Journal article
NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development
The Journal of clinical investigation, Vol.127(10), pp.3796-3809
10/02/2017
DOI: 10.1172/JCI91561
PMCID: PMC5617672
PMID: 28891811
Abstract
Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.
Details
- Title: Subtitle
- NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development
- Creators
- Nivedita M Ratnam - Department of Cancer Biology and Genetics.Jennifer M Peterson - The Ohio State UniversityErin E Talbert - The Ohio State UniversityKatherine J Ladner - The Ohio State UniversityPriyani V Rajasekera - The Ohio State UniversityCarl R Schmidt - Division of Surgical Oncology.Mary E Dillhoff - Division of Surgical Oncology.Benjamin J Swanson - Department of Pathology, and.Ericka Haverick - Division of Surgical Oncology.Raleigh D Kladney - The Ohio State UniversityTerence M Williams - The Ohio State UniversityGustavo W Leone - Medical University of South CarolinaDavid J Wang - The Ohio State UniversityDenis C Guttridge - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.127(10), pp.3796-3809
- DOI
- 10.1172/JCI91561
- PMID
- 28891811
- PMCID
- PMC5617672
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- P30 CA138313 / NCI NIH HHS
- Language
- English
- Date published
- 10/02/2017
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984259656702771
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