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The role of chronic inflammation in lung tumorigenesis and the identification of potential biomarkers for lung cancer treatment

Liu, Chia-Hsin (2019) The role of chronic inflammation in lung tumorigenesis and the identification of potential biomarkers for lung cancer treatment. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Lung cancer is a significant public health concern as the leading cancer-related deaths in the United States. Chronic inflammation is strongly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increases the risk of lung cancer. The inflammatory responses in the tumor microenvironment not only promote tumor progression but also have effects on treatment efficacy such as immunotherapy. In addition, Metalloproteinases (MMPs), which increase expression in COPD have been reported to correlate with tumor recurrence in surgically resected non-small cell lung cancer.
In the first study, we used the cigarette smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to generate genetic instability and parallelly provided repeated LPS to induce chronic lung inflammation. This novel exposure paradigm creates an immunosuppressive microenvironment favorable of tumor progression similar to that of inflammation-associated lung tumorigenesis in patients. Furthermore, the model was used to evaluate the efficacy of anti-PD-1 immunotherapy as well as myeloid-derived suppressor cells depletion on lung tumorigenesis. In addition, we identified immune gene signatures, which predict treatment responses and survival outcome of patients with NSCLC treated with either PD-1 blockade or conventional therapies.
In the second study, we conducted transcriptome analysis of lung adenocarcinoma cases in two discovery cohorts and discovered metalloproteinases (MMPs)-enriched gene clusters, which contained MMPs and related genes. We further identified a MMPs-gene signature from the two MMPs-gene clusters, which predicted recurrence and worse overall survival in patients with stage I lung adenocarcinoma after surgical resection. The high MMPs-gene signature expression remained an independent risk factor after adjusting covariates and showed enrichment in KRAS-mutant lung tumors. Finally, the MMPs-gene signature was successfully validated in an independent cohort. The MMPs-gene signature is a potential prognostic biomarker to stratify patients with stage I lung adenocarcinoma into subgroups based on their risk of recurrence for aiding physicians to decide the use of adjuvant therapeutics.
For public health significance, our study provided a clinically-relevant lung cancer animal model in elucidating the effects of chronic inflammation on lung tumorigenesis and the efficacy of cancer therapies. The utility of gene signatures in predicting lung cancer treatment and survival could be useful for personalized therapeutics.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Liu, Chia-Hsinarron12182012@gmail.comchl2160000-0002-8998-4098
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDi, YuanPupeterdi@pitt.edu
Committee MemberPitt, Bruce Rbrucep@pitt.edu
Committee MemberKeohavong, Phouthonepho1@pitt.edu
Committee MemberLu, Binfengbinfeng@pitt
Date: 26 September 2019
Date Type: Publication
Defense Date: 18 July 2019
Approval Date: 26 September 2019
Submission Date: 19 July 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 106
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: inflammation, lung cancer, anti-PD-1 treatment, immune gene signature
Date Deposited: 26 Sep 2019 16:46
Last Modified: 28 Feb 2020 14:21
URI: http://d-scholarship.pitt.edu/id/eprint/37144

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