Peter Carmeliet

Vesalius Research Center, Louvain, Flanders, Belgium

Are you Peter Carmeliet?

Claim your profile

Publications (619)6337.29 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: For eukaryotic cells to function properly, they divide their intracellular space in subcellular compartments, each harboring specific metabolic activities. In recent years, it has become increasingly clear that compartmentalization of metabolic pathways is a prerequisite for certain cellular functions. This has for instance been documented for cellular migration, which relies on subcellular localization of glycolysis or mitochondrial respiration in a cell type-dependent manner. Although exciting, this field is still in its infancy, partly due to the limited availability of methods to study the directionality of metabolic pathways and to visualize metabolic processes in distinct cellular compartments. Nonetheless, advances in this field may offer opportunities for innovative strategies to target deregulated compartmentalized metabolism in disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Current Opinion in Biotechnology 12/2014; 34C:73-81. · 8.04 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability.
    Nature Communications 11/2014; 5:5582. · 10.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The tight interrelationship between peroxisomes and mitochondria is illustrated by their cooperation in lipid metabolism, antiviral innate immunity and shared use of proteins executing organellar fission. In addition, we previously reported that disruption of peroxisome biogenesis in hepatocytes severely impacts on mitochondrial integrity, primarily damaging the inner membrane. Here we investigated the molecular impairments of the dysfunctional mitochondria in hepatocyte selective Pex5 knockout mice. First, by using blue native electrophoresis and in-gel activity stainings we showed that the respiratory complexes were differentially affected with reduction of complexes I and III and incomplete assembly of complex V, whereas complexes II and IV were normally active. This resulted in impaired oxygen consumption in cultured Pex5(-/-) hepatocytes. Second, mitochondrial DNA was depleted causing an imbalance in the expression of mitochondrial- and nuclear-encoded subunits of the respiratory chain complexes. Third, mitochondrial membranes showed increased permeability and fluidity despite reduced content of the polyunsaturated fatty acid docosahexaenoic acid. Fourth, the affected mitochondria in peroxisome deficient hepatocytes displayed increased oxidative stress. Acute deletion of PEX5 in vivo using adeno-Cre virus phenocopied these effects, indicating that mitochondrial perturbations closely follow the loss of functional peroxisomes in time. Likely to compensate for the functional impairments, the volume of the mitochondrial compartment was increased several folds. This was not driven by PGC-1α but mediated by activation of PPARα, possibly through c-myc overexpression. In conclusion, loss of peroxisomal metabolism in hepatocytes perturbs the mitochondrial inner membrane, depletes mitochondrial DNA and causes mitochondrial biogenesis independent of PGC-1α. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 11/2014; 1853(2):285-298. · 5.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The drug discovery landscape has been transformed over the past decade by the discovery of allosteric modulators of all major mammalian receptor superfamilies. Allosteric ligands are a rich potential source of drugs and drug targets with clear therapeutic advantages. G protein-coupled receptors, ligand-gated ion channels and intracellular nuclear hormone receptors have all been targeted by allosteric modulators. More recently, a receptor tyrosine kinase (RTK) has been targeted by an extracellular small-molecule allosteric modulator. Allosteric mechanisms of structurally distinct molecules that target the various receptor families are more alike than originally anticipated and include selectivity, orthosteric probe dependence and pathway-biased signaling.
    Nature Biotechnology 11/2014; 32(11):1113-1120. · 39.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chloroquine (CQ) is exploited in clinical trials as an autophagy blocker to potentiate anticancer therapy, but it is unknown if it solely acts by inhibiting cancer cell-autonomous autophagy. Our recent study shows that besides blocking cancer cell growth, CQ also affects endothelial cells (ECs) and promotes tumor vessel normalization. This vessel normalizing effect of CQ reduces tumor hypoxia, cancer cell intravasation and metastasis, while improving the delivery and response to chemotherapy. By compromising autophagy in melanoma cells or using mice with a conditional knockout of ATG5 in ECs, we found that the favorable effects of CQ on the tumor vasculature does not rely on autophagy. CQ-induced vessel normalization rely mainly on altered endolysosomal trafficking and sustained NOTCH1 signaling in ECs. Remarkably these CQ-mediated effects are abrogated when tumors are grown in mice harboring EC-specific deletion of NOTCH1. The autophagy-independent vessel normalization by CQ leading to improved delivery and tumor response to chemotheraphy further advocates its clinical use in combination with anti-cancer treatments.
    Autophagy 10/2014; · 11.42 Impact Factor
  • Mieke Dewerchin, Peter Carmeliet
