Publications by authors named "Ines Gütgemann"

42 Publications

Prognostic Gene Expression, Stemness and Immune Microenvironment in Pediatric Tumors.

Cancers (Basel) 2021 Feb 18;13(4). Epub 2021 Feb 18.

Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany.

Pediatric tumors frequently arise from embryonal cells, often displaying a stem cell-like ("small round blue") morphology in tissue sections. Because recently "stemness" has been associated with a poor immune response in tumors, we investigated the association of prognostic gene expression, stemness and the immune microenvironment systematically using transcriptomes of 4068 tumors occurring mostly at the pediatric and young adult age. While the prognostic landscape of gene expression (PRECOG) and infiltrating immune cell types (CIBERSORT) is similar to that of tumor entities occurring mainly in adults, the patterns are distinct for each diagnostic entity. A high stemness score (mRNAsi) correlates with clinical and morphologic subtype in Wilms tumors, neuroblastomas, synovial sarcomas, atypical teratoid rhabdoid tumors and germ cell tumors. In neuroblastomas, a high mRNAsi is associated with shortened overall survival. In Wilms tumors a high mRNAsi correlates with blastemal morphology, whereas tumors with predominant epithelial or stromal differentiation have a low mRNAsi and a high percentage of M2 type macrophages. This could be validated in Wilms tumor tissue ( = 78). Here, blastemal areas are low in M2 macrophage infiltrates, while nearby stromal differentiated areas contain abundant M2 macrophages, suggesting local microanatomic regulation of the immune response.
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http://dx.doi.org/10.3390/cancers13040854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922568PMC
February 2021

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Cell Stem Cell 2021 Apr 9;28(4):637-652.e8. Epub 2020 Dec 9.

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands; Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Oncode Institute, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands. Electronic address:

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
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http://dx.doi.org/10.1016/j.stem.2020.11.004DOI Listing
April 2021

Macrophage frequency in the bone marrow correlates with morphologic subtype of myeloproliferative neoplasm.

Ann Hematol 2021 Jan 26;100(1):97-104. Epub 2020 Oct 26.

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

Bone marrow (BM) fibrosis in myeloproliferative neoplasms (MPNs) is associated with a poor prognosis. The development of myelofibrosis and differentiation of mesenchymal stromal cells to profibrotic myofibroblasts depends on macrophages. Here, we compared macrophage frequencies in BM biopsies of MPN patients and controls (patients with non-neoplastic processes), including primary myelofibrosis (PMF, n = 18), essential thrombocythemia (ET, n = 14), polycythemia vera (PV, n = 12), and Philadelphia chromosome-positive chronic myeloid leukemia (CML, n = 9). In PMF, CD68-positive macrophages were greatly increased compared to CML (p = 0.017) and control BM (p < 0.001). Similar findings were observed by CD163 staining (PMF vs. CML: p = 0.017; PMF vs. control: p < 0.001). Moreover, CD68-positive macrophages were increased in PV compared with ET (p = 0.009) and reactive cases (p < 0.001). PMF had higher frequencies of macrophages than PV (CD68: p < 0.001; CD163: p < 0.001) and ET (CD68: p < 0.001; CD163: p < 0.001). CD163 and CD68 were often co-expressed in macrophages with stellate morphology in Philadelphia chromosome-negative MPN, resulting in a sponge-like reticular network that may be a key regulator of unbalanced hematopoiesis in the BM space and may explain differences in cellularity and clinical course.
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http://dx.doi.org/10.1007/s00277-020-04304-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782416PMC
January 2021

Prognostic profiling of the immune cell microenvironment in Ewing´s Sarcoma Family of Tumors.

Oncoimmunology 2019;8(12):e1674113. Epub 2019 Oct 13.

