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

• DOI: 10.1038/s41467-017-01599-w
• Publication Date: 2017-11-13T18:23:02Z
• Authors: Ewelina Krzywinska; Chahrazade Kantar...; 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; Christian Stockmann
• Keywords: Vascular Endothelial Growth Factor A; 0301 basic medicine; 10017 Institute of Anatomy; [SDV.IMM] Life Sciences [q-bio]/Immunology; Science; Medizin; 610 Medicine & health; 1600 General Chemistry; Article; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; Cell Line, Tumor; Animals; Hypoxia; Cells, Cultured; Mice, Knockout; Neovascularization, Pathologic; Q; Neoplasms, Experimental; Hypoxia-Inducible Factor 1, alpha Subunit; 3100 General Physics and Astronomy; Cell Hypoxia; 3. Good health; Killer Cells, Natural; Mice, Inbred C57BL; 570 Life sciences; biology; [SDV.IMM]Life Sciences [q-bio]/Immunology

AbstractProductive 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.