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Introduction
The focus of our work is translational research on human carcinomas. Current projects encompass the search for genes for the early detection of breast and colorectal carcinomas and the development of a molecular imaging procedure using Protoporphyrin-IX.
Additional affiliations
January 2009 - present
January 1995 - present
May 1985 - October 1994
Publications
Publications (119)
Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types. We aimed to identify S100A4-dependent expression alterations to better understand CRC progression and metast...
Background
Photodynamic therapy with a photosensitizer such as protoporphyrin-IX, a light sensitive metabolite of heme synthesis, is a highly selective treatment for various carcinomas. In previous studies, we found a significant down regulation of the relevant enzyme ferrochelatase in gastrointestinal carcinomas leading to an accumulation of proto...
Background: Photodynamic therapy with a photosensitizer such as protoporphyrin-IX, a light sensitive metabolite of heme synthesis, is a highly selective treatment for various carcinomas. In previous studies, we found a significant down regulation of the relevant enzyme ferrochelatase in gastrointestinal carcinomas leading to an accumulation of prot...
Background:
Barrett's esophagus metaplasia is the key precursor lesion of esophageal adenocarcinoma. The aim of this study was to find a subset of markers that may allow the identification of patients at risk for esophageal adenocarcinoma, and to determine genes differentially expressed in esophageal squamous cell carcinoma.
Methods:
Laser captu...
Cancer of the stomach is among the leading causes of death from cancer worldwide. The transcription factor C/EBPβ is frequently overexpressed in gastric cancer and associated with the suppression of the differentiation marker TFF1. We show that the murine C/EBPβ knockout stomach displays unbalanced homeostasis and reduced cell proliferation and tha...
Structure–activity relationship studies are pivotal in the development of existing small interfering RNA (siRNA) nanocarriers and in designing new delivery systems. In this paper, we investigated the ability of four dendritic polyglycerolamines (dPG-NH 2) with increasing amine degree of functionalization (DF) on dendritic polyglycerol (dPG) to comp...
The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation an...
Colorectal cancer (CRC) is the third most common cancer worldwide. The metastatic dissemination of the primary tumor is directly linked to patient survival. We previously discovered the gene metastasis-associated in colon cancer 1 (MACC1). MACC1 has been identified as a new remarkable biomarker for disease prognosis and prediction of therapy respon...
This study aimed at the identification of prognostic gene expression markers in early primary colorectal carcinomas without metastasis at the time point of surgery by analyzing genome-wide gene expression profiles using oligonucleotide microarrays.
Cryo-conserved tumor specimens from 45 patients with early colorectal cancers were examined, with the...
N-Acetylneuraminic acid (Neu5Ac) or sialic acid is a pivotal structural and functional monosaccharide in any mammalian cell surface. In the membrane bound or soluble glycoconjugates, this electronegatively charged sugar is localized in the terminal position. Neu5Ac mediates recognition processes like cell-cell, cell-matrix, receptor-mediator, or ce...
N-Acetylneuraminic acid (Neu5Ac) or sialic acid is a pivotal structural and functional monosaccharide in any mammalian cell surface. In the membrane bound or soluble glycoconjugates, this electronegatively charged sugar is localized in the terminal position. Neu5Ac mediates recognition processes like cell-cell, cell-matrix, receptor-mediator, or ce...
Background
We attempted to identify novel biomarkers and therapeutic targets for esophageal squamous cell carcinoma by gene expression profiling of frozen esophageal squamous carcinoma specimens and examined the functional relevance of a newly discovered marker gene, WDR66.
Methods
Laser capture microdissection technique was applied to collect the...
Significantly enriched Gene Ontology (GO) terms identified for genes differentially expressed in siWDR66 Kyse520 cells. GO analysis was performed using GeneSpring. The 10 GO terms with the significant corrected P-value (FDR false discovery rate corrected for multiple testing) are depicted sorted by p-Value (noncorrected).
The clinicopathologic characterization of the 25 ESCC Patients for survival analysis.
Angiogenesis is a prerequisite for progression of cancers. The number of genes linked to angiogenesis suggests the existence of complex gene-networks, which remain to be elucidated. To identify angiogenesis genes deregulated in carcinomas, we performed a meta-profiling analysis of published gene expression microarray studies. Own microarray and qua...
Cancer and cardiovascular disease are the leading causes of death worldwide. Cardiovascular medications have recently been found to have favorable effects also for the treatment of noncardiovascular diseases, including cancer. In this review, we use a reverse bedside-to-bench approach to investigate the effects of common cardiovascular medications...
