Loss of HIF-1α in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis

Ewelina Krzywinska, Chahrazade Kantari-Mimoun, Yann Kerdiles, Michal Sobecki, Takayuki Isagawa, Dagmar Gotthardt, Magali Castells, Johannes Haubold, Corinne Millien, Thomas Viel, Bertrand Tavitian, Norihiko Takeda, Joachim Fandrey, Eric Vivier, Veronika Sexl and Christian Stockmann ()
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Ewelina Krzywinska: Paris Cardiovascular Research Center
Chahrazade Kantari-Mimoun: Paris Cardiovascular Research Center
Yann Kerdiles: Aix Marseille Université UM2
Michal Sobecki: CEA/CNRS/Université Paris Sud
Takayuki Isagawa: Nagasaki University
Dagmar Gotthardt: University of Veterinary Medicine Vienna
Magali Castells: Paris Cardiovascular Research Center
Johannes Haubold: Universitätsklinikum Essen, Universität Duisburg-Essen
Corinne Millien: Paris Cardiovascular Research Center
Thomas Viel: Paris Cardiovascular Research Center
Bertrand Tavitian: Paris Cardiovascular Research Center
Norihiko Takeda: The University of Tokyo
Joachim Fandrey: Universitätsklinikum Essen, Universität Duisburg-Essen
Eric Vivier: Aix Marseille Université UM2
Veronika Sexl: CEA/CNRS/Université Paris Sud
Christian Stockmann: Paris Cardiovascular Research Center

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels.

Date: 2017
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DOI: 10.1038/s41467-017-01599-w

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