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1.
Clin Transl Gastroenterol ; 11(1): e00124, 2020 01.
Article in English | MEDLINE | ID: mdl-31990698

ABSTRACT

OBJECTIVES: Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death. Unfortunately, recurrence is common even after curative treatment of early-stage patients, and no adjuvant treatment has yet been established. Aberrant expression of OLFM4 in human cancers has been reported; yet, its specific function during tumor development remains poorly understood, and its role in HCC is unknown. The purpose of this study is to examine the prognostic significance of OLFM4 and its functional relevance in determining recurrence in patients with early-stage HCC. METHODS: Immunohistochemical staining to assess expression, cellular distribution, and prognostic significance of OLFM4 was performed in a tissue microarray comprising 157 HCC tissues and matched nontumor tissues. In addition, expression of OLFM4-coding mRNA was assessed in a separate patients' cohort. The findings were validated by in vitro functional studies using siRNA directed against OLFM4 to assess its effect on cell motility and proliferation. RESULTS: The fraction of HCC samples exhibiting positive OLFM4 staining was higher in comparison with that observed in hepatocytes from matched nontumor tissue (61% vs 39%). However, cytoplasmic-only staining for OLFM4 was associated with vascular invasion (P = 0.048), MMP-7 expression (P = 0.002), and poorer survival (P = 0.008). A multivariate analysis confirmed the independent significance of OLFM4 in determining patients' outcome (5-year survival [58.3% vs 17.3%; HR: 2.135 {95% confidence interval: 1.135-4.015}; P = 0.019]). Correspondingly, inhibition of OLFM4 by siRNA modulated the expression of MMP-7 and E-cadherin, causing inhibition of cell proliferation, motility, and migration. DISCUSSION: To the best of our knowledge, we provide the first report on the prognostic significance of OLFM4 in HCC and identify its mechanistic role as crucial mediator of MMP family protein and E-Cadherin in determining cell invasion and metastasis formation.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Cell Movement/genetics , Cell Proliferation/genetics , Granulocyte Colony-Stimulating Factor/metabolism , Liver Neoplasms/metabolism , Antigens, CD/metabolism , Cadherins/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Cell Line, Tumor , Cell Membrane/metabolism , Cytoplasm/metabolism , Female , Gene Knockdown Techniques , Granulocyte Colony-Stimulating Factor/genetics , Hepatocytes/metabolism , Humans , Immunohistochemistry , In Vitro Techniques , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Male , Matrix Metalloproteinase 7/metabolism , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Proportional Hazards Models , RNA, Small Interfering , Survival Rate
2.
Cancer Cell ; 24(1): 15-29, 2013 Jul 08.
Article in English | MEDLINE | ID: mdl-23845441

ABSTRACT

We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.


Subject(s)
Colorectal Neoplasms/etiology , Mutation , Proto-Oncogene Proteins B-raf/genetics , Animals , Cell Transformation, Neoplastic , Colorectal Neoplasms/drug therapy , Cyclin-Dependent Kinase Inhibitor p16 , Drug Screening Assays, Antitumor , MAP Kinase Signaling System , Mice , Microsatellite Instability , Neoplasm Invasiveness , Neoplasm Proteins/physiology , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Tumor Suppressor Protein p53/physiology , Wnt Signaling Pathway
3.
PLoS One ; 8(2): e56760, 2013.
Article in English | MEDLINE | ID: mdl-23460812

ABSTRACT

INTRODUCTION: Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. AIMS AND METHODS: Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. RESULTS: The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. CONCLUSION: This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.


