@article{DiersBaumLehmannetal.2022, author = {Diers, Johannes and Baum, Philip and Lehmann, Kai and Uttinger, Konstatin and Baumann, Nikolas and Pietryga, Sebastian and Hankir, Mohammed and Matthes, Niels and Lock, Johann F. and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Disproportionately high failure to rescue rates after resection for colorectal cancer in the geriatric patient population - A nationwide study}, series = {Cancer Medicine}, volume = {11}, journal = {Cancer Medicine}, number = {22}, doi = {10.1002/cam4.4784}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312858}, pages = {4256-4264}, year = {2022}, abstract = {Background Colorectal cancer incidence increases with patient age. The aim of this study was to assess, at the nationwide level, in-hospital mortality, and failure to rescue in geriatric patients (≥ 80 years old) with colorectal cancer arising from postoperative complications. Methods All patients receiving surgery for colorectal cancer in Germany between 2012 and 2018 were identified in a nationwide database. Association between age and in-hospital mortality following surgery and failure to rescue, defined as death after complication, were determined in univariate and multivariate analyses. Results Three lakh twenty-eight thousands two hundred and ninety patients with colorectal cancer were included of whom 77,287 were 80 years or older. With increasing age, a significant relative increase in right hemicolectomy was observed. In general, these patients had more comorbid conditions and higher frailty. In-hospital mortality following colorectal cancer surgery was 4.9\% but geriatric patients displayed a significantly higher postoperative in-hospital mortality of 10.6\%. The overall postoperative complication rate as well as failure to rescue increased with age. In contrast, surgical site infection (SSI) and anastomotic leakage (AL) did not increase in geriatric patients, whereas the associated mortality increased disproportionately (13.3\% for SSI and 29.9\% mortality for patients with AI, both p < 0.001). Logistic regression analysis adjusting for confounders showed that geriatric patients had almost five-times higher odds for death after surgery than the baseline age group below 60 (OR 4.86; 95\%CI [4.45-5.53], p < 0.001). Conclusion Geriatric patients have higher mortality after colorectal cancer surgery. This may be partly due to higher frailty and disproportionately higher rates of failure to rescue arising from postoperative complications.}, language = {en} } @article{MuellerKoehlerHendricksetal.2021, author = {M{\"u}ller, Sophie and K{\"o}hler, Franziska and Hendricks, Anne and Kastner, Carolin and B{\"o}rner, Kevin and Diers, Johannes and Lock, Johan F. and Petritsch, Bernhard and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Brain metastases from colorectal cancer: a systematic review of the literature and meta-analysis to establish a guideline for daily treatment}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {4}, issn = {2072-6694}, doi = {10.3390/cancers13040900}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228883}, year = {2021}, abstract = {Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words "brain", "metastas*", "tumor", "colorectal", "cancer", and "malignancy". In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1\% and 11.5\%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8\% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment.}, language = {en} } @article{SchmidtDenkWiegering2020, author = {Schmidt, Stefanie and Denk, Sarah and Wiegering, Armin}, title = {Targeting protein synthesis in colorectal cancer}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {5}, issn = {2072-6694}, doi = {10.3390/cancers12051298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206014}, year = {2020}, abstract = {Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.