutive lesions (OR 3.1; 95% CI 3.0 to 3.3). Age ≥ 85 versus <45 years was associated with ORs of 2.4 (95% CI 1.8 to 3.1) for intermediate polyps and 3.2 (95% CI 2.3 to 4.5) for diminutive polyps. Pedunculated versus sessile morphology was associated with a higher risk of AN in intermediate (OR 2.0; 95% CI 1.9 to 2.2) and diminutive (OR 3.5; 95% CI 2.9 to 4.1) lesions. In the combined analysis for subcentimetric lesions, ORs were 2.7 (95% CI 2.2 to 3.3) for age ≥ 85 versus <45 years, 1.1 (95% CI 1.1 to 1.2) for male sex, 1.6 (95% CI 1.4 to 1.7) for occult blood, 1.3 (95% CI 1.2 to 1.5) for overt blood in stool, 1.3 (95% CI 1.2 to 1.4) for more than four lesions, and 2.2 (95% CI 2.1 to 2.3) for pedunculated versus sessile lesions. At median risk index values, the NNS was 9.3 (95% CI 9.1 to 9.5) in individuals with intermediate lesions and 29.4 (95% CI 28.5 to 30.2) in those with diminutive lesions. Compared with the NNS of 15 of the whole cohort, the majority of intermediate, but a minority of diminutive, lesions were deemed at high risk of AN. CONCLUSION: This study successfully identified risk factors and established a risk index for subcentimetric lesions. This has implications for the work-up of patients with subcentimetric lesions identified on diagnostic imaging.

A direct comparison of the prevalence of advanced adenoma and cancer between surveillance and screening colonoscopies.

BACKGROUND/AIMS: Surveillance colonoscopy is recommended after polypectomy of adenoma and surgery for colorectal cancer. The purpose of this study was to assess the frequency of advanced adenoma and cancer in colonoscopies performed for surveillance compared to screening colonoscopies. METHODS: Analysis of relative frequencies of findings in colonoscopies performed for post-adenoma surveillance (post-ad), post-cancer surveillance (post-crc), screening, and follow-up of a positive fecal occult blood test (FOBT). Logistic regression was used to identify the risk for advanced adenoma (adenoma ≥10 mm, containing high-grade dysplasia, or villous histology) and cancer. RESULTS: 324,912 colonoscopies were included in the analysis: 81,877 post-ad, 26,896 post-crc, 178,305 screening, 37,834 positive FOBT. Advanced adenoma (cancer) was diagnosed in 8.0% (0.4%) of post-ad, 5.0% (1.0%) of post-crc, 7.4% (1.1%) of screening, and 11.7% (3.6%) of positive FOBT colonoscopies. Compared to screening, the odds ratios for finding advanced adenoma were 0.93 (95% CI 0.88-0.98) for post-ad, 0.96 (0.86-1.08) for post-crc, and 1.18 (1.09-1.28) for positive FOBT colonoscopies. The odds ratios for the diagnosis of cancer were 0.29 (0.24-0.36) for post-ad, 0.81 (0.61-1.07) for post-crc, and 2.77 (2.43-3.17) for positive FOBT. CONCLUSION: Colonoscopy for post-ad surveillance but not colonoscopy for post-crc surveillance is associated with a lower risk of diagnosis of advanced adenoma and cancer.

γ-Catenin is an independent prognostic marker in early stage colorectal cancer.

PURPOSE: Expression and role of γ-catenin in colorectal carcinogenesis is not well understood. We aimed at characterizing γ-catenin's expression pattern during colorectal carcinogenesis. METHODS: The expression pattern of γ-catenin was characterized in adenomas, primary colorectal carcinomas, and their corresponding metastases. Since this descriptive immunohistochemical analysis revealed upregulation of γ-catenin in the invasive front of both primary tumors and metastases, a tissue microarray (TMA) was performed, allowing for correlation of subcellular expression patterns with disease recurrence and cancer-specific survival. Comparison of γ-catenin expression with that of ß-catenin was performed. RESULTS: In normal colonic epithelium and adenomas, γ-catenin was weakly expressed at the membrane. In central areas of primary colorectal carcinomas, membranous and cytoplasmatic expression was present, with cytoplasmatic and nuclear upregulation of γ-catenin in the invasive fronts. Expression patterns found in metastases resembled those of their respective primary tumors. Subsequent TMA analysis showed that upregulation of cytoplasmatic γ-catenin in the invasive fronts of curatively resected early T2 and T3 colorectal carcinomas was associated with shortened disease-free survival and an increased risk of death (p=0.003; hazard ratio = 2.98; 95% confidence interval, 1.44-6.18). CONCLUSIONS: The correlation of upregulated cellular γ-catenin levels with higher recurrences and impaired survival suggests a tumor promoting role of γ-catenin in colorectal cancer. γ-Catenin may therefore serve as a marker for identifying patients who are at increased risk of disease recurrence who may benefit from closer follow-up and adjuvant therapy.