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Placental growth factor (PLGF) belongs to the VEGF family, which among the three VEGF receptors binds exclusively to VEGFR1, present on various cell types. Isoform PLGF-2 also binds the neuropilin co-receptors. PLGF is dispensable for development and health but has a prominent role in pathology including cancer. This has triggered the question whether PLGF targeting might offer an alternative to current antiangiogenesis therapy, which encounters problems of refractoriness and acquired resistance.Areas covered: This article reviews the available literature on the characteristics of PLGF, its role(s) in cancer and the findings on PLGF inhibition in preclinical models with attention to as yet unresolved questions and summarizes data from initial clinical trials.Expert opinion: Preclinical studies show that inhibition of PLGF, either by genetic inhibition or by pharmacological blockade using distinct independently generated anti-PLGF antibodies, slows down tumor growth and metastasis and even induces regression of pre-existing medulloblastoma, the most frequent brain cancer in children. These promising preclinical findings, together with the acceptable safety profile of anti-PLGF administration in Phase I clinical trials, have attracted attention to PLGF as a potential target for therapy.
    Expert Opinion on Therapeutic Targets 10/2014; · 4.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis contributes to the development of numerous disorders. Even though fibroblast growth factors (FGFs) were discovered as mediators of angiogenesis more than 30 years ago, their role in developmental angiogenesis still remains elusive. We use a recently described chemical probe, SSR128129E (SSR), that selectively inhibits the action of multiple FGF receptors (FGFRs), in combination with the zebrafish model to examine the role of FGF signaling in vascular development. We observe that while FGFR signaling is less important for vessel guidance, it affects vascular outgrowth and is especially required for the maintenance of blood vessel integrity by ensuring proper cell-cell junctions between endothelial cells. In conclusion, our work illustrates the power of a small molecule probe to reveal insights into blood vessel formation and stabilization and thus of broad interest to the vascular biology community.
    Chemistry & Biology 09/2014; · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinically approved therapies that target angiogenesis in tumors and ocular diseases focus on controlling pro-angiogenic growth factors in order to reduce aberrant microvascular growth. Although research on angiogenesis has revealed key mechanisms that regulate tissue vascularization, therapeutic success has been limited owing to insufficient efficacy, refractoriness and tumor resistance. Emerging concepts suggest that, in addition to growth factors, vascular metabolism also regulates angiogenesis and is a viable target for manipulating the microvasculature. Recent studies show that endothelial cells rely on glycolysis for ATP production, and that the key glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) regulates angiogenesis by controlling the balance of tip versus stalk cells. As endothelial cells acquire a tip cell phenotype, they increase glycolytic production of ATP for sprouting. Furthermore, pharmacological blockade of PFKFB3 causes a transient, partial reduction in glycolysis, and reduces pathological angiogenesis with minimal systemic harm. Although further assessment of endothelial cell metabolism is necessary, these results represent a paradigm shift in anti-angiogenic therapy from targeting angiogenic factors to focusing on vascular metabolism, warranting research on the metabolic pathways that govern angiogenesis.
    Journal of Cell Science 09/2014; · 5.33 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ's vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs in vivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment.
    Cancer cell. 08/2014; 26(2):190-206.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vascular endothelial growth factor (VEGF) is a key growth factor driving angiogenesis (i.e. the formation of new blood vessels) in health and disease. Pharmacological blockade of VEGF signaling to inhibit tumor angiogenesis is clinically approved but the survival benefit is limited as patients invariably acquire resistance. This is partially mediated by the intrinsic flexibility of tumor cells to adapt to VEGF-blockade. However, it has become clear that tumor stromal cells also contribute to the resistance. Originally, VEGF was thought to specifically target endothelial cells (ECs) but it is now clear that many stromal cells also respond to VEGF signaling, making anti-VEGF therapy more complex than initially anticipated. A more comprehensive understanding of the complex responses of stromal cells to VEGF-blockade might inform the design of improved anti-angiogenic agents.
    Cytokine & Growth Factor Reviews 08/2014; · 6.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Macrophage specific knockout of PHD-2 prolylhydroxylase domain protein 2 (PHD-2-/-), the crucial cellular oxygen sensor, increased anti-inflammatory M2 macrophages, angiogenesis and arteriogenesis in mice. As macrophages and angiogenesis are known to enhance progression of atherosclerotic plaques, we hypothesized that macrophage PHD-2-/- would increase plaque size and progression.
