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  • Plate, Karl H. (16)
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Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma (2015)
Scholz, Alexander ; Harter, Patrick Nikolaus ; Cremer, Sebastian ; Yalcin, Burak H. ; Gurnik, Stefanie ; Yamaji, Maiko ; Di Tacchio, Mariangela ; Sommer, Kathleen ; Baumgarten, Peter ; Bähr, Oliver ; Steinbach, Joachim Peter ; Trojan, Jörg ; Glas, Martin ; Herrlinger, Ulrich ; Krex, Dietmar ; Meinhardt, Matthias ; Weyerbrock, Astrid ; Timmer, Marco ; Goldbrunner, Roland ; Deckert, Martina ; Braun, Christian ; Schittenhelm, Jens ; Früh, Jochen ; Ullrich, Evelyn ; Mittelbronn, Michel Guy André ; Plate, Karl H. ; Reiss, Yvonne
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression (2012)
Reis, Marco ; Czupalla, Cathrin Jacqueline ; Ziegler, Nicole ; Devraj, Kavi ; Zinke, Jenny ; Seidel, Sascha ; Heck, Rosario ; Thom, Sonja ; Macas, Jadranka ; Bockamp, Ernesto ; Fruttiger, Marcus ; Taketo, Makoto Mark ; Dimmeler, Stefanie ; Plate, Karl H. ; Liebner, Stefan
Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.
Wnt/beta-catenin signaling controls development of the blood–brain barrier (2008)
Liebner, Stefan ; Corada, Monica ; Bangsow, Thorsten ; Babbage, Jane ; Taddei, Andrea ; Czupalla, Cathrin Jacqueline ; Reis, Marco ; Felici, Angelina ; Wolburg, Hartwig ; Fruttiger, Marcus ; Taketo, Makoto Mark ; Melchner, Harald von ; Plate, Karl H. ; Gerhardt, Holger ; Dejana, Elisabetta
The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/beta-catenin (beta-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of beta-cat in vivo enhances barrier maturation, whereas inactivation of beta-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of beta-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of beta-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of beta-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.
EGFL7 meets miRNA-126 : an angiogenesis alliance (2010)
Nikolic, Iva ; Plate, Karl H. ; Schmidt, Mirko Hans Heinrich
Blood vessels form de novo through the tightly regulated programs of vasculogenesis and angiogenesis. Both processes are distinct but one of the steps they share is the formation of a central lumen, when groups of cells organized as vascular cords undergo complex changes to achieve a tube-like morphology. Recently, a protein termed epidermal growth factor-like domain 7 (EGFL7) was described as a novel endothelial cell-derived factor involved in the regulation of the spatial arrangement of cells during vascular tube assembly. With its impact on tubulogenesis and vessel shape EGFL7 joined the large family of molecules governing blood vessel formation. Only recently, the molecular mechanisms underlying EGFL7's effects have been started to be elucidated and shaping of the extracellular matrix (ECM) as well as Notch signaling might very well play a role in mediating its biological effects. Further, findings in knock-out animal models suggest miR-126, a miRNA located within the egfl7 gene, has a major role in vessel development by promoting VEGF signaling, angiogenesis and vascular integrity. This review summarizes our current knowledge on EGFL7 and miR-126 and we will discuss the implications of both bioactive molecules for the formation of blood vessels.
Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases (2015)
Harter, Patrick Nikolaus ; Bernatz, Simon ; Scholz, Alexander ; Zeiner, Pia Susan ; Zinke, Jenny ; Kiyose, Makoto ; Blasel, Stella ; Beschorner, Rudi ; Senft, Christian Alexander ; Bender, Benjamin ; Ronellenfitsch, Michael Wilfried ; Wikman, Harriet ; Glatzel, Markus ; Meinhardt, Matthias ; Juratli, Tareq A. ; Steinbach, Joachim Peter ; Plate, Karl H. ; Wischhusen, Jörg ; Weide, Benjamin ; Mittelbronn, Michel Guy André
Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of ‘globular’ receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of ‘globular’ fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of ‘globular’ fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of ‘globular’ fields well. Our computational study, therefore, suggests that ‘globular’ fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex.