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

Ewing´s Sarcoma Family of Tumors (ESFT) are clinically aggressive bone and soft tissue tumors in children and young adults. Analysis of the immune tumor microenvironment (TME) provides insight into tumor evolution and novel treatment options. So far, the scarcity of immune cells in ESFT has hindered a comprehensive analysis of rare subtypes. We determined the relative fraction of 22 immune cell types using 197 microarray gene expression datasets of primary ESFT tumor samples by using CIBERSORT, a deconvolution algorithm enumerating infiltrating leucocytes in bulk tumor tissue. The most abundant cells were macrophages (mean 43% of total tumor-infiltrating leukocytes, TILs), predominantly immunosuppressive M2 type macrophages, followed by T cells (mean 23% of TILs). Increased neutrophils, albeit at low number, were associated with a poor overall survival (OS) ( = .038) and increased M2 macrophages predicted a shorter event-free survival (EFS) ( = .033). High frequency of T cells and activated NK cells correlated with prolonged OS ( = .044 and = .007, respectively). A small patient population (9/32) with combined low infiltrating M2 macrophages, low neutrophils, and high total T cells was identified with favorable outcome. This finding was confirmed in a validation cohort of patients with follow up (11/38). When comparing the immune TME with expression of known stemness genes, hypoxia-inducible factor 1 α (HIF1α) correlated with high abundance of macrophages and neutrophils and decreased T cell levels. The immune TME in ESFTs shows a distinct composition including rare immune cell subsets that in part may be due to expression of HIF1α.
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http://dx.doi.org/10.1080/2162402X.2019.1674113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844324PMC
October 2019

Increased IgG4-positive plasma cells in nodular-sclerosing Hodgkin lymphoma: a diagnostic pitfall.

Histopathology 2020 Jan 26;76(2):244-250. Epub 2019 Nov 26.

Institute of Pathology, Rheinisch Friedrich-Wilhelm University, University Hospital Bonn, Bonn, Germany.

Aims: Despite increasing interest in the recently established immunoglobulin 4-related disease (IgG4-RD), its pathogenesis and aetiology remain largely unclear. Characteristic histopathological features are one of the key elements of diagnosis, including 'storiform' fibrosis, obliterative phlebitis, increased lymphoplasmacytic infiltration and increased levels of IgG4 in serum and tissue. Histopathological features of IgG4-RD are striking but not specific, and can pose a pitfall for surgical pathologists. This paper aims to determine the actual amount of IgG4+ plasma cells in nodular-sclerosing Hodgkin lymphoma (NSHL) and its potential to be misdiagnosed in routine clinical practice.

Methods And Results: IgG4+ plasma cells per high-power field (HPF) and the ratio of IgG4+ versus IgG+ plasma cells (IgG4/IgG ratio) in lymph node biopsies of 24 patients with nodular-sclerosing Hodgkin lymphoma (NSHL) were determined using immunohistochemistry and consensus scoring criteria as used for IgG4-RD. Ten lymph node biopsies with reactive follicular hyperplasia were assessed for comparison. Higher numbers of IgG4+ plasma cells (P < 0.001) were observed in NSHL versus follicular hyperplasia (mean 34 versus 8 per HPF) with a mean IgG4/IgG ratio of 0.38 versus 0.18. Five cases (21%) fulfilled the consensus criteria of IgG4-RD, with >50 IgG4+ plasma cells per HPF and an IgG4/IgG ratio of >0.4. The mean count of IgG4+ plasma cells per HPF in NSHL varied greatly (3-88) with increased numbers of IgG4+ plasma cells seen near areas of fibrosclerosis.

Conclusions: Significantly higher levels of IgG4+ plasma cells are common in NSHL, emphasising the need to exclude Reed-Sternberg cells by morphology and immunohistochemistry in biopsies where IgG4-RD is suspected.
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http://dx.doi.org/10.1111/his.13965DOI Listing
January 2020

[The geriatric syndrome of anemia-Summary of the symposium of the working group anemia during the annual meeting of the German Geriatric Society 2018 in Cologne, Germany].

Z Gerontol Geriatr 2019 Jul 23;52(4):370-376. Epub 2019 Apr 23.

Klinik für Geriatrie, Alexianer Krefeld GmbH, Krefeld, Deutschland.

This year's symposium of the working group anemia of the German Geriatric Society (DGG) aimed to underline the multicausality of anemia in the aged and to highlight definition parallels with geriatric syndromes. For these reasons, nutritional and malignant causes for anemia were discussed and the influence of oxidative stress on the development of anemia was underlined. The need for ongoing research in the field of anemia in the aged was emphasized by the lack of perioperative transfusion strategies in geriatric patients.
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http://dx.doi.org/10.1007/s00391-019-01545-zDOI Listing
July 2019

[Anemia in the aged - a geriatric syndrome? : Second position paper on anemia in the aged by the working group anemia of the German Geriatric Society].

Z Gerontol Geriatr 2018 Dec 4;51(8):921-923. Epub 2018 Oct 4.

FB Geriatrie, Medizinische Klinik, Bonifatius Hospital Lingen (Ems), Lingen (Ems), Deutschland.

