Till Krech
Hannover Medical School
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Featured researches published by Till Krech.
Hepatology | 2014
Katharina John; Johannes Hadem; Till Krech; Kristin Wahl; Michael P. Manns; Steven Dooley; Sándor Bátkai; Thomas Thum; Klaus Schulze-Osthoff; Heike Bantel
Acute liver failure (ALF) represents a life‐threatening situation characterized by sudden and massive liver cell death in the absence of preexisting liver disease. Although most patients require liver transplantation to prevent mortality, some recover spontaneously and show complete liver regeneration. Because of the rarity of this disease, the molecular mechanisms regulating liver regeneration in ALF patients remain largely unknown. In this study, we investigated the role of microRNAs (miRs) that have been implicated in liver injury and regeneration in sera from ALF patients (nu2009=u200963). Patients with spontaneous recovery from ALF showed significantly higher serum levels of miR‐122, miR‐21, and miR‐221, compared to nonrecovered patients. In liver biopsies, miR‐21 and miR‐221 displayed a reciprocal expression pattern and were found at lower levels in the spontaneous survivors, whereas miR‐122 was elevated in both serum and liver tissue of those patients. As compared to nonrecovered patients, liver tissue of spontaneous survivors revealed not only increased hepatocyte proliferation, but also a strong down‐regulation of miRNA target genes that impair liver regeneration, including heme oxygenase‐1, programmed cell death 4, and the cyclin‐dependent kinase inhibitors p21, p27, and p57. Conclusion: Our data suggest that miR‐122, miR‐21, and miR‐221 are involved in liver regeneration and might contribute to spontaneous recovery from ALF. Prospective studies will show whether serological detection of those miRNAs might be of prognostic value to predict ALF outcome. (Hepatology 2014;60:1346–1355)
Hepatology | 2013
Kristin Wahl; Martin Siegemund; Frank Lehner; Florian W. R. Vondran; Andreas K. Nussler; Florian Länger; Till Krech; Roland E. Kontermann; Michael P. Manns; Klaus Schulze-Osthoff; Klaus Pfizenmaier; Heike Bantel
As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis‐sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC‐targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR‐targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR‐targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor‐free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR‐targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients. Conclusion: EGFR‐targeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor‐free liver tissue and might therefore represent a promising novel strategy for HCC treatment. (HEPATOLOGY 2013)
PLOS ONE | 2012
Vindhya Palagani; Mona El Khatib; Uta Kossatz; Przemyslaw Bozko; Martin Müller; Michael P. Manns; Till Krech; Nisar P. Malek; Ruben R. Plentz
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
International Journal of Cancer | 2008
Matthias Christgen; Henriette Bruchhardt; Matthias Ballmaier; Till Krech; Florian Länger; Hans Kreipe; Ulrich Lehmann
The cell‐surface glycoprotein KAI1 suppresses tumor growth and metastasis in various animal models. Downregulation of KAI1 has been implicated in the progression of cancer. However, the mechanisms of KAI1 inactivation are poorly understood. This is the first study that investigates expression and regulation of KAI1 in human breast cancer. KAI1 expression was analyzed on custom‐made tissue microarrays comprising 209 well‐characterized breast cancers and normal mammary gland tissue. Strong KAI1 immunoreactivity was observed throughout the normal mammary gland epithelium. In breast cancer tissue, KAI1 immunoreactivity was lost in 161/209 (77%) cases. Strikingly, KAI1 was preferentially lost in estrogen receptor (ER)‐positive breast cancers (p < 0.001). This was validated by real‐time RT‐PCR analyses showing a 7.5‐fold downregulation of KAI1 mRNA in ER‐positive relative to ER‐negative tumors (p = 0.028). Notably, this was also corroborated by Affymetrix microarray expression data of an independent cohort of 49 breast cancers. Class comparison analysis identified KAI1 as downregulated in ER‐positive tumors. Subsequently, human breast cancer cell lines were employed to test a potential role of ER‐activity in the downregulation of KAI1, as suggested by our expression analyses. Exposure of ER‐positive breast cancer cells to fulvestrant, a clinically approved ER‐antagonist that reverses ER‐mediated gene repression, induced a significant upregulation of KAI1 and inhibited cell proliferation as well as migration. In summary, we demonstrate for the first time that KAI1 is a target of ER‐mediated gene‐repression, and thus, it is downregulated in ER‐positive breast cancer. Importantly, KAI1 might be reinducible by endocrine therapy with ER‐antagonists in patients suffering from ER‐positive breast cancer.
