Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
1.
Cell ; 154(3): 651-63, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23911327

ABSTRACT

Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.


Subject(s)
Endothelial Cells/metabolism , Glycolysis , Neovascularization, Physiologic , Phosphofructokinase-2/metabolism , Animals , Cell Line, Tumor , Cells, Cultured , Endothelial Cells/cytology , Female , Gene Deletion , Gene Silencing , Humans , Male , Mice , Mice, Inbred C57BL , Phosphofructokinase-2/genetics , Pseudopodia/metabolism , Zebrafish
2.
Cell ; 136(5): 839-851, 2009 Mar 06.
Article in English | MEDLINE | ID: mdl-19217150

ABSTRACT

A key function of blood vessels, to supply oxygen, is impaired in tumors because of abnormalities in their endothelial lining. PHD proteins serve as oxygen sensors and may regulate oxygen delivery. We therefore studied the role of endothelial PHD2 in vessel shaping by implanting tumors in PHD2(+/-) mice. Haplodeficiency of PHD2 did not affect tumor vessel density or lumen size, but normalized the endothelial lining and vessel maturation. This resulted in improved tumor perfusion and oxygenation and inhibited tumor cell invasion, intravasation, and metastasis. Haplodeficiency of PHD2 redirected the specification of endothelial tip cells to a more quiescent cell type, lacking filopodia and arrayed in a phalanx formation. This transition relied on HIF-driven upregulation of (soluble) VEGFR-1 and VE-cadherin. Thus, decreased activity of an oxygen sensor in hypoxic conditions prompts endothelial cells to readjust their shape and phenotype to restore oxygen supply. Inhibition of PHD2 may offer alternative therapeutic opportunities for anticancer therapy.


Subject(s)
Blood Vessels/cytology , DNA-Binding Proteins/metabolism , Endothelial Cells/metabolism , Immediate-Early Proteins/metabolism , Neoplasm Metastasis , Neoplasms/blood supply , Oxygen/metabolism , Animals , Blood Vessels/embryology , Blood Vessels/metabolism , Cell Shape , DNA-Binding Proteins/genetics , Endothelial Cells/cytology , Glycolysis , Heterozygote , Hypoxia/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases , Immediate-Early Proteins/genetics , Mice , Neoplasms/pathology , Procollagen-Proline Dioxygenase
3.
Nature ; 561(7721): 63-69, 2018 09.
Article in English | MEDLINE | ID: mdl-30158707

ABSTRACT

Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation.


Subject(s)
Endothelial Cells/enzymology , Endothelial Cells/pathology , Glutamate-Ammonia Ligase/metabolism , Glutamine/biosynthesis , Neovascularization, Pathologic , Actins/metabolism , Animals , Cell Movement , Endothelial Cells/metabolism , Female , Glutamate-Ammonia Ligase/deficiency , Glutamate-Ammonia Ligase/genetics , Glutamate-Ammonia Ligase/physiology , HEK293 Cells , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/enzymology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Lipoylation , Mice , Palmitic Acid/metabolism , Protein Processing, Post-Translational , Stress Fibers/metabolism , rho GTP-Binding Proteins/chemistry , rho GTP-Binding Proteins/metabolism , rho-Associated Kinases/metabolism
4.
Nature ; 542(7639): 49-54, 2017 02 02.
Article in English | MEDLINE | ID: mdl-28024299

ABSTRACT

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid ß-oxidation, impairs lymphatic development. LECs use fatty acid ß-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid ß-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.


Subject(s)
Fatty Acids/chemistry , Fatty Acids/metabolism , Lymphangiogenesis , Lymphatic Vessels/cytology , Lymphatic Vessels/metabolism , Acetates/pharmacology , Acetyl Coenzyme A/metabolism , Acetylation/drug effects , Animals , Carnitine O-Palmitoyltransferase/antagonists & inhibitors , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Cell Differentiation/drug effects , Cell Differentiation/genetics , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Epigenesis, Genetic , Female , Histones/metabolism , Homeodomain Proteins/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Lymphangiogenesis/drug effects , Lymphangiogenesis/genetics , Lymphatic Vessels/drug effects , Mice , Mice, Inbred C57BL , Oxidation-Reduction/drug effects , Protein Biosynthesis , Transcription, Genetic , Tumor Suppressor Proteins/metabolism , Umbilical Arteries/cytology , Up-Regulation
5.
EMBO J ; 36(16): 2334-2352, 2017 08 15.
Article in English | MEDLINE | ID: mdl-28659375