    Cardiovascular Research 07/2014; 103(suppl 1):S87. · 5.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Knockout of the oxygen-sensor HIF prolyl hydroxylase 1 (PHD1) was shown to switch metabolism towards glycolysis and reduced cellular oxygen consumption. As we recently showed a pro-atherosclerotic effect of plaque hypoxia, we hypothesised that reduced cellular oxygen consumption in PHD1 knockout mice alleviates atherosclerosis development. Low density lipoprotein receptor knockout (LDLr-/-, control) and LDLr-/-PHD1-/- mice (n=17 and 10, respectively) were placed on a western-type diet (WTD, 0.25 % cholesterol) for 8 weeks to induce atherosclerosis. Mice were injected with pimonidazole (100 mg/kg i.p.) prior to sacrifice to detect hypoxia in atherosclerotic plaques. Atherogenesis was attenuated in PHD1-/- mice, as shown by reduced aortic root plaque size (-35%, p=0.008, H&E) and necrotic core content (-38%, p=0.004, H&E). Plaque hypoxia was significantly reduced in PHD1-/- mice (-32%, p=0.02), despite unchanged MAC3 macrophage content, suggestive of reduced macrophage oxygen consumption. PHD1 deficiency led to significantly lowered plasma cholesterol (-21%, p<0.001) and triglyceride (TG) levels (-22%, p<0.001), as well as adipocyte size (-17% cell surface area, p=0.02, H&E), despite unchanged food intake. Hepatic cholesterol and TG re-entry in the circulation was similar in LDLr-/-PHD1-/- and control (n=6/group, WTD for 3 weeks), as studied after i.v. Triton WR1339 administration (500mg/kg). Also, hepatic cholesterol and TG content (μg lipid/mg protein) were unchanged in the atherosclerosis study, while liver weight decreased (-12%, p=0.004), suggesting that hepatic lipid synthesis is not affected by PHD1. In addition to impacting lipid metabolism, PHD1 deficient mice presented with relative leukopenia. Flow cytometry of whole blood showed reduced leucocyte count in PHD1-/- (-39% CD45+ leucocytes, p=0.001), affecting all leucocyte subsets, including Ly6C-high monocytes (-62%, p=0.03). It remains to be established, whether the leukopenia is a normalisation of WTD-induced hyper-inflammation or repression of leucocytes. Functionally, however, bone marrow-derived PHD1-/- macrophages were more resistant to ER stress-induced apoptosis (7-ketocholesterol, -50% TUNEL/total cell count, p<0.0001) and had improved efferocytosis capacity in vitro compared to control (+70%, p=0.03), which may have underlain the observed reduction in necrotic core formation. In conclusion, PHD1 deficiency promoted an atheroprotective metabolic phenotype, by improving lipid metabolism and macrophage phagocytosis and reducing inflammation, potentially pointing towards hitherto overlooked regulators of lipid metabolism.
    Cardiovascular Research 07/2014; 103(suppl 1):S2. · 5.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified.
    Angiogenesis 07/2014; · 4.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cells have been at the centre of cell metabolism research, but the metabolism of stromal and immune cells has received less attention. Nonetheless, these cells influence the progression of malignant, inflammatory and metabolic disorders. Here we discuss the metabolic adaptations of stromal and immune cells in health and disease, and highlight how metabolism determines their differentiation and function.
    Nature 07/2014; 511(7508):167-76. · 42.35 Impact Factor
  • Circulation Research 07/2014; 115(2):205-7. · 11.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We hypothesized that vascular endothelial growth factor (VEGF)-containing hydrogels that gelify in situ after injection into a traumatized spinal cord, could stimulate spinal cord regeneration. Injectable hydrogels composed of 0.5% Pronova UPMVG MVG alginate, supplemented or not with fibrinogen, were used. The addition of fibrinogen to alginate had no effect on cell proliferation in vitro but supported neurite growth ex vivo. When injected into a rat spinal cord in a hemisection model, alginate supplemented with fibrinogen was well tolerated. The release of VEGF that was incorporated into the hydrogel was influenced by the VEGF formulation [encapsulated in microspheres or in nanoparticles or in solution (free)]. A combination of free VEGF and VEGF-loaded nanoparticles was mixed with alginate:fibrinogen and injected into the lesion of the spinal cord. Four weeks post injection, angiogenesis and neurite growth were increased compared to hydrogel alone. The local delivery of VEGF by injectable alginate:fibrinogen-based hydrogel induced some plasticity in the injured spinal cord involving fiber growth into the lesion site. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2345–2355, 2014.
    Journal of Biomedical Materials Research Part A 07/2014; 102(7). · 2.83 Impact Factor
  • Source
    Jermaine Goveia, Peter Stapor, Peter Carmeliet
    [Show abstract] [Hide abstract]
    ABSTRACT: The endothelium is the orchestral conductor of blood vessel function. Pathological blood vessel formation (a process termed pathological angiogenesis) or the inability of endothelial cells (ECs) to perform their physiological function (a condition known as EC dysfunction) are defining features of various diseases. Therapeutic intervention to inhibit aberrant angiogenesis or ameliorate EC dysfunction could be beneficial in diseases such as cancer and cardiovascular disease, respectively, but current strategies have limited efficacy. Based on recent findings that pathological angiogenesis and EC dysfunction are accompanied by EC-specific metabolic alterations, targeting EC metabolism is emerging as a novel therapeutic strategy. Here, we review recent progress in our understanding of how EC metabolism is altered in disease and discuss potential metabolic targets and strategies to reverse EC dysfunction and inhibit pathological angiogenesis.
    EMBO Molecular Medicine 07/2014; · 7.80 Impact Factor
  • Source
    Dataset: CoverFinal