The Journal of Pathology | 2009
Matthias Christgen; Henriette Bruchhardt; Catarina Hadamitzky; Cornelia Rudolph; Doris Steinemann; Dorothea Gadzicki; Britta Hasemeier; Daniel Römermann; Tim Focken; Till Krech; Matthias Ballmaier; Brigitte Schlegelberger; Hans Kreipe; Ulrich Lehmann
Infiltrating lobular breast cancer (ILBC) is a clinically and biologically distinct tumour entity defined by a characteristic linear cord invasion pattern and inactivation of the CDH1 tumour suppressor gene encoding for E‐cadherin. ILBCs also lack β‐catenin expression and show aberrant cytoplasmic localization of the E‐cadherin binding protein p120‐catenin. The lack of a well‐characterized ILBC cell line has hampered the functional characterization of ILBC cells in vitro. We report the establishment of a permanent ILBC cell line, named IPH‐926, which was derived from a patient with metastatic ILBC. The DNA fingerprint of IPH‐926 verified genetic identity with the patient and had no match among the human cell line collections of several international biological resource banks. IPH‐926 expressed various epithelial cell markers but lacked expression of E‐cadherin due to a previously unreported, homozygous CDH1 241ins4 frameshift mutation. Detection of the same CDH1 241ins4 mutation in archival tumour tissue of the corresponding primary ILBC proved the clonal origin of IPH‐926 from this particular tumour. IPH‐926 also lacked β‐catenin expression and showed aberrant cytoplasmic localization of p120‐catenin. Array‐CGH analysis of IPH‐926 revealed a profile of genomic imbalances that included many distinct alterations previously observed in primary ILBCs. Spectral karyotyping of IPH‐926 showed a hyperdiploid chromosome complement and numerous clonal, structural aberrations. IPH‐926 cells were anti‐cancer drug‐resistant, clonogenic in soft agar, and tumourigenic in SCID mice. In xenograft tumours, IPH‐926 cells recapitulated the linear cord invasion pattern that defines ILBCs. In summary, IPH‐926 significantly extends the biological spectrum of the established breast cancer cell lines and will facilitate functional analyses of genuine human ILBC cells in vitro and in vivo. Copyright
PLOS ONE | 2014
Moritz Kleine; Marc Riemer; Till Krech; Daphne E. DeTemple; Mark D. Jäger; Frank Lehner; Michael P. Manns; Jürgen Klempnauer; Jürgen Borlak; Hueseyin Bektas; Florian W. R. Vondran
Being an integral part of basic, translational and clinical research, the demand for primary human hepatocytes (PHH) is continuously growing while the availability of tissue resection material for the isolation of metabolically competent PHH remains limited. To overcome current shortcomings, this study evaluated the use of explanted diseased organs from liver transplantation patients as a potential source of PHH. Therefore, PHH were isolated from resected surgical specimens (Rx-group; nu200a=u200a60) and explanted diseased livers obtained from graft recipients with low labMELD-score (Ex-group; nu200a=u200a5). Using established protocols PHH were subsequently cultured for a period of 7 days. The viability and metabolic competence of cultured PHH was assessed by the following parameters: morphology and cell count (CyQuant assay), albumin synthesis, urea production, AST-leakage, and phase I and II metabolism. Both groups were compared in terms of cell yield and metabolic function, and results were correlated with clinical parameters of tissue donors. Notably, cellular yields and viabilities were comparable between the Rx- and Ex-group and were 5.3±0.5 and 2.9±0.7×106 cells/g liver tissue with 84.3±1.3 and 76.0±8.6% viability, respectively. Moreover, PHH isolated from the Rx- or Ex-group did not differ in regards to loss of cell number in culture, albumin synthesis, urea production, AST-leakage, and phase I and II metabolism (measured by the 7-ethoxycoumarin-O-deethylase and uracil-5′-diphosphate-glucuronyltransferase activity). Likewise, basal transcript expressions of the CYP monooxygenases 1A1, 2C8 and 3A4 were comparable as was their induction when treated with a cocktail that consisted of 3-methylcholantren, rifampicin and phenobarbital, with increased expression of CYP 1A1 and 3A4 mRNA while transcript expression of CYP 2C8 was only marginally changed. In conclusion, the use of explanted diseased livers obtained from recipients with low labMELD-score might represent a valuable source of metabolically competent PHH which are comparable in viability and function to cells obtained from specimens following partial liver resection.