ABSTRACT

Endothelial cell (EC) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in ECs is unknown. Here, we show that depriving ECs of glutamine or inhibiting glutaminase 1 (GLS1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in ECs did not cause energy distress, but impaired tricarboxylic acid (TCA) cycle anaplerosis, macromolecule production, and redox homeostasis. Only the combination of TCA cycle replenishment plus asparagine supplementation restored the metabolic aberrations and proliferation defect caused by glutamine deprivation. Mechanistically, glutamine provided nitrogen for asparagine synthesis to sustain cellular homeostasis. While ECs can take up asparagine, silencing asparagine synthetase (ASNS, which converts glutamine-derived nitrogen and aspartate to asparagine) impaired EC sprouting even in the presence of glutamine and asparagine. Asparagine further proved crucial in glutamine-deprived ECs to restore protein synthesis, suppress ER stress, and reactivate mTOR signaling. These findings reveal a novel link between endothelial glutamine and asparagine metabolism in vessel sprouting.


Subject(s)
Asparagine/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Endothelial Cells/drug effects , Endothelial Cells/physiology , Glutamine/metabolism , Neovascularization, Physiologic/drug effects , Culture Media/chemistry , Endothelial Cells/metabolism , Glutaminase/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Metabolic Networks and Pathways , Neovascularization, Pathologic
6.
Biochem Biophys Res Commun ; 503(1): 26-31, 2018 09 03.
Article in English | MEDLINE | ID: mdl-29730294

ABSTRACT

During embryonic development, lymphatic endothelial cells (LECs) differentiate from venous endothelial cells (VECs), a process that is tightly regulated by several genetic signals. While the aquatic zebrafish model is regularly used for studying lymphangiogenesis and offers the unique advantage of time-lapse video-imaging of lymphatic development, some aspects of lymphatic development in this model differ from those in the mouse. It therefore remained to be determined whether fatty acid ß-oxidation (FAO), which we showed to regulate lymphatic formation in the mouse, also co-determines lymphatic development in this aquatic model. Here, we took advantage of the power of the zebrafish embryo model to visualize the earliest steps of lymphatic development through time-lapse video-imaging. By targeting zebrafish isoforms of carnitine palmitoyltransferase 1a (cpt1a), a rate controlling enzyme of FAO, with multiple morpholinos, we demonstrate that reducing CPT1A levels and FAO flux during zebrafish development impairs lymphangiogenic secondary sprouting, the initiation of lymphatic development in the zebrafish trunk, and the formation of the first lymphatic structures. These findings not only show evolutionary conservation of the importance of FAO for lymphatic development, but also suggest a role for FAO in co-regulating the process of VEC-to-LEC differentiation in zebrafish in vivo.


Subject(s)
Fatty Acids/metabolism , Lymphatic Vessels/embryology , Lymphatic Vessels/metabolism , Zebrafish/embryology , Zebrafish/metabolism , Animals , Animals, Genetically Modified , Carnitine O-Palmitoyltransferase/antagonists & inhibitors , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Cell Differentiation , Endothelial Cells/cytology , Endothelial Cells/metabolism , Gene Targeting , Lymphangiogenesis/genetics , Lymphangiogenesis/physiology , Models, Animal , Oxidation-Reduction , Time-Lapse Imaging , Zebrafish/genetics , Zebrafish Proteins/antagonists & inhibitors , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
7.
Neurobiol Dis ; 58: 258-69, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23777740

ABSTRACT

Although peroxisome biogenesis and ß-oxidation disorders are well known for their neurodevelopmental defects, patients with these disorders are increasingly diagnosed with neurodegenerative pathologies. In order to investigate the cellular mechanisms of neurodegeneration in these patients, we developed a mouse model lacking multifunctional protein 2 (MFP2, also called D-bifunctional protein), a central enzyme of peroxisomal ß-oxidation, in all neural cells (Nestin-Mfp2(-/-)) or in oligodendrocytes (Cnp-Mfp2(-/-)) and compared these models with an already established general Mfp2 knockout. Nestin-Mfp2 but not Cnp-Mfp2 knockout mice develop motor disabilities and ataxia, similar to the general mutant. Deterioration of motor performance correlates with the demise of Purkinje cell axons in the cerebellum, which precedes loss of Purkinje cells and cerebellar atrophy. This closely mimics spinocerebellar ataxias of patients affected with mild peroxisome ß-oxidation disorders. However, general knockouts have a much shorter life span than Nestin-Mfp2 knockouts which is paralleled by a disparity in activation of the innate immune system. Whereas in general mutants a strong and chronic proinflammatory reaction proceeds throughout the brain, elimination of MFP2 from neural cells results in minor neuroinflammation. Neither the extent of the inflammatory reaction nor the cerebellar degeneration could be correlated with levels of very long chain fatty acids, substrates of peroxisomal ß-oxidation. In conclusion, MFP2 has multiple tasks in the adult brain, including the maintenance of Purkinje cells and the prevention of neuroinflammation but this is not mediated by its activity in oligodendrocytes nor by its role in very long chain fatty acid degradation.


