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Title page for ETD etd-10092016-213121


Type of Document Dissertation
Author Perry, Allyson Gail
URN etd-10092016-213121
Title The Role of Nuclear Factor Kappa B in Myeloid Cells During Lung Carcinogenesis
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Barbara Fingleton Committee Chair
Ann Richmond Committee Member
Pampee Young Committee Member
Timothy Blackwell Committee Member
Keywords
  • lung cancer
  • myeloid cell
  • neutrophil
  • interleukin-1 beta
  • nuclear factor kappa B
  • cathepsin G
  • inflammation
Date of Defense 2016-08-12
Availability unrestricted
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.
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