Subject(s)
Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/surgery , Receptors, TNF-Related Apoptosis-Inducing Ligand/deficiency , Aged , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Cell Membrane/metabolism , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/pathology , Prognosis , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Staining and Labeling
4.
Oncotarget ; 3(10): 1182-93, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23045412

ABSTRACT

Approximately 7.5% of all colorectal cancers are considered to originate from the alternative, serrated route. Here, we investigate the expression of the c-MYC oncogene and the SIRT1 protein deacetylase by immunohistochemical staining in subgroups of colorectal serrated lesions that were characterized by different molecular alterations. The expression of c-MYC and SIRT1 correlated with the presence of KRAS and BRAF mutations and high expression of c-MYC and SIRT1 was strongly associated with higher grades of malignancy. In contrast, in the majority of serrated lesions without KRAS or BRAF mutations, c-MYC and SIRT1 expression was not found increased. In this group only a subset of mostly high grade intraepithelial neoplasia and carcinoma was characterized by elevated c-MYC and SIRT1 expression. This was associated with nuclear localization of beta-catenin, indicating that Wnt pathway activation may confer transcriptional induction of c-MYC. In summary, we established a link between oncogenic K-Ras and B-Raf, suggesting post-transcriptional regulation of c-MYC through MAPK/ERK1/2 pathway activation, as well as for Wnt signalling to the activation of the c-MYC oncogene, and consequently of SIRT1 in the serrated route. The increasing expressions with higher grades of malignancy suggest crucial functions for c-MYC and SIRT1 in the progression of serrated lesions to colorectal cancer. These functions may include antagonizing of apoptosis and senescence, which are characteristic features of serrated lesions.


Subject(s)
Adenoma/pathology , Cell Transformation, Neoplastic/pathology , Colonic Polyps/pathology , Colorectal Neoplasms/pathology , Precancerous Conditions/pathology , Proto-Oncogene Proteins c-myb/metabolism , Sirtuin 1/metabolism , Adenoma/metabolism , Adult , Aged , Aged, 80 and over , Cell Transformation, Neoplastic/metabolism , Colonic Polyps/metabolism , Colorectal Neoplasms/metabolism , DNA, Neoplasm/genetics , Female , Humans , Immunoenzyme Techniques , Male , Middle Aged , Mutation/genetics , Neoplasm Grading , Neoplasm Invasiveness , Polymerase Chain Reaction , Precancerous Conditions/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins/genetics
5.
Histopathology ; 60(3): 416-26, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22276605

ABSTRACT

AIMS: A test predicting distant metastases would be valuable for prognostication in colon cancer (CC). In previous studies, CC with microsatellite instability (MSI) showed a reduced risk of distant metastases. High expression of CD133 and ß-catenin, both related to cancer stem cell phenotypes, might be predictive markers for metastasis. The aim of this study was to develop a simple and robust test for risk assessment of distant metastases in CC. METHODS AND RESULTS: In a case-control study, 57 cases of right-sided CC specimens with synchronous distant metastases were matched with 57 CC without distant metastases. Immunohistochemistry for MLH1, CD133 and nuclear ß-catenin was carried out. To define the diagnostic algorithm the tumours were first stratified according to their MLH1 expression. Loss of MLH1 expression was correlated significantly with a very low risk of distant metastases (5.3%; P = 0.00003). In MLH1-positive cases, combined high scores of CD133 and ß-catenin were associated with a very high rate of distant metastases (94.4%), whereas the risk was intermediate for carcinomas with either low CD133 and/or low ß-catenin expression (P = 0.0007). A validation study using an independent set of 68 right-sided CC specimens showed a clear trend towards risk stratification according to the algorithm; however, sample sizes were small, and associations were not statistically significant. CONCLUSIONS: By the use of three markers, this algorithm allowed identification of subgroups of right-sided CC patients with extremely high and extremely low risk of distant metastases.