Subject(s)
Deficiency Diseases/complications , Encephalitis/etiology , Fatty Acids/metabolism , Nerve Degeneration/etiology , Peroxisomal Multifunctional Protein-2/deficiency , Purkinje Cells/pathology , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/genetics , Age Factors , Animals , Antigens, Differentiation/metabolism , Brain/metabolism , Brain/pathology , Calcium-Binding Proteins/metabolism , Cytokines/metabolism , Gas Chromatography-Mass Spectrometry , Gene Expression Regulation/genetics , Locomotion/physiology , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Myelin Basic Protein/metabolism , Nestin/genetics , Peroxisomal Multifunctional Protein-2/genetics
8.
Nat Genet ; 34(4): 383-94, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12847526

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Endothelial Growth Factors/genetics , Intercellular Signaling Peptides and Proteins/genetics , Lymphokines/genetics , Aged , Alleles , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/etiology , Amyotrophic Lateral Sclerosis/pathology , Animals , Cell Death/drug effects , Child , Child, Preschool , Endothelial Growth Factors/physiology , Endothelial Growth Factors/therapeutic use , Female , Genetic Variation , Haplotypes , Humans , Intercellular Signaling Peptides and Proteins/physiology , Intercellular Signaling Peptides and Proteins/therapeutic use , Ischemia/pathology , Lymphokines/physiology , Lymphokines/therapeutic use , Male , Mice , Mice, Knockout , Mice, Transgenic , Middle Aged , Motor Neurons/drug effects , Motor Neurons/pathology , Nerve Degeneration/genetics , Paralysis/etiology , Spinal Cord Ischemia/drug therapy , Spinal Cord Ischemia/pathology , Sweden , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
9.
Nat Med ; 11(9): 998-1004, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16116431

ABSTRACT

Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.


Subject(s)
Lymphangiogenesis/physiology , Xenopus laevis/growth & development , Xenopus laevis/genetics , Animals , Homeodomain Proteins/physiology , Larva/genetics , Larva/growth & development , Lymphangiogenesis/genetics , Lymphatic System/anatomy & histology , Lymphatic System/growth & development , Tumor Suppressor Proteins
10.
Nat Neurosci ; 9(3): 340-8, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16462734

ABSTRACT

Vascular endothelial growth factor C (VEGF-C) was first identified as a regulator of the vascular system, where it is required for the development of lymphatic vessels. Here we report actions of VEGF-C in the central nervous system. We detected the expression of the VEGF-C receptor VEGFR-3 in neural progenitor cells in Xenopus laevis and mouse embryos. In Xenopus tadpole VEGF-C knockdowns and in mice lacking Vegfc, the proliferation of neural progenitors expressing VEGFR-3 was severely reduced, in the absence of intracerebral blood vessel defects. In addition, Vegfc-deficient mouse embryos showed a selective loss of oligodendrocyte precursor cells (OPCs) in the embryonic optic nerve. In vitro, VEGF-C stimulated the proliferation of OPCs expressing VEGFR-3 and nestin-positive ventricular neural cells. VEGF-C thus has a new, evolutionary conserved function as a growth factor selectively required by neural progenitor cells expressing its receptor VEGFR-3.


Subject(s)
Brain/embryology , Cell Differentiation/physiology , Nerve Growth Factors/metabolism , Neurons/metabolism , Stem Cells/metabolism , Vascular Endothelial Growth Factor C/metabolism , Animals , Brain/cytology , Brain/metabolism , Cells, Cultured , Evolution, Molecular , Intermediate Filament Proteins/metabolism , Larva , Lateral Ventricles/cytology , Lateral Ventricles/embryology , Lateral Ventricles/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Nestin , Neurons/cytology , Oligodendroglia/cytology , Oligodendroglia/metabolism , Optic Nerve/cytology , Optic Nerve/embryology , Optic Nerve/metabolism , Rats , Rats, Wistar , Stem Cells/cytology , Vascular Endothelial Growth Factor C/genetics , Vascular Endothelial Growth Factor Receptor-3/metabolism , Xenopus laevis
11.
Nat Neurosci ; 8(1): 85-92, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15568021

ABSTRACT

Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.


