Proteins as biomarkers for tobacco-induced lung cancer development and chemoprevention

Background: Lung cancer continues to be the most common cancer diagnosed in the world and is the leading cause of cancer-related death in both men and women in the United States. The non-small cell lung cancer (NSCLC) subtype adenocarcinoma is the leading histological type clinically diagnosed in the United States, accounting for over 30% of all cases. We embark upon two strategies with promising clinical implications: identification of (informative) molecular biomarkers related to the development of tobacco-induced lung cancer and the discovery of novel chemopreventive agents.;Hypotheses: Current clinical protein biomarkers for detection of lung cancer lack sensitivity and specificity. The proteomics field can contribute greatly to the understanding of mechanisms in cancer progression and treatment response. Therefore, in Chapter 2 we hypothesized that by using proteomic approaches in a well-defined preclinical mouse lung tumorigenesis model induced using the tobacco carcinogen NNK, protein biomarkers could be obtained to provide an accurate view of molecular alterations during lung cancer development. Such biomarkers can provide utility for early detection, but also in the validation of chemoprevention strategies. Smokers are at risk for a variety of health concerns including lung cancer. Non-invasive biological fluids such as blood plasma contains molecular profiles related to current health status. Therefore, in Chapter 3 taking advantage of proteomic techniques and proteins identified in Chapter 2, we hypothesized that dynamic changes in protein expression profiles in the blood plasma of smokers characterized by a proteomics approach would assist in identifying early molecular changes related to tobacco-induced diseases such as lung cancer. Selenium-containing compounds are promising chemopreventive agents against lung cancer development. Developments of agents that can target molecular pathways that are critical in lung carcinogenesis, such as nitric oxide synthase (iNOS) and nitric oxide production, known to be involved in the promotion/progression phases of lung carcinogenesis, are needed and may be beneficial in chemoprevention of lung cancer in both smokers and former smokers. Therefore, in Chapter 4 we hypothesized that substitution of sulfur for selenium in an inducible nitric oxide synthase inhibitor, S,S'-(1,4-phenylenebis[1,2-ethanediyl])bisisothiourea (PBIT), would enhance its chemopreventive activity.;Results: We discovered proteins, including the 14-3-3 protein isoforms (theta, epsilon, sigma, and zeta), annexin A5, Clara cell 10 kDa protein (CC10), high mobility group box 1, and carbonyl reductase 2 that were differentially expressed in the lungs of mice treated with the tobacco carcinogen NNK versus vehicle (control)-treated mice during the progression of adenocarcinoma development; some of these changes were further modulated by p-XSC. These proteins are involved in a variety of biological functions that are critical in lung carcinogenesis, as well as in its prevention. (Chapter 3) We identified differentially expressed plasma proteins in healthy chronic cigarette smokers compared to healthy non-smokers. Several of the proteins identified, including ITI-HC3 and VDBP, associated with immunity and inflammatory responses, and 14-3-3 sigma and zeta, identified in Chapter 2, have been shown to be associated with tobacco-related diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. (Chapter 4) We found Se-PBIT to be superior to both PBIT and p-XSC as an inducer of apoptosis and inhibitor of cell growth in NSCLC cells, as determined by analysis of its effects on important molecular targets involved in cell growth inhibition, induction of apoptosis, and cell cycle regulation.;Conclusions: Based on our results, we were able to demonstrate the utility of a well-defined animal model in developing candidate protein biomarkers for lung cancer. Such biomarkers may be useful in early detection of the disease, as well as in the efficacy of chemopreventive agents. (Chapter 3) Our clinical pilot study results demonstrated for the first time that chronic cigarette smoking can influence the expression profile of the human plasma proteome and these changes may be indicative of future health concerns. (Chapter 4) We demonstrated that selenium in the form of Se-PBIT is a promising candidate for chemoprevention of NSCLC and appears superior to PBIT and p-XSC. (Abstract shortened by UMI.)...