Subject(s)
Adenocarcinoma/diagnosis , Algorithms , Colonic Neoplasms/diagnosis , Immunohistochemistry/methods , AC133 Antigen , Adaptor Proteins, Signal Transducing/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/secondary , Aged , Antigens, CD/metabolism , Biomarkers, Tumor/metabolism , Case-Control Studies , Cell Nucleus/metabolism , Cell Nucleus/pathology , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Female , Glycoproteins/metabolism , Humans , Male , Microsatellite Instability , MutL Protein Homolog 1 , Neoplasm Grading , Neoplasm Metastasis/diagnosis , Neoplasm Metastasis/genetics , Nuclear Proteins/metabolism , Peptides/metabolism , Predictive Value of Tests , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Risk Assessment , beta Catenin/metabolism
6.
Exp Mol Pathol ; 92(1): 111-7, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22101256

ABSTRACT

BACKGROUND: Aldehyde dehydrogenase-1 (ALDH1) is involved in the regulation of cell proliferation and differentiation. Moreover, it is a marker for cancer stem cells (CSC). As CSCs were shown to be the driving force of tumor progression and metastases we suspected that the expression of ALDH1 correlated with the prognostic 5 year survival of colorectal cancer. METHODS: ALDH1 expression was analyzed in a highly stratified collective of 186 T3 N0 M0 G2 primary colorectal cancer specimens applying immunohistochemistry. For the analysis a scoring system for the expression of ALDH1 was developed that was aided by the pattern of the subcellular expression of beta-catenin which is a well known indicator for colorectal CSCs. RESULTS: First, ALDH1 expression could be assigned to two groups which correlated with the absence or presence of nuclear beta-catenin expression. Second, ALDH1 group 2 expression patterning correlated highly significantly with low long term survival (p=0.010) of patients with T3 N0 M0 G2 colorectal cancer. This correlation was found univariately and when applying the multivariate Cox-model. CONCLUSION: ALDH1 expression pattern is an independent prognostic marker for survival of T3 N0 M0 G2 colorectal cancer patients.


Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/pathology , Isoenzymes/metabolism , Neoplastic Stem Cells/pathology , Retinal Dehydrogenase/metabolism , beta Catenin/metabolism , Aged , Aldehyde Dehydrogenase 1 Family , Blotting, Western , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Multivariate Analysis , Neoplastic Stem Cells/metabolism , Prognosis , Tissue Array Analysis
7.
PLoS One ; 7(12): e51654, 2012.
Article in English | MEDLINE | ID: mdl-23284732

ABSTRACT

BACKGROUND: The fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL) are almost invariably expressed in colorectal cancer (CRC) represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor. AIM AND METHODS: Thus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI) had an effect on survival and thus a prognostic effect. RESULTS: As expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]). CONCLUSIONS: In contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting compounds might be due to insufficient selection of patients bearing tumors with membrane-bound TRAIL-receptors.


Subject(s)
Adenocarcinoma/genetics , Colorectal Neoplasms/genetics , Microsatellite Instability , Mutation/genetics , Proto-Oncogene Proteins/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , ras Proteins/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Cadherins/metabolism , Cell Membrane/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA/genetics , Female , Humans , Immunoenzyme Techniques , Male , Neoplasm Staging , Prognosis , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins p21(ras) , Real-Time Polymerase Chain Reaction , Survival Rate , Tissue Array Analysis , ras Proteins/metabolism
8.
BMC Cancer ; 11: 518, 2011 Dec 14.
Article in English | MEDLINE | ID: mdl-22168803

ABSTRACT

BACKGROUND: The transcription factor SOX2, which is involved in the induction of pluripotent stem cells and contributes to colorectal carcinogenesis, is associated with a poor prognosis in colon cancer (CC). Furthermore, SOX2 is a repressor of the transcriptional activity of ß-catenin in vitro. Since the majority of CC develop via an activation of the Wnt/ß-catenin signalling pathway, indicated by nuclear expression of ß-catenin, we wanted to investigate the expression patterns of SOX2 and ß-catenin and correlate them with the occurrence of lymph node and distant metastases as indicators of malignant progression. METHODS: The expression of SOX2 and ß-catenin was investigated in a case control study utilizing a matched pair collection (N = 114) of right-sided CCs with either corresponding distant metastases (N = 57) or without distant spread (N = 57) by applying immunohistochemistry. RESULTS: Elevated protein expression of SOX2 significantly correlated with the presence of lymph node- (p = 0.006) and distant metastases (p = 0.022). Nuclear ß-catenin expression correlated significantly only with distant metastases (p = 0.001). Less than 10% of cases showed a coexpression of high levels of ß-catenin and SOX2. The positivity for both markers was also associated with a very high risk for lymph-node metastases (p = 0.007) and distant spread (p = 0.028). CONCLUSION: We demonstrated that increased expression of either SOX2 or nuclear ß-catenin are associated with distant metastases in right-sided CC. Additionally, SOX2 is also associated with lymph-node metastases. These data underline the importance of stemness-associated markers for the identification of CC with high risk for distant spread.