Subject(s)
Amyotrophic Lateral Sclerosis/physiopathology , Motor Neurons/drug effects , Nerve Degeneration/physiopathology , Neuroprotective Agents/administration & dosage , Vascular Endothelial Growth Factor A/administration & dosage , Amyotrophic Lateral Sclerosis/genetics , Animals , Axonal Transport , Cell Survival/drug effects , Disease Models, Animal , Humans , Injections, Intraventricular , Neuromuscular Junction/drug effects , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Superoxide Dismutase/genetics , Vascular Endothelial Growth Factor A/pharmacokinetics , Vascular Endothelial Growth Factor A/pharmacology
12.
Cell Stem Cell ; 20(3): 360-373.e7, 2017 03 02.
Article in English | MEDLINE | ID: mdl-27889318

ABSTRACT

Whether new neurons are added in the postnatal cerebral cortex is still debated. Here, we report that the meninges of perinatal mice contain a population of neurogenic progenitors formed during embryonic development that migrate to the caudal cortex and differentiate into Satb2+ neurons in cortical layers II-IV. The resulting neurons are electrically functional and integrated into local microcircuits. Single-cell RNA sequencing identified meningeal cells with distinct transcriptome signatures characteristic of (1) neurogenic radial glia-like cells (resembling neural stem cells in the SVZ), (2) neuronal cells, and (3) a cell type with an intermediate phenotype, possibly representing radial glia-like meningeal cells differentiating to neuronal cells. Thus, we have identified a pool of embryonically derived radial glia-like cells present in the meninges that migrate and differentiate into functional neurons in the neonatal cerebral cortex.


Subject(s)
Cell Differentiation , Cell Movement , Cerebral Cortex/cytology , Meninges/cytology , Neurogenesis , Neuroglia/cytology , Neurons/cytology , Animals , Animals, Newborn , Cell Lineage , Embryo, Mammalian/cytology , Excitatory Amino Acid Transporter 1/metabolism , Gene Expression Profiling , HEK293 Cells , Humans , Mice, Inbred C57BL , Nestin/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , Reproducibility of Results , Single-Cell Analysis , Spheroids, Cellular/cytology , Staining and Labeling , Transcriptome/genetics
13.
Cancer Cell ; 19(1): 31-44, 2011 Jan 18.
Article in English | MEDLINE | ID: mdl-21215706

ABSTRACT

Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HRG relies substantially on downregulation of placental growth factor (PlGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PlGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.


Subject(s)
Down-Regulation/genetics , Macrophages/immunology , Neoplasms/immunology , Neoplasms/pathology , Neovascularization, Pathologic/immunology , Pregnancy Proteins/metabolism , Proteins/metabolism , Animals , Antibodies/immunology , Antibodies/pharmacology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Chemotactic Factors/metabolism , Clodronic Acid/pharmacology , Culture Media, Conditioned/pharmacology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dendritic Cells/pathology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Gene Expression/drug effects , Gene Expression/genetics , Humans , Hypoxia/genetics , Hypoxia/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Macrophages/drug effects , Macrophages/metabolism , Macrophages/pathology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Microvessels/drug effects , Microvessels/pathology , Microvessels/ultrastructure , Neoplasm Metastasis/genetics , Neoplasm Metastasis/immunology , Neoplasm Metastasis/pathology , Neoplasms/blood supply , Neoplasms/genetics , Neoplasms/metabolism , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Placenta Growth Factor , Pregnancy Proteins/genetics , Pregnancy Proteins/immunology , Proteins/genetics , Proteins/pharmacology
14.
Cell ; 131(3): 463-75, 2007 Nov 02.
Article in English | MEDLINE | ID: mdl-17981115

ABSTRACT

Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment.


Subject(s)
Antibodies, Monoclonal/pharmacology , Blood Vessels/drug effects , Blood Vessels/physiology , Drug Resistance, Neoplasm/drug effects , Pregnancy Proteins/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/pharmacology , Cell Line , Cell Movement/drug effects , Drug Screening Assays, Antitumor , Drug-Related Side Effects and Adverse Reactions , Health , Humans , Lymphangiogenesis/drug effects , Macrophages/cytology , Macrophages/drug effects , Mice , Neoplasm Metastasis , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Placenta Growth Factor , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL