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  • 1
    Abstract: Purpose: Constitutively active WNT signaling is a hallmark of colorectal cancers and a driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here, we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer.Experimental Design: We used transcriptomic, proteomic, and in situ analyses to identify ADNP expression in colorectal cancer and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine in vivo Clinical associations were determined in a cohort of 221 human colorectal cancer cases.Results: ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion, and proliferation of colon cancer cells and accelerated tumor growth in xenografts in vivo Treatment with subnarcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor-bearing animals. In human patients with colon cancer, high ADNP expression was linked to good prognosis.Conclusions: Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer. Clin Cancer Res; 23(11); 2769-80. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27903678
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  • 2
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; HEPATOCELLULAR-CARCINOMA ; GENES ; GROWTH-FACTOR RECEPTOR ; TUMOR PROGRESSION ; snail ; hepatitis
    Abstract: The cell adhesion molecule E-cadherin has critical functions in development and carcinogenesis. Impaired expression of E-cadherin has been associated with disrupted tissue homeostasis, progression of cancer and a worse patient prognosis. So far, the role of E-cadherin in homeostasis and carcinogenesis of the liver is not well understood. By use of a mouse model with liver-specific deletion of E-cadherin and administration of the carcinogen diethylnitrosamin, we demonstrate that loss of E-cadherin expression in hepatocytes results in acceleration of the growth of hepatocellular carcinoma (HCC). In contrast, liver regeneration is not disturbed in mice lacking E-cadherin expression in hepatocytes. In human HCC we observed four different expression patterns of E-cadherin. Notably, atypical cytosolic expression of E-cadherin was positively correlated with a poorer patient prognosis: The median overall survival of patients with HCC expressing E-cadherin on the membrane only was 221 weeks (95% confidence interval (CI), 51-391) compared to 131 weeks in patients with cytosolic expression (95% CI, 71 - 191 weeks; p〈0.05). In conclusion, we demonstrate that impaired expression of E-cadherin promotes hepatocellular carcinogenesis and is associated with a worse prognosis in humans.
    Type of Publication: Journal article published
    PubMed ID: 24840851
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  • 3
    Abstract: Neuroendocrine carcinomas (NECs) of the colorectum are rare but highly aggressive neoplasms. These tumors show some shared genetic alterations with colorectal adenocarcinomas, and most of them have adjacent glandular adenoma or adenocarcinoma components. However, genetic data on colorectal NECs still are sparse and insufficient for definite conclusions regarding their molecular origin. Based on morphological characterization, panel and whole-exome sequencing, we here present results from an in-depth analysis of a collection of 15 colorectal NECs with glandular components, 10 of which by definition were mixed adenoneuroendocrine carcinomas (MANECs). Among shared genetic alterations of both tumor components, we most frequently found TP53, KRAS and APC mutations that also had highest allele frequencies. Mutations exclusive to glandular or neuroendocrine components outnumbered shared mutations but occurred at lower allele frequencies. Our findings not only provide additional evidence for a common clonal origin of colorectal NECs and adjacent glandular tumor components, but strongly suggest their development through the classical adenoma-carcinoma sequence. Moreover, our data imply early separation of glandular and neuroendocrine components during malignant transformation with subsequent independent mutational evolution.
    Type of Publication: Journal article published
    PubMed ID: 27586204
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  • 4
    Abstract: Colorectal cancers show significant tumor cell heterogeneity within the same core genetic background. Epithelial-mesenchymal transition (EMT) is an important functional aspect of this heterogeneity and hallmark of colorectal cancer progression. Here, we identify CYB5R1, an enzyme involved in oxidative stress protection and drug metabolism, as an indicator of EMT in colon cancer. We demonstrate high CYB5R1 expression in colorectal cancer cells undergoing EMT at the infiltrative tumor edge and reveal an extraordinarily strong association of CYB5R1 expression with two core EMT gene expression signatures in a large independent colon cancer data set from The Cancer Genome Atlas (TCGA). Furthermore, we demonstrate that CYB5R1 is required for an infiltrative tumor cell phenotype, and robustly linked with poor prognosis in colorectal cancer. Our findings have important implications for colon cancer cells undergoing EMT and may be exploited for diagnostic and therapeutic purposes.