Subject(s)
Adenocarcinoma/metabolism , Colonic Neoplasms/metabolism , Neoplasm Proteins/metabolism , SOXB1 Transcription Factors/metabolism , Adenocarcinoma/secondary , Aged , Case-Control Studies , Colonic Neoplasms/secondary , Female , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Middle Aged , beta Catenin/metabolism
9.
Pigment Cell Melanoma Res ; 24(4): 631-42, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21599871

ABSTRACT

Recent observations suggest that melanoma cells drive disease progression by switching back and forth between phenotypic states of proliferation and invasion. Phenotype switching has been linked to changes in Wnt signalling, and we therefore looked for cell phenotype-specific differences in the levels and activity of ß-catenin and its LEF/TCF co-factors. We found that while cytosolic ß-catenin distribution is phenotype-specific (membrane-associated in proliferative cells and cytosolic in invasive cells), its nuclear distribution and activity is not. Instead, the expression patterns of two ß-catenin co-factors, LEF1 and TCF4, are both phenotype-specific and inversely correlated. LEF1 is preferentially expressed by differentiated/proliferative phenotype cells and TCF4 by dedifferentiated/invasive phenotype cells. Knock-down experiments confirmed that these co-factors are important for the phenotype-specific expression of M-MITF, WNT5A and other genes and that LEF1 suppresses TCF4 expression independently of ß-catenin. Our data show that melanoma cell phenotype switching behaviour is regulated by differential LEF1/TCF4 activity.


Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Lymphoid Enhancer-Binding Factor 1/genetics , Melanoma/genetics , Melanoma/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing/drug effects , Humans , Lymphoid Enhancer-Binding Factor 1/metabolism , Models, Biological , Neoplasm Invasiveness , Phenotype , Transcription Factor 4 , Transcription Factors/metabolism , Wnt Proteins/pharmacology , beta Catenin/metabolism
10.
Mod Pathol ; 24(7): 1015-22, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21423154

ABSTRACT

P16(Ink4a) is an important factor in carcinogenesis and its expression can be linked to oncogene-induced senescence. Oncogene-induced senescence is characterized by growth arrest and occurs as a consequence of oncogene activation due to KRAS or BRAF mutation. It has been shown that the induction of p16(Ink4a) in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours. Loss of p16(Ink4a) is often caused by CDKN2A promoter hypermethylation. This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) in colorectal carcinomas, which is characterized by widespread promoter methylation. In particular, colorectal carcinomas with BRAF mutations have been shown to be strongly associated with CIMP. Also, BRAF mutations are strongly correlated with the serrated route to colorectal cancer. In this study, we investigated p16(Ink4a) expression and promoter methylation in BRAF-mutated serrated lesions of the colon. P16(Ink4a) expression was found to be upregulated in premalignant lesions and was lost in invasive serrated carcinomas. P16(Ink4a) expression and Ki67 expression were mutually exclusive, indicating that p16(Ink4a) acts as cell cycle inhibitor. Additionally, progression of malignant transformation in serrated lesions was accompanied by increasing methylation of the CDKN2A promoter. Therefore, our data provide evidence for oncogene-induced senescence in the serrated route to colorectal cancer with BRAF mutation and upregulation of p16(Ink4a) expression appears to be a useful indicator of induction of senescence. Loss of p16(Ink4a) expression occurs during malignant transformation and is caused mainly by aberrant methylation of the CDKN2A promoter.