Geriatric syndromes are the pathognomonic columns of geriatric medicine. In contrast to many syndromes in younger people, in geriatric patients, the chief complaint does not typically represent the specific pathological condition underlying the change in health status. Geriatric syndromes are usually highly prevalent, multicausal and share a number of common risk factors. In recent years, scientific controversy over anemia in the aged has revealed a high prevalence in geriatric patients, which prompted the "working group on anemia" to publish its first position paper at a European level. The development of anemia is multicausal and the causes of the various forms of anemia range from iron deficiency, malnutrition, chronic inflammation, hormonal dysregulation, functional organ disorders, impaired synthesis to malignancies. The corresponding pathomechanisms are closely associated with the development of other geriatric syndromes such as gait disorders, sarcopenia, frailty, and falls. Against this backdrop, the "working group on anemia" of the German Geriatric Society has devised a second position paper:"Multicausality and the significant association between anemia and assessment-based quantifiable impairments suggest the consideration of anemia in the aged to be a geriatric syndrome."
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http://dx.doi.org/10.1007/s00391-018-1457-xDOI Listing
December 2018

[Clinical hematological symptoms of vitamin B deficiency in old age : Summarized overview of this year's symposium of the Working Group "Anemia in the Aged" on the occasion of the annual conference of the German Geriatric Society (DGG) in Frankfurt].

Z Gerontol Geriatr 2018 Jun 23;51(4):446-452. Epub 2018 May 23.

Klinik für Geriatrie, Alexianer Krefeld GmbH und Klinik für Geriatrische Rehabilitation, Alexianer Tönisvorst GmbH, Tönisvorst, Deutschland.

The interdisciplinary symposium of the working group "anemia in the aged" on the occasion of the annual conference of the German Society of Geriatrics focused this year on vitamin B deficiency in aged patients. Experts from hematopathology, clinical geriatrics and geriatric hematology presented the case of a 78-year-old woman and an interdisciplinary discussion was held on the epidemiology, clinical aspects as well as diagnostic and therapeutic steps. This article reviews the symposium on vitamin B deficiency in the aged in the context of the currently available literature.
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http://dx.doi.org/10.1007/s00391-018-1410-zDOI Listing
June 2018

Low BUB1 expression is an adverse prognostic marker in gastric adenocarcinoma.

Oncotarget 2017 Sep 18;8(44):76329-76339. Epub 2017 Jul 18.

Institute of Pathology, University Hospital Bonn, Bonn, Germany.

Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis and prognostic markers are urgently needed to tailor treatment. We examined the expression of the mitotic spindle checkpoint protein BUB1 (budding uninhibited by benzimidazoles 1) and Ki-67 protein expression by immunohistochemistry in 218 patients with primary gastric adenocarcinomas. Tumors with low frequency of BUB1 expression were associated with larger tumor size (pT) (p < 0.001), higher incidence of lymph node metastases (pN) (p = 0.027), distant metastases (pM) (p = 0.006) and higher UICC stage (p < 0.001). Furthermore, BUB1 expression was inversely correlated with residual tumor stage (p = 0.038). Abundant BUB1 protein expression correlated with frequent Ki-67 protein expression (p < 0.001) and low BUB1 expression was associated with shorter survival (p < 0.001). Univariate and multivariate analyses confirmed BUB1 to be an independent prognostic marker in gastric cancer (p = 0.021).
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http://dx.doi.org/10.18632/oncotarget.19357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652709PMC
September 2017

[Current insights into anemia in old age : Summary of the symposium "Anemia in old age" on the occasion of the annual congress of the German Society for Geriatrics (DGG) 2016 in Stuttgart].

Z Gerontol Geriatr 2018 Apr 6;51(3):343-348. Epub 2017 Apr 6.

Bonifatius Hospital Medizinische Klinik FB Geriatrie, Lingen, Deutschland.

Anemia in advanced age is often a multifactorial condition requiring an interdisciplinary approach. The contributions to the opening interdisciplinary symposium on anemia in older subjects focused on physiological and histopathological as well as on nephrological and neurogeriatric aspects and on the therapeutic implications of this underdiagnosed, yet highly frequent disease. The symposium was the kick-off event for the founding of the German Geriatric Society special interest group on anemia in advanced age.
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http://dx.doi.org/10.1007/s00391-017-1212-8DOI Listing
April 2018

The spleen microenvironment influences disease transformation in a mouse model of KIT-dependent myeloproliferative neoplasm.

Sci Rep 2017 01 27;7:41427. Epub 2017 Jan 27.

