Faculty Collaboration Database

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. J Clin Invest 2017 Oct 02;127(10):3796-3809

Date

09/12/2017

Pubmed ID

28891811

Pubmed Central ID

PMC5617672

DOI

10.1172/JCI91561

Scopus ID

2-s2.0-85030548987 (requires institutional sign-in at Scopus site)   113 Citations

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.

Author List

Ratnam NM, Peterson JM, Talbert EE, Ladner KJ, Rajasekera PV, Schmidt CR, Dillhoff ME, Swanson BJ, Haverick E, Kladney RD, Williams TM, Leone GW, Wang DJ, Guttridge DC

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Female
Growth Differentiation Factor 15
Heterografts
Immunologic Surveillance
MAP Kinase Kinase Kinases
Macrophages
Male
Mice
Mice, Knockout
NF-kappa B
Neoplasm Proteins
Neoplasm Transplantation
Neoplasms, Experimental
Nitric Oxide
Pancreatic Neoplasms
Signal Transduction
Tumor Necrosis Factor-alpha