Subject(s)
Adenoma/genetics , Adenomatous Polyps/genetics , Cell Transformation, Neoplastic/genetics , Colonic Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Genes, p16 , Precancerous Conditions/genetics , Adenoma/pathology , Adenomatous Polyps/pathology , Adult , Aged , Aged, 80 and over , Cellular Senescence/genetics , Colonic Neoplasms/pathology , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA Methylation , DNA Mutational Analysis , Down-Regulation , Humans , Immunohistochemistry , Middle Aged , Mutation , Precancerous Conditions/pathology , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins B-raf/genetics , Up-Regulation
11.
Int J Cardiol ; 150(3): e89-91, 2011 Aug 04.
Article in English | MEDLINE | ID: mdl-20051301

ABSTRACT

A 69-year-old man was presented with a holosystolic and early diastolic murmur in cardiac auscultation, pretibial edema and elevated inflammation markers. Aortic valve and ascending aorta had been replaced 9 months earlier. Transesophageal echocardiography revealed massive eccentric regurgitation and dehiscence of the aortic valve, resulting in a giant circular false aneurysm with connection to the lumen of the aortic arch. CT and MR confirmed extensive leakage in a covered perforation. The false lumen was confined by a newly formed vessel wall, since the native Aorta ascendens had been excised. Smooth muscle cells expressing the progenitor marker CD34 were detected selectively in this region, indicating a contribution of circulating progenitor cells to the false vessel wall. After detection of Staphylococcus epidermidis in blood, another urgent Bentall operation was performed. However, the patient succumbed to right ventricular failure and multiple organ failure on postoperative day 1.


Subject(s)
Aneurysm, False/diagnosis , Aorta, Thoracic/microbiology , Aortic Valve/microbiology , Heart Valve Prosthesis/adverse effects , Prosthesis Failure/adverse effects , Staphylococcal Infections/diagnosis , Staphylococcus epidermidis/isolation & purification , Aged , Aneurysm, False/etiology , Aneurysm, False/microbiology , Aorta, Thoracic/pathology , Aortic Valve/pathology , Humans , Male , Staphylococcal Infections/complications
12.
J Transl Med ; 8: 123, 2010 Nov 22.
Article in English | MEDLINE | ID: mdl-21092222

ABSTRACT

BACKGROUND: Most colorectal carcinomas are driven by an activation of the canonical Wnt signalling pathway, which promotes the expression of multiple target genes mediating proliferation inavasion and invasion. Upon activation of the Wnt signalling pathway its key player ß-catenin translocates from the cytoplasm to the nucleus and binds to members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF-1) family namely LEF-1 and TCF4 which are central mediators of transcription. In this study we investigated the expression of ß-Catenin, LEF1 and TCF4 in colorectal carcinomas and their prognostic significance. METHODS: Immunohistochemical analyses of LEF-1, TCF4 and nuclear ß-Catenin were done using a tissue microarray with 214 colorectal cancer specimens. The expression patterns were compared with each other and the results were correlated with clinicopathologic variables and overall survival in univariate and multivariate analysis. RESULTS: LEF-1 expression was found in 56 (26%) and TCF4 expression in 99 (46%) of colorectal carcinomas and both were heterogeneously distributed throughout the tumours. Comparing LEF-1, TCF4 and ß-catenin expression patterns we found no correlation. In univariate analysis, TCF4 expression turned out to be a negative prognostic factor being associated with shorter overall survival (p = 0.020), whereas LEF-1 expression as well as a LEF-1/TCF4 ratio were positive prognostic factors and correlated with longer overall survival (p = 0.015 respectively p = 0.001). In multivariate analysis, LEF-1 and TCF4 expression were confirmed to be independent predictors of longer respectively shorter overall survival, when considered together with tumour stage, gender and age (risk ratio for LEF-1: 2.66; p = 0.027 risk ratio for TCF4: 2.18; p = 0.014). CONCLUSIONS: This study demonstrates different prognostic values of LEF-1 and TCF4 expression in colorectal cancer patients indicating different regulation of these transcription mediators during tumour progression. Moreover both factors may serve as new potential predictive markers in low stage colon cancer cases in advance.


Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Colorectal Neoplasms/pathology , Lymphoid Enhancer-Binding Factor 1/metabolism , Transcription Factors/metabolism , Humans , Immunohistochemistry , Survival Analysis , Transcription Factor 4
13.
Clin Cancer Res ; 16(22): 5529-38, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20889918

ABSTRACT

PURPOSE: After the advent of targeted therapies for hepatocellular carcinoma (HCC), much work is being done to provide a comprehensive description of the different signaling pathways contributing to cell survival and proliferation in this tumor. Apoptotic signaling mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents an important mechanism of tumor surveillance, but its importance in the development of HCC is not known. We thus investigated the cellular distribution and the prognostic importance of TRAIL receptors in HCC. EXPERIMENTAL DESIGN: Immunohistochemical staining for TRAIL receptors was evaluated in HCC tissues and in matched surrounding nontumor tissues of 157 HCC patients treated with liver transplantation or partial hepatectomy. Survival was analyzed in 93 patients who underwent partial hepatectomy. RESULTS: The fraction of HCC samples with positive membrane staining for TRAIL receptor 1 (TRAIL-R1) and 2 (TRAIL-R2) was 1.4- and 2.7-fold lower compared with that of hepatocytes from surrounding tissues (P = 0.01). Loss of either TRAIL-R1 or TRAIL-R2, as confirmed by a multivariate analysis, significantly worsened 5-year survival of HCC patients {survival, 27% versus 52% and 15% versus 43%; hazard ratio (HR), 2.3 [95% confidence interval (CI), 1.1-4.4] and 2.4 (95% CI, 1.1-5.2), respectively}. Loss of both TRAIL receptors further decreased survival of patients [HR, 5.72 (95% CI, 2.1-15.5) versus double-negative staining; P = 0.001], indicating an additive effect on survival of TRAIL-R1 and TRAIL-R2. CONCLUSIONS: This pilot study suggests that loss of TRAIL receptors is a frequent feature of HCCs and an independent predictor of survival in patients undergoing partial hepatectomy. Future therapeutic protocols are likely to profit from the characterization of their expression and cellular distribution. Clin Cancer Res; 16(22); 5529-38. ©2010 AACR.


Subject(s)
Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/diagnosis , Liver Neoplasms/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/biosynthesis , Female , Humans , Immunohistochemistry , Male , Middle Aged , Prognosis , Survival Analysis , Tissue Distribution
14.
Cancer Cell ; 18(2): 135-46, 2010 Aug 09.
Article in English | MEDLINE | ID: mdl-20708155

ABSTRACT

Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. We demonstrate that intestinal epithelial cell specific expression of oncogenic K-ras(G12D) in mice induces serrated hyperplasia, which is characterized by p16(ink4a) overexpression and induction of senescence. Deletion of Ink4a/Arf in K-ras(G12D) expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras represents a key player during an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development.


Subject(s)
Cellular Senescence/genetics , Colorectal Neoplasms/pathology , Cyclin-Dependent Kinase Inhibitor p16/physiology , Oncogenes , Animals , Cell Division , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Disease Progression , Genes, APC , Genes, ras , Humans , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mutation , Signal Transduction , Wnt Proteins/metabolism
15.
Int J Colorectal Dis ; 25(11): 1301-9, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20737155

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , gamma Catenin/metabolism , Adult , Aged , Aged, 80 and over , Cohort Studies , Colorectal Neoplasms/diagnosis , Cytoplasm/metabolism , Demography , Disease-Free Survival , Female , Humans , Immunohistochemistry , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Tissue Array Analysis , Up-Regulation , beta Catenin/metabolism
16.
Cancer Invest ; 27(8): 844-50, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19626493

ABSTRACT

CD133, CD44, and CD166 are cell surface markers that have recently been associated with colorectal cancer stem cells. As which of these markers has the greatest impact on patient prognosis is currently unknown, we compared their expression and prognostic significance in 110 colorectal adenocarcinomas. We demonstrate that expression of CD133 correlates with that of CD166, while both do not correlate with CD44. We show that CD133 is the best sole marker to predict low patient survival, while the combined analysis of all three markers may be superior in identification of low-, intermediate-, and high-risk cases of colorectal cancer.