University of Bonn Medical School, Institute of Pathology, Department of Developmental Pathology, 53127 Bonn, Germany.

Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KIT receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. We found that KIT mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. Moreover, we found mobilization of stem cells from bone marrow to the spleen. Splenectomy prior to KIT induction prevented expansion of red blood cells, but rapidly lead to a state of aplastic anemia and bone marrow fibrosis, reminiscent of post polycythemic myeloid metaplasia, the spent phase of polycythemia vera. Our results show that the extramedullary hematopoietic niche microenvironment significantly influences disease outcome in KIT mutant mice, turning this model a valuable tool for studying the interplay between functionally abnormal hematopoietic cells and their microenvironment during development of polycythemia vera-like disease and myelofibrosis.
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http://dx.doi.org/10.1038/srep41427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269732PMC
January 2017

The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling.

Blood 2017 01 28;129(4):460-472. Epub 2016 Sep 28.

Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.

Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor-related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders.
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http://dx.doi.org/10.1182/blood-2016-05-714659DOI Listing
January 2017

MYC regulates the antitumor immune response through CD47 and PD-L1.

Science 2016 Apr 10;352(6282):227-31. Epub 2016 Mar 10.

Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.
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http://dx.doi.org/10.1126/science.aac9935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940030PMC
April 2016

Fibroblast growth factor receptor 1 gene amplification in gastric adenocarcinoma.

Hum Pathol 2015 Oct 23;46(10):1488-95. Epub 2015 Jun 23.

Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany; Center for Integrated Oncology Cologne/Bonn, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. Electronic address:

Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis. Thus, identification of novel therapeutic targets is highly desirable. Here, we examined gene copy number of fibroblast growth factor receptor 1 (FGFR1), a potential target for tyrosine kinase inhibitors, and clinicopathologic parameters in a large cohort of gastric adenocarcinomas. We performed fluorescence in situ hybridization analysis of 293 gastric adenocarcinomas using tissue microarrays. Amplification of the FGFR1 gene is a rare but noticeable event that can be found in 2% (6/293) of cases and was associated with poor 10-year survival (median 15.3 months in FGFR1-amplified cases versus 36 months in nonamplified cases, P = .047) and a higher rate of distant metastasis (P = .025). FGFR1 appears to represent a potential new therapeutic target in a subset of patients with gastric carcinoma. Identification of gastric cancers harboring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using tyrosine kinase inhibitors.
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http://dx.doi.org/10.1016/j.humpath.2015.06.007DOI Listing
October 2015

Combinations of immunostimulatory antibodies with synergistic effects against spontaneous cancer.

Oncoimmunology 2014;3:e27812. Epub 2014 Jan 16.

Departamento de Inmunología; Centro de Investigación Médica Aplicada (CIMA); Universidad de Navarra; Pamplona, Spain ; Departamento de Oncología; Clínica Universidad de Navarra; Pamplona, Spain.

Immunostimulatory monoclonal antibodies can be given in combinations, hence modulating the activity of 2 or more receptors of the immune system. Some of these combinations have been shown to synergize at the elicitation of therapeutically relevant immune responses in transgenic mice developing spontaneous, oncogene-driven tumors, including multifocal hepatocellular carcinomas expressing ovalbumin as a surrogate tumor-associated antigen.
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http://dx.doi.org/10.4161/onci.27812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091451PMC
January 2014

Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model.

Clin Cancer Res 2013 Nov 12;19(22):6151-62. Epub 2013 Sep 12.

Authors' Affiliations: Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra; Department of Oncology, Clinica Universidad de Navarra; Liver Unit, Clínica Universidad de Navarra and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Pamplona, Spain; Oncology Drug Discovery division, Bristol-Myers Squibb, Lawrenceville, New Jersey; and Department of Pathology, University of Bonn, Bonn, Germany.

Purpose: Immunostimulatory monoclonal antibodies (ISmAb) that unleash antitumor immune responses are showing efficacy in cancer clinical trials. Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation. A combination of these ISmAbs (anti-CD137 + anti-OX40 + anti-B7-H1) was tested using a transgenic mouse model of multifocal and rapidly progressing hepatocellular carcinoma, in which c-myc drives transformation and cytosolic ovalbumin (OVA) is expressed in tumor cells as a model antigen.

Experimental Design: Flow-cytometry and immunohistochemistry were used to quantify tumor-infiltrating lymphocytes (TIL) elicited by treatment and assess their activation status and cytolytic potential. Tolerance induction and its prevention/reversal by treatment with the combination of ISmAbs were revealed by in vivo killing assays.

Results: The triple combination of ISmAbs extended survival of mice bearing hepatocellular carcinomas in a CD8-dependent fashion and synergized with adoptive T-cell therapy using activated OVA-specific TCR-transgenic OT-1 and OT-2 lymphocytes. Mice undergoing therapy showed clear increases in tumor infiltration by activated and blastic CD8(+) and CD4(+) T lymphocytes containing perforin/granzyme B and expressing the ISmAb-targeted receptors on their surface. The triple combination of ISmAbs did not result in enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity but other antigens expressed by cell lines derived from such hepatocellular carcinomas were recognized by endogenous TILs. Adoptively transferred OVA-specific OT-1 lymphocytes into tumor-bearing mice were rendered tolerant, unless given the triple mAb therapy.

Conclusion: Extension of survival and dense T-cell infiltrates emphasize the translational potential of combinational immunotherapy strategies for hepatocellular carcinoma. Clin Cancer Res; 19(22); 6151-62. ©2013 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1189DOI Listing
November 2013

Increased circulating levels of neurotrophins and elevated expression of their high-affinity receptors on skin and gut mast cells in mastocytosis.

Blood 2013 Sep 18;122(10):1779-88. Epub 2013 Jul 18.

Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.

Mastocytosis is a rare heterogeneous disease characterized by increase of mast cells (MCs) in different organs. Neurotrophins (NTs) have been shown to promote differentiation and survival of MCs, which in turn represent a major source of NTs. Thus, a contribution of NTs to mastocytosis seems highly conceivable but has not yet been investigated. We could demonstrate expression of high-affinity NT receptors tropomyosin-related kinase A (TrkA) for nerve growth factor (NGF)-β, TrkB for brain-derived neurotrophic factor, and NT-4 and TrkC for NT-3 on skin MCs; and of TrkA and TrkC on intestinal MCs of patients with mastocytosis. Moreover, increased expression of NGF-β; NT-3; TrkA, TrkB, and TrkC; and isoforms truncated TrkB-T1 and truncated TrkC were observed on skin MCs. Patients with mastocytosis featured elevated serum levels of NGF, NT-3, and NT-4. Levels of NGF-β and NT-4 correlated with tryptase levels, suggesting a link between MC load and blood levels of NGF and NT-4. Migration of CD117+ progenitor cells from the blood was enhanced toward NGF-β gradient in both mastocytosis and controls. Together with enhanced NT levels, the elevated expression of modified Trk receptors on skin and gut MCs might contribute to the pathophysiology of mastocytosis in autocrine and paracrine loops.
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http://dx.doi.org/10.1182/blood-2012-12-469882DOI Listing
September 2013

Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma.

Histopathology 2013 Aug 28;63(2):157-66. Epub 2013 Jun 28.

Institute of Pathology, University Hospital of Bonn, Bonn, Germany.

Aims: Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR-specific inhibitor BGJ398 on FGFR1-amplified pancreatic tumour cells in vitro.

Methods And Results: Fluorescence in-situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1-amplified cases. The FGFR1-amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398.

Conclusions: FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1-amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs.
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http://dx.doi.org/10.1111/his.12115DOI Listing
August 2013

Sorafenib in patients with refractory or recurrent multiple myeloma.

Hematol Oncol 2013 Dec 15;31(4):197-200. Epub 2013 Mar 15.

Department of Internal Medicine III, Center for Integrated Oncology (CIO), University of Bonn, Bonn, Germany.

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and rapidly accelerated fibrosarcoma kinases, targeting signal transduction and angiogenic pathways. It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma. In total, 11 patients were enrolled. Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression. Of the side effects, 8.8% grade 3 and 1.1% grade 4 occurred. Sorafenib treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24.4 months and 6.9 month, respectively. Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras-/BRAF-/vascular endothelial growth factor receptor pathway activation and combination therapy approaches.
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http://dx.doi.org/10.1002/hon.2043DOI Listing
December 2013

Alterations of global histone H4K20 methylation during prostate carcinogenesis.

BMC Urol 2012 Mar 13;12. Epub 2012 Mar 13.

Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsklinikum Bonn, Bonn, Germany.

Background: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis.

Methods: Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels.

Results: Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy.

Conclusions: H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.
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http://dx.doi.org/10.1186/1471-2490-12-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323457PMC
March 2012

Global histone H3K27 methylation levels are different in localized and metastatic prostate cancer.