}, language = {en} } @article{SchmidtHaywardCoelhoetal.2019, author = {Schmidt, Thomas S. B. and Hayward, Matthew R. and Coelho, Luiis P. and Li, Simone S. and Costea, Paul I. and Voigt, Anita Y. and Wirbel, Jakob and Maistrenko, Oleksandr M. and Alves, Renato J. C. and Bergsten, Emma and de Beaufort, Carine and Sobhani, Iradj and Heintz-Buschart, Anna and Sunagawa, Shinichi and Zeller, Georg and Wilmes, Paul and Bork, Peer}, title = {Extensive transmission of microbes along the gastrointestinal tract}, series = {eLife}, volume = {8}, journal = {eLife}, doi = {10.7554/eLife.42693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228954}, pages = {e42693, 1-18}, year = {2019}, abstract = {The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease.}, subject = {Barrier}, language = {en} } @phdthesis{Pfann2020, author = {Pfann, Christina}, title = {Untersuchungen zu neuen therapeutischen Ans{\"a}tzen zur Beeinflussung der MYC-Expression im kolorektalen Karzinom}, doi = {10.25972/OPUS-21668}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216687}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Eine ver{\"a}nderte Expression des Transkriptionsfaktors MYC wird als entscheidender Faktor f{\"u}r Tumorentstehung und -progress im kolorektalen Karzinom gesehen. Somit ist die Hemmung dessen Expression und Funktion ein zentraler Ansatz bei der zielgerichteten Tumortherapie. Als geeignete Strategie, sowohl die Halbwertszeit als auch die Translation von MYC zu verringern, erschien eine duale PI3K-/mTOR-Hemmung durch den small molecule-Inhibitor BEZ235. Gegenteilig ist jedoch unter Behandlung mit BEZ235 eine verst{\"a}rkte MYC-Expression in verschiedenen Kolonkarzinom-Zelllinien zu beobachten. Neben verst{\"a}rkter Transkription, konnte eine verst{\"a}rkte IRES-abh{\"a}ngige Translation von MYC nach Hemmung der mTOR-/5´Cap-abh{\"a}ngigen Translation durch BEZ235, als Ursache der MYC-Induktion nachgewiesen werden. Es konnte gezeigt werden, dass die Induktion von MYC nach PI3K-/mTOR-Hemmung durch eine kompensatorische Aktivierung des MAPK-Signalwegs in Folge einer FOXO-abh{\"a}ngigen Induktion von Rezeptortyrosinkinasen, stattfindet. Eine m{\"o}gliche Strategie, diese Feedback-Mechanismen zu umgehen, ist die direkte Hemmung der Translationsinitiation. Hierf{\"u}r wurden Rocaglamid und dessen Derivat Silvestrol als small molecule-Inhibitoren der eIF4A-Helikase verwendet. Im Gegensatz zur PI3K/mTOR-Hemmung, ist durch eIF4A-Inhibition eine Reduktion der MYC-Proteinexpression in verschiedenen Kolonkarzinom-Zelllinien zu erreichen - ohne einhergehende MAPK-Aktivierung. Anhand der Ergebnisse kann postuliert werden, dass Silvestrol das Potential besitzt, sowohl die Cap-/eIF4F-abh{\"a}ngie als auch die somit eIF4A-abh{\"a}ngige IRES-vermittelte Translation von MYC zu hemmen. Weiterhin kann eine proliferationshemmende Wirkung durch Silvestrol auf Kolonkarzinom-Zellen in vitro, via Zellzyklusarrest und Induktion von Apoptose, gezeigt werden. Dies stellt die Voraussetzung f{\"u}r eine potentielle Eignung als tumorhemmender Wirkstoff in der Therapie des kolorektalen Karzinoms dar.}, language = {de} } @article{BaurNietzerKunzetal.2020, author = {Baur, Florentin and Nietzer, Sarah L. and Kunz, Meik and Saal, Fabian and Jeromin, Julian and Matschos, Stephanie and Linnebacher, Michael and Walles, Heike and Dandekar, Thomas and Dandekar, Gudrun}, title = {Connecting cancer pathways to tumor engines: a stratification tool for colorectal cancer combining human in vitro tissue models with boolean in silico models}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {1}, issn = {2072-6694}, doi = {10.3390/cancers12010028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193798}, pages = {28}, year = {2020}, abstract = {To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.}, language = {en} } @article{VogtmannHuaZelleretal.2016, author = {Vogtmann, Emily and Hua, Xing and Zeller, Georg and Sunagawa, Shinichi and Voigt, Anita Y. and Hercog, Rajna and Goedert, James J. and Shi, Jianxin and Bork, Peer and Sinha, Rashmi}, title = {Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155362}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166904}, pages = {e0155362}, year = {2016}, abstract = {Accumulating evidence indicates that the gut microbiota affects colorectal cancer development, but previous studies have varied in population, technical methods, and associations with cancer. Understanding these variations is needed for comparisons and for potential pooling across studies. Therefore, we performed whole-genome shotgun sequencing on fecal samples from 52 pre-treatment colorectal cancer cases and 52 matched controls from Washington, DC. We compared findings from a previously published 16S rRNA study to the metagenomics-derived taxonomy within the same population. In addition, metagenome-predicted genes, modules, and pathways in the Washington, DC cases and controls were compared to cases and controls recruited in France whose specimens were processed using the same platform. Associations between the presence of fecal Fusobacteria, Fusobacterium, and Porphyromonas with colorectal cancer detected by 16S rRNA were reproduced by metagenomics, whereas higher relative abundance of Clostridia in cancer cases based on 16S rRNA was merely borderline based on metagenomics. This demonstrated that within the same sample set, most, but not all taxonomic associations were seen with both methods. Considering significant cancer associations with the relative abundance of genes, modules, and pathways in a recently published French metagenomics dataset, statistically significant associations in the Washington, DC population were detected for four out of 10 genes, three out of nine modules, and seven out of 17 pathways. In total, colorectal cancer status in the Washington, DC study was associated with 39\% of the metagenome-predicted genes, modules, and pathways identified in the French study. More within and between population comparisons are needed to identify sources of variation and disease associations that can be reproduced despite these variations. Future studies should have larger sample sizes or pool data across studies to have sufficient power to detect associations that are reproducible and significant after correction for multiple testing.}, language = {en} } @article{PeterBultinckMyantetal.2014, author = {Peter, Stefanie and Bultinck, Jennyfer and Myant, Kevin and Jaenicke, Laura A. and Walz, Susanne and M{\"u}ller, Judith and Gmachl, Michael and Treu, Matthias and Boehmelt, Guido and Ade, Casten P. and Schmitz, Werner and Wiegering, Armin and Otto, Christoph and Popov, Nikita and Sansom, Owen and Kraut, Norbert and Eilers, Martin}, title = {H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase}, series = {EMBO Molecular Medicine}, volume = {6}, journal = {EMBO Molecular Medicine}, number = {12}, issn = {1757-4684}, doi = {10.15252/emmm.201403927}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118132}, pages = {1525-41}, year = {2014}, abstract = {Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.}, language = {en} } @article{WiegeringPfannUtheetal.2013, author = {Wiegering, Armin and Pfann, Christina and Uthe, Friedrich Wilhelm and Otto, Christoph and Rycak, Lukas and M{\"a}der, Uwe and Gasser, Martin and Waaga-Gasser, Anna-Maria and Eilers, Martin and Germer, Christoph-Thomas}, title = {CIP2A Influences Survival in Colon Cancer and Is Critical for Maintaining Myc Expression}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0075292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97252}, year = {2013}, abstract = {The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor that stabilises the c-Myc protein. CIP2A is overexpressed in several tumours, and expression levels are an independent marker for long-term outcome. To determine whether CIP2A expression is elevated in colon cancer and whether it might serve as a prognostic marker for survival, we analysed CIP2A mRNA expression by real-time PCR in 104 colon cancer samples. CIP2A mRNA was overexpressed in colon cancer samples and CIP2A expression levels correlated significantly with tumour stage. We found that CIP2A serves as an independent prognostic marker for disease-free and overall survival. Further, we investigated CIP2A-dependent effects on levels of c-Myc, Akt and on cell proliferation in three colon cancer cell lines by silencing CIP2A using small interfering (si) and short hairpin (sh) RNAs. Depletion of CIP2A substantially inhibited growth of colon cell lines and reduced c-Myc levels without affecting expression or function of the upstream regulatory kinase, Akt. Expression of CIP2A was found to be dependent on MAPK activity, linking elevated c-Myc expression to deregulated signal transduction in colon cancer.}, language = {en} }