Publication Stats

49k Citations
6,337.29 Total Impact Points

Institutions

  • 2008–2014
    • Vesalius Research Center
      Louvain, Flanders, Belgium
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
    • University Pompeu Fabra
      • Center for Genomic Regulation (CRG)
      Barcelona, Catalonia, Spain
    • Universitair Psychiatrisch Centrum KU Leuven
      Cortenberg, Flanders, Belgium
  • 1989–2014
    • University of Leuven
      • • Vesalius Research Center
      • • Laboratory of Neurobiology and Gene Therapy
      • • Center for Molecular and Vascular Biology
      • • Department of Reproduction, Development and Regeneration
      • • Research unit for Experimental Psychology
      Louvain, Flanders, Belgium
  • 2013
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
    • National and Kapodistrian University of Athens
      • Division of Clinical Therapeutics
      Athens, Attiki, Greece
  • 2007–2012
    • University of Liège
      • Laboratory of Tumor and Development Biology
      Liège, WAL, Belgium
    • CRG Centre for Genomic Regulation
      Barcino, Catalonia, Spain
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
  • 2004–2012
    • Université de Rouen
      • Microbiology Signals and Microenvironment Lab (LMSM) (EA 4312)
      Mont-Saint-Aignan, Upper Normandy, France
  • 2000–2012
    • Massachusetts General Hospital
      • Department of Radiation Oncology
      Boston, MA, United States
    • Maastricht University
      • • Cardiologie
      • • Farmacologie
      Maastricht, Provincie Limburg, Netherlands
  • 1995–2012
    • Vlaams Instituut voor Biotechnologie
      Gand, Flanders, Belgium
  • 1988–2012
    • Universitair Ziekenhuis Leuven
      • • Department of Cardiovascular diseases
      • • Department of General internal medicine
      Leuven, VLG, Belgium
  • 2011
    • Max Planck Institute for Molecular Biomedicine
      • Molecular Neurogenetics Laboratory
      Muenster, North Rhine-Westphalia, Germany
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Uppsala University
      • The Rudbeck Laboratory
      Uppsala, Uppsala, Sweden
    • University of Colorado
      • Department of Anesthesiology
      Denver, CO, United States
  • 2009–2011
    • Universität Heidelberg
      • Department of General, Visceral and Transplantation Surgery
      Heidelberg, Baden-Wuerttemberg, Germany
    • Charité Universitätsmedizin Berlin
      • Medical Department, Division of Hepatology and Gastroenterology
      Berlin, Land Berlin, Germany
  • 2005–2011
    • Goethe-Universität Frankfurt am Main
      • Zentrum für Molekulare Medizin
      Frankfurt am Main, Hesse, Germany
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
    • The Catholic University of America
      Washington, Washington, D.C., United States
    • University of Geneva
      • Division of Angiology and Hemostasis
      Genève, GE, Switzerland
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 2010
    • Yale University
      • Section of Cardiovascular Medicine
      New Haven, CT, United States
  • 2002–2010
    • University of Helsinki
      • Molecular/Cancer Biology Laboratory
      Helsinki, Southern Finland Province, Finland
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2007–2008
    • Leiden University Medical Centre
      • Department of Anatomy and Embryology
      Leiden, South Holland, Netherlands
  • 2006–2008
    • Dartmouth Medical School
      • Department of Medicine
      Hanover, New Hampshire, United States
    • CSU Mentor
      Long Beach, California, United States
  • 2002–2007
    • University of Amsterdam
      • • Department of Pathology
      • • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
  • 2003
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Monash University (Malaysia)
      Labuan, Labuan, Malaysia
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 1998–2002
    • The Scripps Research Institute
      La Jolla, California, United States
  • 2001
    • Hebrew University of Jerusalem
      • Department of Biochemistry and Molecular Biology
      Jerusalem, Jerusalem District, Israel
  • 1999–2001
    • Kinki University
      • Department of Neurosurgery
      Ōsaka, Ōsaka, Japan
    • Flanders Mechatronics Technology Centre
      Louvain, Flanders, Belgium
  • 1996–1999
    • Umeå University
      • • Department of Medical Biosciences
      • • Department of Medical Biochemistry and Biophysics
      Umeå, Vaesterbotten, Sweden
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1996–1997
    • University of Notre Dame
      • Department of Chemistry and Biochemistry
      United States
  • 1994
    • Princeton University
      Princeton, New Jersey, United States
    • Whitehead Institute for Biomedical Research
      Cambridge, Massachusetts, United States