Cancer Invest 2012 Feb 7;30(2):92-7. Epub 2011 Dec 7.

Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsklinikum Bonn, Bonn, Germany.

Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis.
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http://dx.doi.org/10.3109/07357907.2011.636117DOI Listing
February 2012

Deep sequencing of MYC DNA-binding sites in Burkitt lymphoma.

PLoS One 2011 10;6(11):e26837. Epub 2011 Nov 10.

Institute of Pathology, Charité-University Medicine, Campus Benjamin Franklin, Berlin, Germany.

Background: MYC is a key transcription factor involved in central cellular processes such as regulation of the cell cycle, histone acetylation and ribosomal biogenesis. It is overexpressed in the majority of human tumors including aggressive B-cell lymphoma. Especially Burkitt lymphoma (BL) is a highlight example for MYC overexpression due to a chromosomal translocation involving the c-MYC gene. However, no genome-wide analysis of MYC-binding sites by chromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) has been conducted in BL so far.

Methodology/principal Findings: ChIP-Seq was performed on 5 BL cell lines with a MYC-specific antibody giving rise to 7,054 MYC-binding sites after bioinformatics analysis of a total of approx. 19 million sequence reads. In line with previous findings, binding sites accumulate in gene sets known to be involved in the cell cycle, ribosomal biogenesis, histone acetyltransferase and methyltransferase complexes demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC-binding sites also accumulate in many B-cell relevant genes. To assess the functional consequences of MYC binding, the ChIP-Seq data were supplemented with siRNA- mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Interestingly, amongst others, genes involved in the B-cell function were up-regulated in response to MYC silencing.

Conclusion/significance: The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in BL and shed further light on the enormous complexity of the MYC regulatory network. Especially our observations that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an up-regulation of B-cell genes highlight an interesting aspect of BL biology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026837PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213110PMC
May 2012

H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1.

Hum Pathol 2010 Feb 6;41(2):181-9. Epub 2009 Nov 6.

Department of Pathology, University of Bonn, Sigmund-Freud-Strabetae 25, 53127 Bonn, Germany.

Methylation of core histones regulates chromatin structure and gene expression. Recent studies have demonstrated that these methylation patterns have prognostic value for some tumors. Therefore, we investigated dimethylation of histone H3 at lysine 4 (H3K4diMe) and H3K4 methylating (Ash2 complex) and demethylating enzymes (LSD1) in carcinomas of the hepatic and gastrointestinal tract. High levels of H3K4diMe were rarely observed in 15.7% of hepatocellular carcinoma (8/51) unlike other carcinomas including, in ascending order, cholangiocellular carcinoma/adenocarcinoma of the extrahepatic biliary tract, gastric carcinoma, pancreatic ductal adenocarcinoma, and neuroendocrine carcinoma (P < .001). Ash2 was expressed in 84.4% of hepatocellular carcinomas (38/45) and correlated directly with H3K4diMe modification (correlation coefficient r = 0.53) and LSD1 expression (r = 0.35). In contrast to other carcinomas, 65.9% (29/44) of hepatocellular carcinomas analyzed showed no LSD1 expression (P < .001). Interestingly, hepatocellular carcinomas without LSD1 expression appeared to be frequently Ash2 and H3K4diMe weak or negative (P = .004). In summary, high H3K4diMe expression is rare in hepatocellular carcinoma compared with other carcinomas (negative predictive value 92.3%), which may aid in the differential diagnosis. Lack of H3K4diMe is possibly due to complex epigenetic regulation involving Ash2 and LSD1.
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http://dx.doi.org/10.1016/j.humpath.2009.08.007DOI Listing
February 2010

Global levels of histone modifications predict prostate cancer recurrence.

Prostate 2010 Jan;70(1):61-9

Klinik und Poliklinik für Urologie, Universitätsklinikum Bonn, Bonn, Germany.

Purpose: Epigenetic alterations such as DNA methylation and histone modifications play important roles in carcinogenesis. It was reported that global histone modification patterns are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone lysine (H(x)K(y)) and histone acetyl (H(x)Ac) modifications in prostate tissue.

Materials And Methods: A tissue microarray with 113 prostate cancer (PCA), 23 non-malignant prostate tissues was stained with antibodies against H3K4 mono-(H3K4me1), di-(H3K4me2), tri-(H3K4me3) methylation, H3K9me1, H3K9me2, H3K9me3, H3 and H4 pan-acetylation (H3Ac, H4Ac). We also analyzed H3K4 methylation in patients with advanced PCA (hormone-refractory PCA-HRPC, n = 34; hormone-dependent PCA, n = 30). Sections were scored according the staining intensity and the proportion of epithelial cells showing nuclear staining.