    Type of Publication: Journal article published
    PubMed ID: 27120783
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  • 5
    Keywords: CELL LUNG-CANCER ; DNA ; MARKER ; UP-REGULATION ; MUTATION ; COLORECTAL-CANCER ; p53 ; HOMOLOG ; TUMOR-SUPPRESSOR ; MicroRNAs
    Abstract: PURPOSE: Here, we determined whether epigenetic inactivation of miR-34a and miR-34b/c genes may serve as a prognostic marker for distant metastases in colon cancer. EXPERIMENTAL DESIGN: Using a case-control study design of 94 primary colon cancer samples with and without liver metastases, we determined CpG methylation frequencies of miR-34a and miR-34b/c promoters, expression of miR-34a, and its targets c-Met, Snail, and beta-catenin and their prognostic value. RESULTS: miR-34a methylation was detected in 45.1% (n = 42 of 93) of the samples and strongly associated with metastases to the liver (P = 0.003) and lymph nodes (P = 0.006). miR-34b/c methylation was detected in 91.9% of the samples (n = 79/86). A significant inverse correlation between miR-34a methylation and expression of mature miR-34a (P = 0.018) was detected. Decreased miR-34a expression was associated with upregulation of c-Met, Snail, and beta-catenin protein levels (P = 0.031, 0.132, and 0.004), which were associated with distant metastases (P = 0.001, 0.017, and 0.005). In a confounder-adjusted multivariate regression model miR-34a methylation, high c-Met and beta-catenin levels provided the most significant prognostic information about metastases to the liver (P = 0.014, 0.031, and 0.058) and matched pairs showed a higher prevalence of these risk factors in the samples with distant spread (P = 0.029). Finally, we obtained statistical evidence indicating that the simultaneous detection of these three markers has the highest prognostic value. CONCLUSIONS: Silencing of miR-34a and upregulation of c-Met, Snail, and beta-catenin expression is associated with liver metastases of colon cancer. Detection of miR-34a silencing in resected primary colon cancer may be of prognostic value, especially in combination with detection of c-Met and beta-catenin expression.
    Type of Publication: Journal article published
    PubMed ID: 23243217
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  • 6
    Keywords: EXPRESSION ; PATHWAY ; TARGET ; COLORECTAL-CANCER ; STEM-CELLS ; C-MYC ; CYCLIN D1 ; WNT/BETA-CATENIN ; EPITHELIAL-MESENCHYMAL TRANSITION ; TUMOR-SUPPRESSOR PTEN
    Abstract: We determined whether active PI3K signaling together with nuclear accumulation of beta-Catenin is necessary to fully activate canonical WNT signaling and examined the association of both signaling pathways with colon cancer progression. Using reporter gene assays we examined the activation of beta-Catenin mediated transcription upon PI3K inhibition with or without beta-Catenin nuclear accumulation. Ectopically induced as well as constitutively active WNT signaling strictly required PI3K activity whereas PI3K inhibition had no effect on beta-Catenin subcellular localization but impaired beta-Catenin binding to WNT target gene promoters and decreased WNT target gene expression. Transcriptional activity of nuclear beta-Catenin depended on active PI3K signaling as nuclear accumulation of beta-Catenin failed to induce WNT reporter gene transcription upon PI3K inhibition. PI3K dependend transcriptional transactivation of beta-Catenin relies on events beyond phosphorylation at the AKT target site serine 552, as S552D-phosphomimetic beta-Catenin mutants were unable to restore WNT signaling when inhibiting PI3K. To study the prognostic value of PI3K pathway activation (activating PIK3CA mutations or loss of PTEN expression) and nuclear beta-Catenin expression, both variables were determined in 55 matched pairs of primary right sided colon cancer cases with or without distant metastasis. Activating mutations in the PIK3CA gene or loss of PTEN expression did not correlate with distant metastasis while high nuclear beta-Catenin expression combined with activation of the PI3K pathway identified cases in which distant metastasis had occurred. Activation of the PI3K pathway was not associated with nuclear beta-Catenin expression. We conclude that the transcriptional activity of nuclear beta-Catenin depends on PI3K activity. However, PI3K on its own does not affect beta-Catenin subcellular localization. Both factors synergize for full WNT signaling activity and are associated with distant metastasis in colon cancer. Thus, the detection of high nuclear beta-Catenin expression and simultaneous PI3K pathway activation identifies colon cancer patients with a high risk for distant metastasis.