Attitude to secondary prevention and concerns about colonoscopy are independent predictors of acceptance of screening colonoscopy.

BACKGROUND: Colonoscopy in combination with endoscopic polypectomy has been shown to be an efficient measure for reducing colorectal cancer incidence. In Germany, a colorectal cancer screening program based on colonoscopy for individuals aged 55 and above was introduced in 2002. However, for largely unknown reasons, participation rates remain low. The purpose of this study was to identify factors influencing compliance with colorectal cancer screening. METHODS: A structured survey of 239 individuals aged 55-79 years was performed. Statistical analysis included chi(2) test, t test, principal component analysis, and logistic regression. RESULTS: 56% of previously screened, but only 26% of non-screened individuals had received a recommendation to undergo screening colonoscopy. 50% of the non-screened believed a screening colonoscopy should only be performed in case of complaints. Univariate analysis identified participation in any secondary prevention measures (p < 0.001), concerns about colonoscopy (p < 0.012), and knowledge about colorectal cancer (p < 0.001) as critical issues distinguishing between groups. Multivariate analysis revealed that secondary prevention (p < 0.001) and concerns about colonoscopy (p = 0.026) were independent predictors of compliance with screening recommendations. CONCLUSION: Our survey has identified critical factors deterring compliance with colorectal cancer screening recommendations. This will help to direct future campaigns in order to increase participation in colorectal cancer screening.

Wnt signaling as a therapeutic target for cancer.

The Wnt/beta-catenin signaling pathway is tightly regulated and has important functions in development, tissue homeostasis, and regeneration. Deregulation of Wnt/beta-catenin signaling is frequently found in various human cancers. Eighty percent of colorectal cancers alone reveal activation of this pathway by either inactivation of the tumor-suppressor gene adenomatous polyposis coli or mutation of the proto-oncogene beta-catenin. Activation of Wnt/beta-catenin signaling has been found to be important for both initiation and progression of cancers of different tissues. Therefore, targeted inhibition of Wnt/beta-catenin signaling is a rational and promising new approach for the therapy of cancers of various origins.

[Colorectal cancer: prevention and early detection]. / Kolorektales Karzinom: Prävention und Früherkennung.

Colorectal cancer is one of the leading causes of cancer associated morbidity and mortality. Main risk factors include advanced age, affected family members, male sex and lifestyle factors. The development of early adenoma to invasive cancer requires 10 and more years. Therefore, prevention via colonoscopy with polypectomy and early detection of asymptomatic stages is possible. Colonoscopy is a diagnostic and therapeutic tool with the highest sensitivity for precancerous lesions and early cancers of the colon. New fecal immunological tests reveal a higher sensitivity for advanced adenoma and cancer than guaiac based hemoccult tests while maintaining a high specificity. Molecular stool and blood tests are promising new developments. However, similar to virtual colonoscopy and colon capsule endoscopy, they have so far not been established as routine instruments for prevention and early detection of colorectal cancer.

Conference scene: DGVS spring conference 2009.

The 3rd annual DGVS Spring Conference of the German Society for Gastroenterology (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) was held at the Seminaris Campus Hotel in Berlin, Germany, on 8-9 May, 2009. The conference was organized by Roland Schmid and Matthias Ebert from the Technical University of Munich, Germany. The central theme of the meeting was 'translational gastrointestinal oncology: towards personalized medicine and individualized therapy'. The conference covered talks on markers for diagnosis, screening and surveillance of colorectal cancer, targets for molecular therapy, response prediction in clinical oncology, development and integration of molecular imaging in gastrointestinal oncology and translational research in clinical trial design. Owing to the broad array of topics and limitations of space, this article will focus on biomarkers, response prediction and the integration of biomarkers into clinical trials. Presentations mentioned in this summary were given by Matthias Ebert (Technical University of Munich, Germany), Esmeralda Heiden (Epigenomics, Berlin, Germany), Frank Kolligs (University of Munich, Germany), Florian Lordick (University of Heidelberg, Germany), Hans Jorgen Nielsen (University of Copenhagen, Denmark), Anke Reinacher-Schick (University of Bochum, Germany), Christoph Röcken (University of Berlin, Germany), Wolff Schmiegel (University of Bochum, Germany) and Thomas Seufferlein (University of Halle, Germany).