Results: H3K4me1, H3K9me2, H3K9me3, H3Ac, and H4Ac were significantly reduced in PCA compared to non-malignant prostate tissue. H3Ac and H3K9me2 levels allowed discrimination of PCA and non-malignant prostate tissue highly specifically (>91%) and sensitively (>78%) as determined via ROC analyses (AUC >0.91). Histone lysine methylation and histone acetylation marks were correlated with clinical-pathological parameters (i.e., digital rectal examination, preoperative PSA, pT-stage, lymph node metastasis, Gleason score). In addition, H3K4me1 was a significant predictor of PSA recurrence following radical prostatectomy. H3K4me1, H3K4me2, and H3K4me3 levels were significantly increased in HRPC.

Conclusions: Global histone modification levels may help to identify patients with adverse prognosis, and represent a target for the future therapy of PCA.
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http://dx.doi.org/10.1002/pros.21038DOI Listing
January 2010

Lymph node dissection in primary intrahepatic malignant mesothelioma: case report and implications for diagnosis and therapy.

Langenbecks Arch Surg 2009 Nov 12;394(6):1123-30. Epub 2009 Mar 12.

Department of Surgery, University of Bonn Medical Center, Bonn, Germany.

Introduction: In this rare case of intrahepatic malignant mesothelioma with subsequent lymph node metastases, hepatic segmentectomy in combination with repeated lymphadenectomy resulted in prolonged survival, currently 37 months after initial diagnosis.

Discussion: Immunohistochemically, vascular endothelial growth factor receptor-1 expressing tumor cells were surrounded by a dense D 2-40-positive lymphangiovascular network, suggesting tumor induced lymphangiogenesis correlating to 2-deoxy-2[(18)F]fluoro-d-glucose-positron emission tomography/computed tomography-positive recurrent intraabdominal and intrathoracic lymphatic tumor spread. Therefore, extended lymphadenectomy during primary tumor resection and combined adjuvant chemotherapy with promising anticancer agents possessing antilymphangiogenic and antimetabolite properties should be considered to prolong survival in cases of extrathoracic malignant mesothelioma. Additionally, as shown in our case, individual operative concepts and (sometimes) multiple operations can be beneficial for highly selected patients. Importantly, a case-by-case optimized antitumor regimen requires interdisciplinary expertise and consensus of all involved faculties.
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http://dx.doi.org/10.1007/s00423-009-0476-xDOI Listing
November 2009

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation.

Hepatology 2009 Feb;49(2):471-81

Department of Pathology, University of Bonn, Bonn, Germany.

The reason the adaptive immune system fails in advanced liver tumors is largely unclear. To address this question, we have developed a novel murine model that combines c-myc-induced autochthonous tumorigenesis with expression of a cognate antigen, ovalbumin (OVA). When c-myc/OVA transgenic mice were crossed with liver-specific inducer mice, multifocal hepatocellular carcinomas co-expressing OVA developed in a tetracycline-dependent manner with a short latency and 100% penetrance. Transferred OVA-specific T cells, although infiltrating the tumor at high numbers, were hyporesponsive, as evidenced by a lack of in vivo cytotoxicity and interferon gamma production. This allowed the tumor to progress even in the presence of large numbers of antigen-specific T cells and even after vaccination (OVA+CpG-DNA). Interestingly, T cell receptor down-modulation was observed, which may explain antigen-specific hyporesponsiveness. This model is helpful in understanding liver cancer-specific mechanisms of T cell tolerance and dissection of antigen-specific and nonspecific mechanisms of immunotherapies in the preclinical phase.
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http://dx.doi.org/10.1002/hep.22652DOI Listing
February 2009

Stem cell marker expression in small cell lung carcinoma and developing lung tissue.

Hum Pathol 2008 Nov 24;39(11):1597-605. Epub 2008 Jul 24.

Institut of Pathology, University of Bonn, Bonn, Germany.