    Type of Publication: Journal article published
    PubMed ID: 24930890
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  • 7
    Keywords: EXPRESSION ; GENE ; NF-KAPPA-B ; ACTIVATION ; PROGRESSION ; METASTASIS ; COLORECTAL-CANCER ; microenvironment ; inflammation ; TUMOR-INITIATING CELLS
    Abstract: The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IkappaB kinase alpha (IKKalpha) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKalpha kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon gamma (IFNgamma)-expressing M1-like myeloid cells. In IKKalpha mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKalpha mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKalpha as a promising target for colorectal cancer (CRC) therapy.
    Type of Publication: Journal article published
    PubMed ID: 24882009
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  • 8
    Keywords: EXPRESSION ; proliferation ; TUMOR PROGRESSION ; STEM-CELLS ; PROGNOSTIC-SIGNIFICANCE ; beta-catenin ; microenvironment ; E-cadherin ; TUMORIGENESIS ; WNT ACTIVITY
    Abstract: Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal cancers phenocopy colonic crypt architecture and thus preserve structural organization of the normal intestinal epithelium. A subset of colon cancers showed crypt-like compartments with high WNT activity and nuclear beta-Catenin at the leading tumor edge, adjacent proliferation, and enhanced Cytokeratin 20 expression in most differentiated tumor epithelia of the tumor center. This architecture strongly depended on growth conditions, and was fully reproducible in mouse xenografts of cultured and primary colon cancer cells. Full crypt-like organization was associated with low tumor grade and was an independent prognostic marker of better survival in a collection of 221 colorectal cancers. Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments. Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.
    Type of Publication: Journal article published
    PubMed ID: 25111606
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  • 9
    Keywords: EXPRESSION ; PROGRESSION ; COLON-CANCER ; METAANALYSIS ; TARGET GENES ; APC ; MICROSATELLITE-INSTABILITY
    Abstract: The majority of sporadic forms of colorectal carcinomas is characterized by deregulation of Wnt/beta-catenin signaling early in colorectal carcinogenesis. As a consequence, ITF-2B protein levels are increased in adenomas of these patients. However, ITF-2B protein levels are strongly reduced with increasing carcinoma stages, suggesting that reduction of ITF-2B protein is required for progression of adenomas to colorectal carcinomas. To find out if ITF-2B protein levels are correlated with the survival of patients with colorectal carcinomas, a tissue microarray containing samples from 213 colorectal carcinomas (T-categories T2 and T3) with corresponding survival information was stained with an ITF-2B antibody. In addition, we analyzed if detection of ITF-2B in microsatellite instable and microsatellite stable carcinomas as well as in colorectal carcinomas with KRAS mutations is correlated with survival. Detection of cytoplasmic ITF-2B protein was associated with better overall and progression free survival of patients with colorectal carcinomas (P=0.033 and 0.024, respectively). Multivariate Cox regression analysis revealed an increased risk to suffer from poor overall survival and recurrent disease if no cytoplasmic ITF-2B was detectable (HR=1.91; P=0.033 and HR=1.75; P=0.033, respectively). Similarly, patients with MSS carcinomas had a better overall survival, if they showed cytoplasmic positivity for ITF-2B (P=0.013). Remarkably, patients with colorectal carcinomas carrying KRAS mutations had a better overall and progression free survival rate if the carcinomas were positive for cytoplasmic ITF-2B (HR=4.71; P=0.002 and HR=2.57; P=0.024, respectively). These data suggest that cytoplasmic protein levels of ITF-2B could be used as a prognostic marker for patients with colorectal carcinomas.
    Type of Publication: Journal article published
    PubMed ID: 26328254
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  • 10
    Abstract: About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling, which promotes tumor invasion and progression. Here, we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models, and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells. In KRAS-mutant colon cancer, regulation of MAPK signaling was preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marked a progenitor cell compartment of growth-fueling colon cancer cells in vivo Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer. Cancer Res; 77(7); 1763-74. (c)2017 AACR.
    Type of Publication: Journal article published
    PubMed ID: 28202525
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