Subject(s)
Adenocarcinoma/immunology , Antigens, CD/analysis , Biomarkers, Tumor/analysis , Cell Adhesion Molecules, Neuronal/analysis , Colorectal Neoplasms/immunology , Fetal Proteins/analysis , Glycoproteins/analysis , Hyaluronan Receptors/analysis , Neoplastic Stem Cells/immunology , Peptides/analysis , AC133 Antigen , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/mortality , Colorectal Neoplasms/therapy , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Predictive Value of Tests , Proportional Hazards Models , Risk Assessment , Time Factors , Treatment Outcome
17.
Eur J Cancer ; 45(11): 2034-40, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19403300

ABSTRACT

Nuclear beta-catenin and CD133 are linked with two hallmarks of colon cancer, wingless-type mouse mammary tumour virus integration site (WNT)-pathway dysregulation and colon cancer stem cells (Co-CSCs), respectively. Both molecules may be related, as Co-CSCs were proposed to require activated WNT-signalling and as CD133 was postulated as a WNT/beta-catenin target gene. Herein, we investigated the expression of these markers on serial sections of 162 stage IIA colonic adenocarcinomas. We found that the expression of these molecules is statistically independent and that they mark distinct but overlapping subpopulations of the tumour cells. Moreover, we show that their combined evaluation can identify colon cancer cases with vastly reduced survival (hazard ratio (HR) 13.4, 95% confidence interval (CI): 4.7-38.2) and a high risk of tumour progression (HR 6.8, 95%CI: 3.1-15.0). In conclusion, the independence of these markers may on the one hand have implications for their presumed value to identify Co-CSCs; on the other hand it allows their combined analysis to become a powerful tool to identify high risk cases of stage IIA colon cancer.


Subject(s)
Adenocarcinoma/metabolism , Antigens, CD/analysis , Biomarkers, Tumor/analysis , Colorectal Neoplasms/metabolism , Glycoproteins/analysis , Peptides/analysis , beta Catenin/analysis , AC133 Antigen , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/mortality , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Risk , Survival Analysis
18.
Gastroenterology ; 137(2): 639-48, 648.e1-9, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19394332

ABSTRACT

BACKGROUND & AIMS: The ubiquitously expressed basic helix-loop-helix transcription factor ITF-2B has an important role in differentiation processes, and its transcription is regulated by beta-catenin. The ITF-2 gene is located in the chromosomal region 18q21; allelic loss of this locus occurs in 70% of colorectal cancers. We analyzed the expression, regulation, and function of ITF-2B in colorectal carcinogenesis. METHODS: The loss-of-heterozygosity (LOH) status of 18q21 and expression of ITF-2B were studied in colorectal carcinomas using polymerase chain reaction-based methods and immunohistochemistry. The biologic effects of ITF-2B were studied in colorectal cancer cells. Reporter gene assays and chromatin immunoprecipitation were utilized to analyze effects of ITF-2B on gene transcription. RESULTS: ITF-2B is strongly expressed in colon adenomas but frequently down-regulated in carcinomas because of LOH at 18q21. ITF-2B induces cell cycle arrest and regulates the expression of p21(Cip1) via newly identified E-boxes in the CDKN1A gene, independently of p53. Loss of ITF-2B expression correlates with loss of p21(Cip1) expression in primary colon carcinomas. CONCLUSIONS: Accumulation of mutations and allelic losses are driving forces of colorectal carcinogenesis. ITF-2B, which is up-regulated during early colorectal carcinogenesis because of loss of adenomatous polyposis coli, is a target for LOH on chromosome 18q, along with deleted in colorectal carcinoma and Smad4. This finding, along with the fact that ITF-2B is a regulator of the key cell cycle inhibitor p21(Cip1), indicates that ITF-2B is a tumor suppressor that has an important function at the adenoma to carcinoma transition.