Genes, Chromosomes and Cancer | 2013
Matthias Christgen; Monika Noskowicz; Elisa Schipper; Henriette Christgen; Charlotte Heil; Till Krech; Florian Länger; Hans Kreipe; Ulrich Lehmann
Infiltrating lobular breast cancer (ILBC) is a tumor‐biologically distinct breast cancer subtype. A high frequency of oncogenic PIK3CA mutations has been reported in ILBC, which may allow for targeted therapy with newly developed PI3K inhibitors. This is of particular clinical relevance for ILBC patients, who have failed to respond to current treatment regimes and suffer from tumor recurrence or dissemination. In anticipation of this therapeutic strategy, we investigated PIK3CA mutations in ILBC with special reference to late stage tumor progression. A total of 88 ILBCs from 73 patients, including primary tumors (PTs, n = 43), ipsilateral locally recurrent tumors (LRTs, n = 15), and distant organ metastases (DOMs, n = 30), were compiled on tissue microarrays. Established ILBC marker proteins were evaluated by immunohistochemistry and PIK3CA hot spot mutations in exons 9 and 20 by direct sequencing. Matched PT/LRT, PT/DOM, and DOM/DOM cases were characterized on a patient‐by‐patient basis. Following correction for redundant patient representations, mutation frequencies were compared in PTs versus LRTs or DOMs. Nearly all specimens were E‐cadherin‐negative (99%), estrogen receptor (ER)‐positive (91%), and lacked basal epithelial markers (100%), demonstrating correct ILBC classification. PIK3CA mutations were detected in 32/88 (36%) specimens. The mutation rate was similar in PTs (33%) and DOMs (26%, P = 0.769), but approximately two‐fold increased in LRTs (69%, P = 0.022). Consistently, matched PT/LRT and LRT/DOM cases showed additional PIK3CA mutations in LRTs. Intriguingly, these findings imply that PIK3CA mutations are positively selected for during ILBC progression to local recurrence but not distant metastasis, which may have clinical implications for PI3K inhibitor‐based therapy.
Cancer Letters | 2012
Till Krech; Elisa Scheuerer; Robert Geffers; Hans Kreipe; Ulrich Lehmann; Matthias Christgen
Contribution of the ABCB1/MDR1/P-glycoprotein drug transporter to breast cancer resistance has been controversial. One issue is that ABCB1-dependent drug-resistance has primarily been investigated in mammary epithelial cell models technically manipulated to overexpress ABCB1, either by gene transfer using appropriate expression vectors or by chronic anticancer drug-selection. However, an unmodified human breast cancer cell line with an endogenous overexpression of ABCB1 has not been described thus far. Using Affymetrix microarray analyses, we identified an endogenous overexpression of several tumor-biologically relevant transcripts including ABCB1, BCAR4, CCL28, SCGB2A2 and PIP in IPH-926, an anticancer drug-resistant human lobular breast cancer cell line derived from a chemo-refractory mammary carcinoma patient. In a panel of twenty breast cancer cell lines examined, overexpression of ABCB1 mRNA and protein was exclusively detected in IPH-926. This was further validated using chronically in vitro drug-selected KB-V-1 cells as a widely used reference model to accurately define an ABCB1 overexpression. IPH-926 and KB-V-1 displayed a similar overexpression of ABCB1. Flow cytometric analyses showed that IPH-926 but not ABCB1-negative breast cancer cells extruded the anticancer agent doxorubicin, a classical substrate of the ABCB1 drug transporter. PSC-833 (valspodar), a selective ABCB1 inhibitor, blocked this efflux, restored apoptotic PARP cleavage and increased doxorubicin sensitivity in IPH-926 and KB-V-1. To our knowledge, IPH-926 represents the first human breast cancer cell line with a genuine, endogenous overexpression of ABCB1. IPH-926 provides evidence that ABCB1 can occasionally cause anticancer drug-resistance in breast cancer patients and offers a new tool for the evaluation of compounds to overcome drug-resistance.
