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 Bcl-2. Our experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. While 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 VEGF-A. The importance of VEGF-A produced by NK cells was verified by experiments with a conditional knock-out of Vegf-A in NK cells. We show that STAT5 normally represses the transcription of VEGF-A in NK cells, both in the mouse and in the human. The 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.
- Received June 17, 2015.
- Revision received February 8, 2016.
- Accepted February 9, 2016.
- Copyright © 2016, American Association for Cancer Research.