Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia

Ralph Klose, Ewelina Krzywinska, Magali Castells, Dagmar Gotthardt, Eva Maria Putz, Chahrazade Kantari-Mimoun, Naima Chikdene, Anna-Katharina Meinecke, Katrin Schrödter, Iris Helfrich, Joachim Fandrey, Veronika Sexl and Christian Stockmann ()
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Ralph Klose: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970
Ewelina Krzywinska: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970
Magali Castells: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970
Dagmar Gotthardt: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna
Eva Maria Putz: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna
Chahrazade Kantari-Mimoun: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970
Naima Chikdene: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970
Anna-Katharina Meinecke: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen
Katrin Schrödter: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen
Iris Helfrich: West German Cancer Center, University of Duisburg-Essen, Hospital Essen, DKTK Essen
Joachim Fandrey: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen
Veronika Sexl: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna
Christian Stockmann: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cardiovascular Research Center, Unit 970

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12528

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