46
Background: The incidence of esophageal adenocarcinoma (EAC) has increased strongly during the past 30 years and 5-year survival remained poor at approximately 20%. Barrett’s esophagus (BE) metaplasia is considered to be the key precursor lesion of EAC. The aim of this study was to generate and validate biomarkers to stratify patients with BE in...
Early invasive growth and metastasis are features of pancreatic cancer that rely on its resistance to anoikis, an apoptosis program activated on loss of matrix anchorage. How anoikis is regulated is unclear. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine-kinase (GNE) was silenced, or p16 was overexpressed, in human pancreatic carcinoma cel...
A: Expression of TGF-ß1 in Hs578T and Hs578BsT cells. Using an polyclonal anti-TGF-ß1 antibody recognising only extracellular TGF-ß1 [11] we could show reduced TGF-ß1 deposition in Hs578T cells compared to Hs578BsT cells. B: Immunohistochemical staining of TGF-ß1 (R&D Systems). Human and murine non-malignant tissue, DCIS and IDC were investigated....
Gastric adenocarcinomas can be divided into two major histological types, the diffuse and intestinal type (Laurén classification). Since they diverge in many clinical and molecular characteristics, it is widely accepted that they represent distinct disease entities that may benefit from different therapeutic approaches. Gene expression profiling st...
IntroductionSample Preparation, Technical Issues, and Data AnalysisConclusions
References
Transforming growth factor beta (TGF-ß) is able to inhibit the proliferation of epithelial cells and is involved in the carcinogenesis of mammary tumors. Three latent transforming growth factor-ß binding proteins (LTBPs) are known to modulate TGF-ß functions.
The current study analyses the expression profiles of LTBP4, its isoforms LTBP1 and LTBP3,...
Table S1. Assays on demand (Applied Biosystems) used for the human RT-PCR. Table S1 gives an overview about the Assays on demand used for the RT-PCR on the human samples. Table S2. Assays on demand (Applied Biosystems) used for the murine RT-PCR. Table S2 gives an overview about the Assays on demand used for the RT-PCR on the murine samples. Table...
A microsystem integrating electrochemical detection for the simultaneous detection of protein markers of breast cancer is reported. The microfluidic platform was realized by high precision milling of polycarbonate sheets and features two well distinguishable sections: a detection zone incorporating the electrode arrays and the fluid storage part. T...
The ductal carcinoma in situ (DCIS) of the mammary gland represents an early, pre-invasive stage in the development of invasive breast carcinoma. Since DCIS is a curable disease, it would be highly desirable to identify molecular markers that allow early detection. Mice transgenic for the WAP-SV40 early genome region were used as a model for DCIS d...
Circulating tumor cells (CTC) released from primary tumor tissues into the bloodstream or lymphatic vessels are able to colonize distant organs giving rise to metastasis, which is the major factor contributing to poor survival of cancer patients. Thus, molecular characterization of CTC is thought to hold the key to enable an early clinical assessme...
Coexpression of YBX1 and YBX1-target genes. Supplement to Figure 8C. Further examples of YBX1 and YBX1 target co-expression in 43 primary colorectal tumors as detected on Affymetrix HG-U95A microarrays. YBX1 targets shown in (A) were also identified in basal-like breast cancer cells (Ref. 37; Finkbeiner, M.R., Astanehe, A., To, K., Fotovati, A., Da...
Table of genes in U0126-responsive clusters. Affymetrix probe-set ids, gene symbols and normalized expression of genes in cluster 02, 10, 13 and 23.
(2.04 MB XLS)
List of overrepresented Gene Ontology (GO) terms related to the products of clustered target genes. Columns indicate the cluster number, GO-identifier, GO-term and false discovery rate (FDR) calculated by the GOSSIP algorithm (Ref. 69; Blüthgen, N., Brand, K., Cajavec, B., Swat, M., Herzel, H., and Beule, D. [2005]. Biological profiling of gene gro...
Clinical data of tissue microarray study. Data collection and description of technique: Ref. 45; Knösel T, Emde A, Schlüns K, Chen Y, Jürchott K, Krause M, Dietel M, Petersen I. (2005). Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer. Neoplasia. 7:741–747. Columns of table: T, TNM stage; N...
Differentially expressed genes in four matched pairs of normal and tumor tissue as determined by SAM analysis. False discovery rate <0.05, fold change >2; red: up-regulated genes; green: down-regulated genes. The list of differentially expressed genes is shown in Table S6.