Subject(s)
Adenocarcinoma/genetics , Adenomatous Polyposis Coli/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 18/genetics , Colorectal Neoplasms/genetics , DNA-Binding Proteins/genetics , Transcription Factors/genetics , Adenocarcinoma/pathology , Adenomatous Polyposis Coli/pathology , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Cell Line, Tumor , Cell Transformation, Neoplastic/pathology , Colorectal Neoplasms/pathology , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Loss of Heterozygosity , Mutation , Neoplasm Proteins/genetics , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Transcription Factor 4
19.
Cancer ; 115(10): 2063-70, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19298008

ABSTRACT

BACKGROUND: Most colon cancers harbor mutations of APC or beta-catenin, both of which may lead to nuclear beta-catenin accumulation in the tumor cells and constitutively activated expression of its target genes. In many colon cancers, however, nuclear beta-catenin accumulation is heterogeneous throughout the tumor and often confined to the tumor margin. Herein, the authors investigated whether the intratumoral distribution of nuclear beta-catenin can serve as a prognostic marker for survival and tumor progression of stage IIA colon cancer patients. METHODS: In total, 142 patients with primarily resected, moderately differentiated stage IIA colon cancer were included in this study. The patterning of nuclear beta-catenin expression was evaluated on immunohistochemically stained whole tissue sections of the tumors and was correlated with cancer-specific survival and disease-free survival using univariate and multivariate statistical analyses. RESULTS: Four distinct patterns of nuclear beta-catenin expression were identified, and 2 main categories comprising tumors with or without intratumoral regulation of nuclear beta-catenin were distinguished. Moreover, the results demonstrated that the patterning, and especially the regulation or absence of regulation of nuclear beta-catenin expression, was a strong predictive marker of patient survival and tumor progression. CONCLUSIONS: The current results indicated that the distribution of nuclear beta-catenin expression can be used as a good prognostic marker in patients with stage IIA colon cancer. Thus, the evaluation of nuclear beta-catenin may help to identify patients who will have a shorter than average survival and patients with a greater risk of disease progression who may be considered for adjuvant therapeutic modalities and intensified clinical aftercare in the future.


Subject(s)
Adenocarcinoma/metabolism , Biomarkers, Tumor/metabolism , Colonic Neoplasms/metabolism , beta Catenin/metabolism , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Cell Nucleus/metabolism , Colonic Neoplasms/mortality , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Prognosis
20.
Gastroenterology ; 136(1): 196-205.e2, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18951899

ABSTRACT

BACKGROUND & AIMS: Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear beta-catenin accumulation, and subsequently, activation of beta-catenin/TCF4 target genes similar to CYCLIN D(1). Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16(INK4A). Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16(INK4A) in colorectal cancer and its correlation with survival. METHODS: Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16(INK4A) gene regulation. Moreover, p16(INK4A) expression was correlated with the 10-year survival of patients with colorectal carcinomas. RESULTS: In colorectal carcinomas, expression of the p16(INK4A) gene is regulated by beta-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion. CONCLUSIONS: beta-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D(1)) and inhibiting genes (p16(INK4A)) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16(INK4A) seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation.


Subject(s)
Colorectal Neoplasms/mortality , Genes, p16 , beta Catenin/physiology , Adult , Aged , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Cell Line, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA-Binding Proteins/metabolism , Enhancer Elements, Genetic , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Neoplasm Invasiveness , Promoter Regions, Genetic , Transcription Factor 4 , Transcription Factors/metabolism
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