Gut | 2014
Silke Marhenke; Laura Elisa Buitrago-Molina; Jessica Endig; Johanna Orlik; Nora Schweitzer; Stephanie Klett; Thomas Longerich; Robert Geffers; Aránzazu Sánchez Muñoz; Craig Dorrell; Sarah-Fee Katz; André Lechel; Honglei Weng; Till Krech; Ulrich Lehmann; Steven Dooley; Karl Lenhard Rudolph; Michael P. Manns; Arndt Vogel
Background and aims The cyclin-dependent kinase inhibitor p21 has been implicated as a tumour suppressor. Moreover, recent genetic studies suggest that p21 might be a potential therapeutic target to improve regeneration in chronic diseases. The aim of this study was to delineate the role of p21 in chronic liver injury and to specify its role in hepatocarcinogenesis in a mouse model of chronic cholestatic liver injury. Methods The degree of liver injury, regeneration and tumour formation was assessed in Mdr2−/− mice and compared with Mdr2/ p21−/− mice. Moreover, the role of p21 was evaluated in hepatoma cells in vitro and in human hepatocellular carcinoma (HCC). Results Mdr2−/− mice developed HCCs as a consequence of chronic inflammatory liver injury. In contrast, tumour development was profoundly delayed in Mdr2/ p21−/− mice. Delayed tumour development was accompanied by markedly impaired liver regeneration in Mdr2/ p21−/− mice. Moreover, the regenerative capacity of the Mdr2/ p21−/− livers in response to partial hepatectomy declined with age in these mice. Hepatocyte transplantation experiments revealed that impaired liver regeneration was due to intrinsic factors within the cells and changes in the Mdr2/ p21−/− microenvironment. In human HCCs, a subset of tumours expressed p21, which was associated with a significant shorter patient survival. Conclusions We provide experimental evidence that p21 is required for sustained liver regeneration and tumour development in chronic liver injury indicating that p21 needs to be tightly regulated in order to balance liver regeneration and cancer risk. Moreover, we identify p21 as a negative prognostic marker in human HCC.
Journal of Biological Chemistry | 2010
Matthias Christgen; Robert Geffers; Matthias Ballmaier; Henriette Christgen; Janette Poczkaj; Till Krech; Hans Kreipe; Ulrich Lehmann
Human solid tumors contain rare cancer side population (SP) cells, which expel the fluorescent dye Hoechst 33342 (H33342) and display cancer stem cell characteristics. Transcriptional profiling of cancer SP cells isolated by H33342 fluorescence analysis is a newly emerging approach to discover cancer stem cell markers and aberrant differentiation pathways. Using Affymetrix expression microarrays and quantitative reverse transcription-PCR, we investigated differential gene expression between SP and non-SP (NSP) cells isolated from human mammary carcinoma cell lines. A total of 136 genes were up-regulated in breast cancer SP relative to NSP cells, one of which was the fetal stem cell factor and Wnt/β-catenin signaling pathway target SOX17. Strikingly, we discovered that SOX17 was down-regulated by H33342 in a dose-dependent manner. In SP cells, which expel H33342, down-regulation of SOX17 was less pronounced than in NSP cells, which retain H33342. As a result of this, SOX17 displayed a 10–20-fold overexpression in cancer SP relative to NSP cells. Similar results were obtained for further stemness-related genes, namely EPC1 and SPRY1. These findings establish a previously unidentified gene-regulatory impact of H33342 as a novel mechanism responsible for differential gene expression in cancer SP cells. This has significant implications for the future interpretation of cancer SP cells.