dc.creator | Perry, Allyson Gail | |
dc.date.accessioned | 2020-08-22T21:11:40Z | |
dc.date.available | 2016-11-23 | |
dc.date.issued | 2016-11-23 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-10092016-213121 | |
dc.identifier.uri | http://hdl.handle.net/1803/14295 | |
dc.description.abstract | Despite recent progress, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States and new therapeutic approaches are needed. Nuclear factor κB (NF-κB) is a master regulator of inflammatory signaling that is overexpressed in most solid tumors. Several mouse models of lung cancer have confirmed the requirement for NF-κB signaling in airway epithelial cells during lung tumorigenesis. However, despite these findings, inhibitors of NF-κB have been ineffective in treating NSCLC patients. Using genetic and pharmacologic inhibition of NF-κB signaling in murine lung cancer models, we found that blockade of NF-κB signaling in the myeloid inflammatory cell population paradoxically increases lung inflammation, airway epithelial cell proliferation, and lung tumorigenesis. We identified cathepsin G-mediated processing of IL-1β by neutrophils as a novel resistance mechanism of NSCLC to NF-κB inhibitors, and combined therapy with an NF-κB inhibitor and IL-1 receptor antagonist reduced tumorigenesis in mouse models of lung cancer. In NSCLC patients, plasma IL-1β concentration inversely correlated with progression-free survival and IL-1β levels were increased following treatment with an NF-κB inhibitor. These studies demonstrate that targeting common signaling pathways can have opposing effects in individual cell types during tumorigenesis; they support the use of rational, combined therapies to treat lung cancer. | |
dc.format.mimetype | application/pdf | |
dc.subject | lung cancer | |
dc.subject | myeloid cell | |
dc.subject | neutrophil | |
dc.subject | interleukin-1 beta | |
dc.subject | nuclear factor kappa B | |
dc.subject | cathepsin G | |
dc.subject | inflammation | |
dc.title | The Role of Nuclear Factor Kappa B in Myeloid Cells During Lung Carcinogenesis | |
dc.type | dissertation | |
dc.contributor.committeeMember | Ann Richmond | |
dc.contributor.committeeMember | Pampee Young | |
dc.contributor.committeeMember | Timothy Blackwell | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Cancer Biology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2016-11-23 | |
local.embargo.lift | 2016-11-23 | |
dc.contributor.committeeChair | Barbara Fingleton | |