Recently, a new article firstly published in the Journal of Clinical Investigation, identified a growth and differentiation factor 15 (GDF-15), which is secreted by pancreatic cancer cells and protect cancer cells against macrophage-mediated killing. In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.
The researchers discovered that GDF-15 maybe have important effects on the early pancreatic cancer cells, and a molecule known as N-F-kappa-B (NF-kB) could help cancer cells produce GDF-15.
Often, if the macrophages want to kill cancer cells, it will secrete some materials, such as tumor necrosis factors and nitric oxide. When GDF-15 exists, macrophages couldn’t release these chemicals, so it could escape the chase of macrophages. Sarcastically, NF-kB in macrophages involve in the process of production for the two chemicals.
Also, researchers think that this macrophages-disarming mechanism can promote the development and survival of early phase tumors. In discussing the impact of GDF-15 in the development of pancreatic cancer, these research results can satisfy the preclinical studies needs.
Researchers carried out the study using pancreatic-cancer cell lines, cells from patient tumors and an animal model, and they found that:
a. NF-kB is the direct regulator of GDF-15;
b. GDF-15 is required for the development of early pancreatic tumors.
c. GDF-15 protects transformed cells against macrophage-mediated killing.
d. GDF-15 suppresses macrophage cytotoxic activity by inhibiting the production of TNF and iNOS.
e. NF-κB and GDF-15 are coexpressed in tumor cells of patients with PDAC.
f. GDF-15 signals in macrophages to suppress NF-κB signaling via TAK-1.
Conclusions: ‘’The study shows that GDF-15 plays an important role in the development of pancreatic cancer and might be required for the development of early pancreatic tumors. NF-kB is important for the secretion and synthesis of GDF-15 from tumor cells in pancreas, which inhibits the NF-kB activity in macrophages and prevents them from killing tumor cells.’’ said by researchers.
Article Title: NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development
Journal: The Journal of Clinical Investigation
Authors: Nivedita M. Ratnam, Jennifer M. Peterson, Erin E. Talbert, Katherine J. Ladner, Priyani V. Rajasekera, Carl R. Schmidt, Mary E. Dillhoff, Benjamin J. Swanson, Ericka Haverick, Raleigh D. Kladney, Terence M. Williams, Gustavo W. Leone, David J. Wang, and Denis C. Guttridge