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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-10092016-213121 |
| Date | 23 November 2016 |
| Creators | Perry, Allyson Gail |
| Contributors | Barbara Fingleton, Ann Richmond, Pampee Young, Timothy Blackwell |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-10092016-213121/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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