(0.22 MB TIF)
Correlation of MEK/ERK-dependent target gene and YBX1 expression in colorectal cancer. We generated 100 random sets of 151 (A), 523 (B) and 851 genes (C), respectively, from the genes represented on the Affymetrix HG-U95A microarray. The size of the gene sets corresponds to (A) the number of proliferation-associated genes up-regulated in four colon...
Normalized expression values obtained by microarray analysis of colorectal cancer cell lines treated with inhibitors. Columns indicate the probe set-ID on Affymetrix HG-U95A microarrays, gene symbol, number of cluster (see Figure 3) and the normalized expression values of all 18 experiments with 3 cell lines, 5 inhibitor treatments and DMSO (solven...
Statistical features of gene clustering were obtained by calculating the distance of each gene to the center of the cluster (parameter: in) and the distance to the center of the closest other cluster (parameter: out). The fit coefficient was computed using the formula: abs (out minus in)/(out plus in).
(1.75 MB XLS)
Inhibitor effects on oncogenic signaling pathways in colorectal cancer cells. (A) Western blot analysis of c-RAF phosphorylated at Ser256 (P-c-RAF), total c-RAF, P-MEK1/2 and P-ERK levels in colon carcinoma cells treated with the indicated inhibitors for 48 h. DMSO, solvent-only control. Total ERK and β-actin levels were determined to control for e...
Effects of YBX1 knock-down on cell growth and cell cycle distribution. (A) Proliferation of HCT116 cells was measured after transfection with YBX1 specific or scrambled siRNAs using the XTT assay. The treatment with transfection reagents alone is shown as mock control. Scr, scrambled siRNA (control). *, p-value: <0.025, single-sided T-test). (B) Pr...
Prediction of transcription factor binding sites. The procedure for identifying transcription factor binding sites in the regulatory sequences of MEK/ERK pathway-regulated genes is described in Materials and Methods. Columns indicate probe set-IDs, gene symbols, the number of the cluster of co-expressed genes and the predicted binding sites for NFY...
Differential gene expression in four colorectal cancers and matched normal tissues. SAM analysis of microarray data (Affymetrix HG-U95A), FDR <0.05, fold change >2.
(0.23 MB XLS)
Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights i...
Detection of proteins that signal the presence or recurrence of cancer is a powerful therapeutic tool for effective early diagnosis and treatment. Carcinoembryonic antigen (CEA) has been extensively studied as a tumor marker in clinical diagnosis. We report on the development of an amperometric biosensor for the detection of CEA based on the immobi...
A microsystem integrating electrochemical biosensoric detection for the simultaneous multiplexed detection of protein markers of breast cancer is reported. The immobilization of antibodies against each of carcinoembryonic antigen (CEA), prostate specific antigen (PSA) and cancer antigen 15-3 (CA15-3) was achieved via crosslinking to a bipodal dithi...
The most fascinating aspect of transcriptomics is that the entire set of messenger RNA (mRNA) molecules or transcripts produced in a population of cells or in tissues can be analyzed simultaneously. The present microarray technology produces devices equivalent to the size of a stamp for gene expression profiling. Analyzing the transcriptome is a ch...
Microarrays are state technologies of the art for the measurement of expression of thousands of genes in a single experiment. The treatment of these data are typically performed with a wide range of tools, but the understanding of complex biological system by means of gene expression usually requires integrating different types of data from multipl...
Gastric adenocarcinoma is characterised by rapid emergence of systemic metastases, resulting in poor prognosis due to vanished curative treatment options. Better understanding of the molecular basis of gastric cancer spread is needed to design innovative treatments. The transcription factor HIF-1alpha (hypoxia-inducible factor 1alpha) is frequently...
Loss of the coxsackie and adenovirus receptor (CAR) has previously been observed in gastric cancer. The role of CAR in gastric cancer pathobiology, however, is unclear. We therefore analysed CAR in 196 R(0)-resected gastric adenocarcinomas and non-cancerous gastric mucosa samples using immunohistochemistry and immunofluorescence. Coxsackie and aden...
The extent to which the location of micrometastases (MIC) or isolated tumor cells (ITC) in sentinel lymph nodes (SLNs) is correlated with the risk of downstream metastases is still unknown. This study examined this issue and compared the impact of MIC/ITC location with other established risk factors.
Paraffin slides of SLNs with MIC/ITC-involvement...
By expression profiling of early staged colon carcinomas, we found regenerating islet-derived 1 alpha (REG1A) to be upregulated in patients with an unfavorable clinical outcome. For validation, REG1A expression was quantified in another colorectal cancer (CRC) patient cohort by Taqman PCR. Aside from tumor and normal tissue from 63 nonpretreated CR...
