title: STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion.
abstract: Natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-deficient NK cells can be rescued by overexpression of BCL2. Our experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-deficient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verified by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These findings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis.
  
  
  CONCLUSIONS
  The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis.
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Grundschober
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal-Murphy
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Straka
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Kudweis
authors.affiliation: Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria. Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna (MUV), Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.affiliation: Department for Biomedical Sciences, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witalisz-Siepracka
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Abbarna A
authors.initials: AA
authors.lastname: Cumaraswamy
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.affiliation: Department for Biomedical Sciences, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Department for Biomedical Sciences, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department for Biomedical Sciences, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria. Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: PARCC Paris - Centre de recherche Cardiovasculaire à l'HEGP Inserm - UMR 970, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria. veronika.sexl@vetmeduni.ac.at.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006801:Humans; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D042461:Vascular Endothelial Growth Factor A