Histopathologic and clinical findings suggest that small cell lung cancer is derived from a multipotent proximal airway epithelial cell. In order to investigate the histogenetic origin of small cell lung cancer, we compared stem cell marker expression in human fetal lung tissue, human adult bronchial tissue, and a cohort of 64 small cell lung cancers. Supporting derivation of a multipotent precursor cell, 87.5% (56/64) of small cell lung cancers showed a dot-like expression of podocalyxin-like protein 1 (PODXL-1), a marker of embryonic and hematopoetic stem cells. Of small cell lung cancers, 98.4% (63/64) ubiquitously expressed Bmi-1, a key player in self-renewal of stem cells. Oct4 and AP2gamma were not expressed. Although podocalyxin-like protein 1 did not correlate with p53 or Wilms tumor suppressor 1, known regulators of podocalyxin-like protein 1, we could demonstrate demethylated CpG islands in the podocalyxin-like protein 1 promoter in small cell lung cancer, indicating epigenetic regulation. During fetal lung development and within adult bronchial mucosa, Bmi-1 was expressed ubiquitously. In contrast, podocalyxin-like protein 1 was detected in few stromal cells during the pseudoglandular phase (n = 7) and, importantly, in clustered epithelial cells within proximal bronchi and the trachea during the canalicular phase (n = 10). Interestingly, podocalyxin-like protein 1 was not expressed in normal or metaplastic adult bronchial epithelium (n = 36) but was expressed in sparse epithelial cells in half of the cases of normal tumor adjacent bronchial mucosa (20/40). Taken together, we show that small cell lung cancers and clustered epithelial cells in developing proximal bronchi share the expression of stem cell markers, suggesting a possible histogenetic link.
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http://dx.doi.org/10.1016/j.humpath.2008.03.008DOI Listing
November 2008

Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition.

Cancer Cell 2008 Jul;14(1):23-35

Institute for Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.

A reduction in the cellular levels of the cyclin kinase inhibitor p27(kip1) is frequently found in many human cancers and correlates directly with patient prognosis. In this work, we identify argyrin A, a cyclical peptide derived from the myxobacterium Archangium gephyra, as a potent antitumoral drug. All antitumoral activities of argyrin A depend on the prevention of p27(kip1) destruction, as loss of p27(kip1) expression confers resistance to this compound. We find that argyrin A exerts its effects through a potent inhibition of the proteasome. By comparing the cellular responses exerted by argyrin A with siRNA-mediated knockdown of proteasomal subunits, we find that the biological effects of proteasome inhibition per se depend on the expression of p27(kip1).
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http://dx.doi.org/10.1016/j.ccr.2008.05.016DOI Listing
July 2008

Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma.

Mod Pathol 2008 Apr 18;21(4):445-54. Epub 2008 Jan 18.

Department of Pathology, Stanford University, Stanford, CA, USA.

Clear cell carcinoma is a clinically and pathologically distinct entity among surface epithelial ovarian neoplasms, recognized for its resistance to standard platinum-based chemotherapy at advanced stage disease and poor prognosis. Despite advances in our understanding of the biology of other surface epithelial ovarian neoplasms, very little is known about the molecular genetic mechanisms that are involved in clear cell tumorigenesis. Early mitotic inhibitor-1 (Emi1) protein is a key cell cycle regulator, that promotes S-phase and mitotic entry by inhibiting the anaphase promoting complex. In cell culture systems, overexpression of Emi1 leads to tetraploidy and genomic instability, especially in the absence of normal p53 function. We investigated Emi1 protein expression in ovarian neoplasms using a tissue microarray constructed from 339 primary ovarian surface epithelial (serous, endometrioid, clear cell, and mucinous) and peritoneal (serous) neoplasms, stromal and mesenchymal tumors, germ cell tumors, and normal ovarian tissue. Significant overexpression of Emi1 protein was present in 82% (27/33) clear cell carcinoma, including one borderline tumor in a diffuse, granular cytoplasmic and perinuclear staining pattern, independent of patient age, presence of ovarian and/or pelvic endometriosis, and FIGO stage. In contrast, only 10% (17/177) primary ovarian and primary peritoneal serous carcinomas, 0% (0/10) mucinous carcinomas, and 19% (6/32) endometrioid carcinomas exhibited significant Emi1 protein overexpression. Accumulation of Emi1 protein was not linked to Ki-67 labeling index, but was directly correlated with cyclin E and inversely correlated with ER in clear cell carcinoma (P<0.001). Emi1 protein expression was present in mixed endometrioid/clear cell tumors but absent in tumors with mixed serous/clear cell histology. These findings represent a potentially important insight into the molecular pathway underlying ovarian carcinogenesis and provide a possible cell cycle model for the development and progression of ovarian clear cell carcinoma.
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http://dx.doi.org/10.1038/modpathol.3801022DOI Listing
April 2008