title: Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia.
abstract: Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. We show that genetic inactivation of vascular endothelial growth factor (VEGF)-A in myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It also improves clearance of senescent tumour cells by natural killer cells and inhibits tumour regrowth after chemotherapy. The effects depend on the chemoattractant chemerin, which is released by the tumour endothelium in response to chemotherapy. The findings define chemerin as a critical mediator of the immune response, as well as an important inhibitor of cancer cachexia. Targeting myeloid cell-derived VEGF signalling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby substantially improving the therapeutic outcome.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Ralph
authors.initials: R
authors.lastname: Klose
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Krzywinska
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Castells
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Chahrazade
authors.initials: C
authors.lastname: Kantari-Mimoun
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Naima
authors.initials: N
authors.lastname: Chikdene
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Meinecke
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schrödter
authors.affiliation: Skin Cancer Unit of the Department of Dermatology, West German Cancer Center, University of Duisburg-Essen, Hospital Essen, DKTK Essen, 45147 Essen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000473:pathology; D018925:Chemokines / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; C523686:chemerin protein, mouse; C467480:vascular endothelial growth factor A, mouse