Dominique Koensgen
Charité
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Featured researches published by Dominique Koensgen.
Cancer Letters | 2009
Sascha Keller; Anne-Kathleen König; Frederik Marme; Steffen Runz; Silke Wolterink; Dominique Koensgen; Alexander Mustea; Jalid Sehouli; Peter Altevogt
Exosomes are membrane vesicles that are released from many different cell types. Tumor derived-exosomes play a role in immune suppression. We hypothesized that in ovarian carcinoma patients exosomes initially produced at the local abdominal site may become systemic. We examined paired samples of ascites and blood from ovarian carcinoma patients for the presence of exosomes. We also studied the requirements for exosomal uptake by immune cells, the role of phosphatidyl-serine (PS) as uptake signal and the effect of exosome application on tumor growth. We used exosomes from ovarian carcinoma cell lines, malignant ascites and sera from ovarian carcinoma patients isolated by ultracentrifugation. PS-displayed by exosomes was detected by Anexin-V-FITC staining of latex beads adsorbed exosomes. For uptake experiments, labeled exosomes were exposed to cells in the presence or absence of cold Annexin-V as competitor. Uptake was examined by fluorescent microscopy and cytofluorographic analysis. Effects of exosomes on tumor growth were studied using SKOV3ip ovarian carcinoma cells in CD1 nu/nu mice. We found that malignant ascites-derived exosomes cargo tumor progression related proteins such as L1CAM, CD24, ADAM10, and EMMPRIN. We observed that exosomes become systemic via the blood stream. Uptake of ovarian carcinoma exosomes by NK cells was found to require PS at the exosomal surface but the presence of PS was not sufficient. Application of malignant ascites-derived exosomes to tumor bearing mice resulted in augmented tumor growth. Exosomes from the serum of tumor patients could be isolated from only one ml of blood and this analysis could serve for diagnostic purposes. We propose that tumor-derived exosomes could play a role in tumor progression.
International Journal of Cancer | 2009
Linda J. Nicholson; Paul R. Smith; Louise Hiller; Peter W. Szlosarek; Christopher Kimberley; Jalid Sehouli; Dominique Koensgen; Alexander Mustea; Peter Schmid; Tim Crook
Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down‐regulation of expression of argininosuccinate synthetase (ASS1), the rate‐limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum‐based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum‐based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine‐depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum‐based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse‐free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer.
Cancer Research | 2011
Nelofer Syed; Helen M. Coley; Jalid Sehouli; Dominique Koensgen; Alexander Mustea; Peter W. Szlosarek; Iain A. McNeish; Sarah Blagden; Peter Schmid; Eleftheria Hatzimichael; Tim Crook
Resistance to platinum- and taxane-based chemotherapy remains a major clinical impediment to effective management of epithelial ovarian cancer (EOC). To gain insights into resistance mechanisms, we compared gene and confirmed expression patterns of novel EOC cell lines selected for paclitaxel and carboplatin resistance. Here, we report that resistance can be conferred by downregulation of the Polo-like kinase Plk2. Mechanistic investigations revealed that downregulation occurred at the level of transcription via associated DNA methylation of the CpG island in the Plk2 gene promoter in cell lines, primary tumors, and patient sera. Inhibitory RNA (RNAi)-mediated knockdown and ectopic overexpression established a critical functional role for Plk2 in determining apoptotic sensitivity to paclitaxel and carboplatin. In drug-resistant human EOC cell lines, Plk2 promoter methylation varied with the degree of drug resistance and transcriptional silencing of the promoter. RNAi-dependent knockdown of Plk2 abrogated G(2)-M cell-cycle blockade by paclitaxel, conferring resistance to both paclitaxel and platinum. Conversely, ectopic expression of Plk2 restored sensitivity to G(2)-M cell-cycle blockade and cytotoxicity triggered by paclitaxel. In clinical cases, DNA methylation of the Plk2 CpG island in tumor tissue was associated with a higher risk of relapse in patients treated postoperatively with carboplatin and paclitaxel (P = 0.003). This trend was also reflected in the analysis of matched serum samples. Taken together, our results implicate Plk2 as a clinically important determinant of chemosensitivity, in support of the candidacy of Plk2 as a theranostic marker to inform EOC management.
Cytokine | 2009
Alexander Mustea; Elena-Ioana Braicu; Dominique Koensgen; Shuhui Yuan; Pengming Sun; Florin Stamatian; W. Lichtenegger; Frank Chih-Kang Chen; Radoslav Chekerov; Jalid Sehouli
OBJECTIVES The fact that ovarian cancer remains confined to the peritoneal cavity even in advanced stages has allowed us to surmise that local immunosuppressive factors could be involved in the tumor biology of ovarian cancer. In this context, IL-10 can be one of the key factors. By studying the kinetics of IL-10 concentrations prior to and after surgery, this study attempts to reveal once more the ability of tumor micro-environment to produce IL-10. Some studies indicate that IL-10 concentration correlates with the tumor burden and can thus predict the surgical outcome. Data concerning this aim from patients with ovarian cancer do not seem to exist. METHODS In this prospective study, serum blood was collected from 27 patients, one day prior to surgery as well as 24h, 4 and 8 days after surgery. The concentration of IL-10 was determined using ELISA. RESULTS While IL-10 levels rise within the first day post-OP, they are found to be reduced significantly when measured at later time points. IL-10 levels also correlate statistically significantly with the tumor grade, with lower IL-10 levels observed in well-differentiated and higher IL-10 levels in undifferentiated or only poorly differentiated tumors. CONCLUSION IL-10 expression levels appear to be a good surrogate marker for tumor grading. If validated, this may in future contribute to the understanding of the biology stage cancers.
Histopathology | 2010
Silvia Darb-Esfahani; Bruno V. Sinn; Wilko Weichert; Jan Budczies; Annika Lehmann; Aurelia Noske; Ann Christin Buckendahl; Berit Maria Müller; Jalid Sehouli; Dominique Koensgen; Balazs Gyorffy; Manfred Dietel; Carsten Denkert
Darb‐Esfahani S, Sinn B V, Weichert W, Budczies J, Lehmann A, Noske A, Buckendahl A‐C, Müller B M, Sehouli J, Koensgen D, Györffy B, Dietel M & Denkert C (2010) Histopathology 56. 727–739 Expression of classical NF‐κB pathway effectors in human ovarian carcinoma
Cytokine | 2015
Dominique Koensgen; D. Bruennert; S. Ungureanu; D. Sofroni; Elena Ioana Braicu; Jalid Sehouli; A. Sümnig; S. Delogu; M. Zygmunt; P. Goyal; M. Evert; S. Olek; K.E. Biebler; Alexander Mustea
Ovarian cancer still represents a challenge in gynecological oncology. Most patients are diagnosed in an advanced tumor stage. No specific screening or prevention strategies for ovarian cancer exist as of yet. Interleukin 8 (IL-8) is a pro-inflammatory chemokine known for its angiogenetic activity, and is supposedly responsible for tumor-associated angiogenesis in several malignant tumors. The aim of the study was to investigate the susceptibility of patients with an IL-8 gene polymorphism to developing ovarian cancer. Four single nucleotide polymorphisms (SNPs) (IL-8 -251, IL-8 +781, IL-8 +1633 and IL-8 +2767) of the IL-8 gene were screened, using the PCR method in 268 patients with ovarian cancer and 426 healthy women as a control group. Significant associations were noted in patients with the IL-8 +781 (T/T) genotype (p=0.0048) with increased frequencies of ovarian cancer, while women with the IL-8 +781 (C/C) allele suffer from ovarian cancer significantly less frequently (p=0.0003). Furthermore, the IL-8 +2767 (T/T) genotype is also associated with a higher risk of ovarian cancer (p=0.0177). Our results indicate, for the first time, that IL-8 polymorphism is associated with ovarian cancer.
Critical Reviews in Oncology Hematology | 2008
Jalid Sehouli; Dominique Koensgen; Gülten Oskay-Özcelik; Alexander Mustea
Endometrial cancer is one of the most common gynaecological cancers in western countries. Most women are diagnosed at an early stage of the disease and can be cured by surgery alone. In patients with poor prognostic factors or an advanced disease, the chance of progression-free survival and overall survival is greatly diminished. Adjuvant chemotherapy is effective for patients with advanced disease. The combination of doxorubicin and cisplatin achieves overall response rates ranging from 34 to 60%, and the addition of paclitaxel seems to improve the outcome of patients with advanced disease, but it induces a significantly higher toxicity. A Gynecologic Oncology Study Group phase-III study is currently exploring the triplet paclitaxel+doxorubicin+cisplatin plus G-CSF vs. the less toxic combination of paclitaxel+carboplatin. Ongoing and planned phase-III trials are evaluating newer combination chemotherapy regimens, a combination of irradiation and chemotherapy and the implementation of targeted therapies with the goal of improving the tumour control rate and quality of life.
Critical Reviews in Oncology Hematology | 2016
Matthias B. Stope; Dominique Koensgen; Martin Burchardt; N. Concin; M. Zygmunt; Alexander Mustea
Ovarian cancer (OC) is a major problem in gynecological oncology. Options for diagnosis and treatment of advanced stages and thus for patient prognosis have not been improved substantially over the past decades. Heat shock proteins (HSP) are characterized as stress-induced molecular chaperones performing cell survival factor functions. In cancer cells, various crucial and clinically important cell responses are vitally influenced and modulated by HSPs, e.g., cell growth and treatment resistance. Despite the limited knowledge on HSPs in OC progression, their roles as biomarkers, prognostic factors and their drug target properties appears promising for future clinical applications and therapeutic approaches.
Supportive Care in Cancer | 2010
Dominique Koensgen; Guelten Oskay-Oezcelik; Ioanna Katsares; Ulla Walle; Christine Klapp; Alexander Mustea; Dirk Stengel; Franz Porzsolt; W. Lichtenegger; Jalid Sehouli
Goals of workQuality of life (Qol) represents a relevant end point in the clinical management of advanced ovarian cancer (AOC). However, there exist only a few specific instruments which have been designed for patients with ovarian cancer. The aim of this study was to develop a systematic checklist (Berlin Symptom Checklist Ovary (BSCL-O)) as an instrument of Qol for patients with AOC and to discriminate between the frequency and the importance of symptoms.Patients and methodsThe main symptoms were identified in a phase I study via free interviews of five patients with ovarian cancer (OC) as well as five medical doctors, family dependants, and care workers. In the phase II study, the capability of BSCL-O was evaluated by questionnaire-guided interviews of 200 patients with primary OC, recurrent OC, metastasized breast cancer, and benign ovarian tumors.Main resultsIn phase I, 36 main symptoms were identified. In phase II, 7,200 answers from 98.5% of all patients were evaluable. Of the 36 symptoms of the BSCL-O, 23 revealed clinical relevance. There was a correlation of frequency and importance of symptoms (p < 0.05). The symptoms of the BSCL-O were deemed twice as strenuous in patients with recurrent OC.ConclusionsThe BSCL-O can measure Qol of patients with OC. The BSCL-O is being validated in a phase III study.
Disease Markers | 2017
Matthias B. Stope; Gerd Klinkmann; Karoline Diesing; Dominique Koensgen; Martin Burchardt; Alexander Mustea
The heat shock protein HSP27 has been correlated in ovarian cancer (OC) patients with aggressiveness and chemoresistance and, therefore, represents a promising potential biomarker for OC diagnosis, prognosis, and treatment response. Notably, secretion of soluble HSP27 has been described by a few cell types and may take place as well in OC cells. Therefore, we studied HSP27 secretion mechanisms under diverse cellular conditions in an OC cell model system. Secretion of HSP27 was characterized after overexpression of HSP27 by transfected plasmids and after heat shock. Intra- and extracellular HSP27 amounts were assessed by Western blotting and ELISA. Protein secretion was blocked by brefeldin A and the impact of the HSP27 phosphorylation status was analyzed overexpressing HSP27 phosphomutants. The present study demonstrated that HSP27 secretion by OVCAR-3 and SK-OV-3 cells depends on intracellular HSP27 concentrations. Moreover, HSP27 secretion is independent of the endoplasmic reticulum secretory pathway and HSP27 phosphorylation. Notably, analysis of OC cell-born exosomes not only confirmed the concentration-dependent correlation of HSP27 expression and secretion but also demonstrated a concentration-dependent incorporation of HSP27 protein into exosomes. Thus, secreted HSP27 may become more important as an extracellular factor which controls the tumor microenvironment and might be a noninvasive biomarker.