Institute for Tumor Biology and Experimental Therapy
Institute for Tumor Biology and Experimental Therapy
Koliaraki V.,Biomedical science Research Center Alexander Fleming |
Pallangyo C.K.,Muhimbili University of Health and Allied Sciences |
Greten F.R.,Institute for Tumor Biology and Experimental Therapy |
Greten F.R.,German Cancer Research Center |
And 2 more authors.
Gastroenterology | Year: 2017
Mesenchymal cells in the intestine comprise a variety of cell types of diverse origins, functions, and molecular markers. They provide mechanical and structural support and have important functions during intestinal organogenesis, morphogenesis, and homeostasis. Recent studies of the human transcriptome have revealed their importance in the development of colorectal cancer, and studies from animal models have provided evidence for their roles in the pathogenesis of colitis-associated cancer and sporadic colorectal cancer. Mesenchymal cells in tumors, called cancer-associated fibroblasts, arise via activation of resident mesenchymal cell populations and the recruitment of bone marrow–derived mesenchymal stem cells and fibrocytes. Cancer-associated fibroblasts have a variety of activities that promote colon tumor development and progression; these include regulation of intestinal inflammation, epithelial proliferation, stem cell maintenance, angiogenesis, extracellular matrix remodeling, and metastasis. We review the intestinal mesenchymal cell-specific pathways that regulate these processes, with a focus on their roles in mediating interactions between inflammation and carcinogenesis. We also discuss how increasing our understanding of intestinal mesenchymal cell biology and function could lead to new strategies to identify and treat colitis-associated cancers. © 2017 AGA Institute
Groner B.L.,Institute for Tumor Biology and Experimental Therapy |
Hynes N.E.,Friedrich Miescher Institute for Biomedical Research
PLoS Biology | Year: 2016
Cancer research has become a global enterprise, and the number of researchers, as well as the cost for their activities, has skyrocketed. The budget for the National Cancer Institute of the United States National Institutes of Health alone was US$5.2 billion in 2015. Since most of the research is funded by public money, it is perfectly legitimate to ask if these large expenses are worth it. In this brief commentary, we recapitulate some of the breakthroughs that mark the history of breast cancer research over the past decades and emphasize the resulting benefits for afflicted women. In 1971, only 40% of women diagnosed with breast cancer would live another 10 years. Today, nearly 80% of women reach that significant milestone in most developed countries. This dramatic change has afforded breast cancer patients many productive years and a better quality of life. Progress resulted largely from advances in the understanding of the molecular details of the disease and their translation into innovative, rationally designed therapies. These developments are founded on the revolution in molecular and cellular biology, an entirely new array of methods and technologies, the enthusiasm, optimism, and diligence of scientists and clinicians, and the considerable funding efforts from public and private sources. We were lucky to be able to spend our productive years in a period of scientific upheaval in which methods and concepts were revolutionized and that allowed us to contribute, within the global scientific community, to the progress in basic science and clinical practice. © 2016 Groner, Hynes.
Schulz M.D.,TU Munich |
Atay C.,TU Munich |
Heringer J.,TU Munich |
Romrig F.K.,TU Munich |
And 22 more authors.
Nature | Year: 2014
Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers1. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota2.Moreover, there is now unequivocal evidence linking dysbiosis to cancer development3.However, the mechanisms by which high-fat diet (HFD)- mediated changes in the microbial community affect the severity of tumorigenes is in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-rasG12Dint, mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut micro biota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-rasG12Dint mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a sign alling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-rasG12Dintmice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts inthe microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals. © 2014 Macmillan Publishers Limited. All rights reserved.
Krause D.S.,Institute for Tumor Biology and Experimental Therapy |
Scadden D.T.,Harvard Stem Cell Institute
Haematologica | Year: 2015
Our understanding of the biology of the normal hematopoietic stem cell niche has increased steadily due to improved murine models and sophisticated imaging tools. Less well understood, but of growing interest, is the interaction between cells in the bone marrow during the initiation, maintenance and treatment of hematologic neoplasms. This review summarizes the emerging concepts of the normal and leukemic hematopoietic bone marrow niche. Furthermore, it reviews current models of how the microenvironment of the bone marrow may contribute to or be modified by leukemogenesis. Finally, it provides the rationale for a “two-pronged” approach, directly targeting cancer cells themselves while also targeting the bone microenvironment to make it inhospitable to malignant cells and, ultimately, eradicating cancer stem-like cells. © 2015 Ferrata Storti Foundation.
Canli O.,Institute for Tumor Biology and Experimental Therapy |
Alankus Y.B.,TU Munich |
Grootjans S.,Ghent University |
Vegi N.,University of Ulm |
And 6 more authors.