Low Wnt/β-catenin signaling determines leaky vessels in the subfornical organ and affects water homeostasis in mice (2019)
Benz, Fabienne ; Wichitnaowarat, Viraya ; Lehmann, Martin ; Germano, Raoul F. V. ; Mihova, Diana ; Macas, Jadranka ; Adams, Ralf Heinrich ; Taketo, Makoto Mark ; Guerit, Sylvaine ; Plate, Karl H. ; Vanhollebeke, Benoit ; Liebner, Stefan
The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characterization of the subfornical organ (SFO) vasculature revealed heterogenous claudin-5 (Cldn5) and Plvap/Meca32 expression indicative for tight and leaky vessels, respectively. Dominant, EC-specific β-catenin transcription in mice, converted phenotypically leaky into BBB-like vessels, by augmenting Cldn5+ vessels, stabilizing junctions and by reducing Plvap/Meca32+ and fenestrated vessels, resulting in decreased tracer permeability. Endothelial tightening augmented neuronal activity in the SFO of water restricted mice. Hence, regulating the SFO vessel barrier may influence neuronal function in the context of water homeostasis.
ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment (2015)
Braczynski, Anne Kristin ; Vlaho, Stefan ; Müller, Klaus ; Wittig, Ilka ; Blank, Anna-Eva ; Tews, Dominique Suzanne ; Drott, Ulrich ; Kleinle, Stephanie ; Abicht, Angela ; Horvath, Rita ; Plate, Karl H. ; Stenzel, Werner ; Goebel, Hans Hilmar ; Schulze-Bonhage, Andreas ; Harter, Patrick Nikolaus ; Kieslich, Matthias ; Mittelbronn, Michel Guy André
TMEM70 is involved in the biogenesis of mitochondrial ATP synthase and mutations in the TMEM70 gene impair oxidative phosphorylation. Herein, we report on pathology and treatment of ATP synthase deficiency in four siblings. A consanguineous family of Roma (Gipsy) ethnic origin gave birth to 6 children of which 4 were affected presenting with dysmorphic features, failure to thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in the TMEM70 gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions, cristae aggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete ATP synthase deficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment.
Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited (2012)
Plate, Karl H. ; Scholz, Alexander ; Dumont, Daniel J.
The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to tumor angiogenesis. Many of these processes have been described in developmental angiogenesis; however, the relative contribution and relevance of these in human brain cancer remain unclear. Preclinical tumor models support a role for sprouting angiogenesis, vascular co-option and myeloid cell-derived angiogenesis in glioma vascularization, whereas a role for the other four mechanisms remains controversial and rather enigmatic. The anti-angiogenesis drug Avastin (Bevacizumab), which targets VEGF, has become one of the most popular cancer drugs in the world. Anti-angiogenic therapy may lead to vascular normalization and as such facilitate conventional cytotoxic chemotherapy. However, preclinical and clinical studies suggest that anti-VEGF therapy using bevacizumab may also lead to a pro-migratory phenotype in therapy resistant glioblastomas and thus actively promote tumor invasion and recurrent tumor growth. This review focusses on (1) mechanisms of tumor angiogenesis in human malignant glioma that are of particular relevance for targeted therapy and (2) controversial issues in tumor angiogenesis such as cancer stem-like cell-derived vasculogenesis and bone-marrow-derived vasculogenesis.
Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation (2014)
Ridder, Kirsten ; Keller, Sascha ; Dams, Maria ; Rupp, Anne-Kathleen ; Schlaudraff, Jessica ; Del Turco, Domenico ; Starmann, Julia ; Macas, Jadranka ; Karpova, Darja ; Devraj, Kavi ; Depboylu, Candan ; Landfried, Britta ; Arnold, Bernd ; Plate, Karl H. ; Höglinger, Günter ; Sültmann, Holger ; Altevogt, Peter ; Momma, Stefan
Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.
Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases (2014)
Harter, Patrick Nikolaus ; Zinke, Jenny ; Scholz, Alexander ; Tichy, Julia Frederike ; Zachskorn, Cornelia ; Kvasnicka, Hans-Michael ; Goeppert, Benjamin ; Delloye-Bourgeois, Céline ; Hattingen, Elke ; Senft, Christian Alexander ; Steinbach, Joachim Peter ; Plate, Karl H. ; Mehlen, Patrick ; Schulte, Dorothea ; Mittelbronn, Michel Guy André
The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.
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