Metastatic disease is a major cause of mortality in colorectal cancer patients. Even after complete resection of isolated liver metastases, recurrence develops in the majority of patients. Therefore, development of strategies to prevent recurrent liver metastases is of major clinical importance. The present prospectively randomised phase III trial...
Vascular endothelial growth factors VEGF-A, VEGF-C and VEGF-D are considered to be potentially angiogenetic and lymphangiogenetic. "Minimal residual disease" is responsible for cancer progression and recurrence. In this study, we investigated the relation between expressions of VEGF-A, VEGF-C and VEGF-D in gastric cancer tissue and the presence of...
Our study examined differences in the presence of mature, DC-Lamp+ DC in the SLN and non-SLN according to the extent of metastatic involvement.
Paraffin blocks of the SLN and non-SLN from patients with primary breast cancer who had undergone SLN biopsy and axillary dissection were separated into three groups: (Group A) no tumor cell involvement in...
Hemes and heme proteins are vital components of essentially every cell of virtually every eukaryote organism. Previously, we demonstrated accumulation of the heme precursor protoporphyrin-IX (PpIX) in gastrointestinal tumor tissues. To elucidate the mechanisms of PpIX accumulation by quantitative reverse transcriptase-polymerase chain reaction (RT-...
Expression of the tumor suppressor p16(INK4a) after stable transfection can restore the susceptibility of epithelial tumor cells to anoikis. This property is linked to increases in the expression and cell-surface presence of the fibronectin receptor. Considering its glycan chains as pivotal signals, we assumed an effect of p16(INK4a) on glycosylati...
Background: The particular role of the sentinel lymph node (SLN) as first site of lymphatic metastases provides a promising model for immunologic studies. We performed a study to compare the presence of mature DC-lamp+ dendritic cells in SLN and Non-SLN of breast cancer patients with different levels of metastatic involvement. Patients and Methods:...
Isolated tumor cells as a consequence of minimal residual disease are often not detectable by routine diagnostic procedures. However, before or after surgery, isolated tumor cells in lymph nodes, the peritoneal cavity, blood, or bone marrow can frequently be identified by immunohistochemical or molecular methods. Failure to reveal the presence of s...
H-REV107-1, a known member of the class II tumor suppressor gene family, is involved in the regulation of differentiation and survival. We analyzed H-REV107-1 in non-small cell lung carcinomas, in normal lung, and in immortalized and tumor-derived cell lines. Sixty-eight percent of lung tumors revealed positive H-REV107-1-specific staining. Further...
Introduction: Hypoxia is a hallmark of solid tumor growth and a negative predictor of patient survival. Adaptation to hypoxia is mainly achieved by the transcription factor HIF-1α, which is upregulated in a diverse range of human and experimental tumors and their metastases. HIF-1α target genes have been implicated in the induction of invasion and...
To investigate the effect of cell surface sialic acid and its linkage on the cell-cell and cell-matrix adhesion of mammary carcinoma cells MD-MB-435.
MD-MB-435 cells were sense-transfected with ST6Gal I cDNA or antisense-transfected with part of the ST6Gal I sequence inserted in pcDNA 3.1 vector, with mock transfection with pcDNA3.1 vector as the c...
Splicing processes might play a major role in carcinogenesis and tumour progression. The Wnt pathway is of crucial relevance for cancer progression. Therefore we focussed on the Wnt/beta-catenin signalling pathway in order to validate the expression of sequences predicted as alternatively spliced by bioinformatic methods. Splice variants of its key...
Vascular endothelial growth factor (VEGF)-D and its homolog VEGF-C influence lymphangiogenesis through activation of VEGF receptor 3 (VEGFR-3), and have been implicated in lymphatic tumor spread. Nodal dissemination of gastric adenocarcinomas critically determines clinical outcome and therapeutic options of affected patients. Therefore, we analyzed...
Isolierte Tumorzellen (ITZ) als Ausdruck einer ,,minimal residuellen Tumormanifestation“ (MRD) entziehen sich in der Regel der perioperativen Routinediagnostik. Tatsächlich sind sie aber relativ oft in Lymphknoten, in der Peritonealhöhle, im Blut oder im Knochenmark präsent. Dies bedeutet ein permanentes Understaging von Tumorpatienten, begründet u...
Laser microdissection with the MMI Cellcut(R) allows the efficient isolation of specific cells. The collected cells yield only tiny amounts of isolated RNA that require dedicated mRNA amplification technology, and ExpressArt(R) from AmpTec offers the unique possibility to exploit the complete samples, irrespective of RNA amounts and without impairi...