Blood | Year: 2016
Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis because imbalanced production of reactive oxygen species (ROS) may lead to oxidative stress and cell death. The antioxidant enzyme glutathione peroxidase 4 (Gpx4) is a key regulator of oxidative stress-induced cell death. We show that mice with deletion of Gpx4 in hematopoietic cells develop anemia and that Gpx4 is essential for preventing receptorinteracting protein 3 (RIP3)-dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation, resulting in necroptosis, which occurs independently of tumor necrosis factor a activation. Although genetic ablation of Rip3 normalizes reticulocyte maturation and prevents anemia, ROS accumulation and lipid peroxidation in Gpx4-deficient cells remain high. Our results demonstrate that ROS and lipid hydroperoxides function as not-yet-recognized unconventional upstream signaling activators of RIP3-dependent necroptosis. © 2016 by The American Society of Hematology.
Glienke W.,Hannover Medical School |
Esser R.,Hannover Medical School |
Priesner C.,Hannover Medical School |
Suerth J.D.,Hannover Medical School |
And 6 more authors.
Frontiers in Pharmacology | Year: 2015
In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy. © 2015 Glienke, Esser, Priesner, Suerth, Schambach, Wels, Grez, Kloess, Arseniev and Koehl.
Stangl S.,Helmholtz Center Munich |
Varga J.,Institute for Tumor Biology and Experimental Therapy |
Freysoldt B.,Helmholtz Center Munich |
Trajkovic-Arsic M.,TU Munich |
And 4 more authors.
Cancer Research | Year: 2014
Although in vivo targeting of tumors using fl uorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell speci fi city. Our novel tumor cell- penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fl uorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule avb3 - integrin antagonist IntegriSense, TPP exhibits a signi fi cantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-speci fic drug delivery and other Hsp70-based targeted therapies. Cancer Res 74(23); 6903-12. ©2014 American Association for Cancer Research.
Bulycheva E.,TU Dresden |
Rauner M.,TU Dresden |
Medyouf H.,Institute for Tumor Biology and Experimental Therapy |
Theurl I.,Innsbruck Medical University |
And 3 more authors.
Leukemia | Year: 2015
Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of 'osteohematology' as an emerging research field in MDS and outline clinical implications. © 2015 Macmillan Publishers Limited All rights reserved
Gupta J.,Barcelona Institute for Research in Biomedicine |
Gupta J.,Institute for Tumor Biology and Experimental Therapy |
Nebreda A.R.,Barcelona Institute for Research in Biomedicine |
Nebreda A.R.,Catalan Institution for Research and Advanced Studies
FEBS Journal | Year: 2015
The p38α mitogen-activated protein kinase pathway not only regulates the production of inflammatory mediators, but also controls processes related to tissue homeostasis, such as cell proliferation, differentiation and survival, which are often disrupted during malignant transformation. The versatility of this signaling pathway allows for the regulation of many specific functions depending on the cell type and context. Here, we discuss mouse models that have been used to identify in vivo functions of p38α signaling in the pathogenesis of inflammatory diseases and cancer. Experiments using genetically modified mice and pharmacological inhibitors support that targeting the p38α pathway could be therapeutically useful for some inflammatory diseases and tumor types. © 2015 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS.
Kaufmann K.B.,Institute for Tumor Biology and Experimental Therapy |
Chiriaco M.,University of Rome Tor Vergata |
Siler U.,University of Zürich |
Finocchi A.,University of Rome Tor Vergata |
And 3 more authors.
Current Gene Therapy | Year: 2014
Several Phase I/II clinical trials aiming at the correction of X-linked CGD by gene transfer into hematopoietic stem cells (HSCs) have demonstrated the therapeutic potential of gene modified autologous HSCs for the treatment of CGD. Resolution of therapy-resistant bacterial and fungal infections in liver, lung and spinal canal of CGD patients were clearly documented in all trials. However, clinical benefits were not sustained over time due to the failure of gene transduced cells to engraft long-term. Moreover, severe adverse effects were observed in some of the treated patients due to insertional mutagenesis leading to the activation of growth promoting genes and to myeloid malignancy. These setbacks fostered the development of novel safety and efficacy improved vectors that have already entered or are about to enter the clinics. Meanwhile, ongoing research is constantly refining the CGD disease phenotype, including the definition of factors that may explain the unique engraftment phenotype observed in CGD gene therapy trials. This review provides a condensed overview on the current knowledge of the molecular pathomechanisms and clinical manifestations of CGD and summarizes the lessons learned from clinical gene therapy trials, the preclinical progress in vector design and the future perspectives for the gene therapy of CGD. © 2014 Bentham Science Publishers.