Date of Award

12-2004

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Hildegard M. Schuller

Committee Members

Potgieter L.N.D, Michael D. Karlstad, Howard K. Plummer

Abstract

Lung cancer is the leading cause of cancer mortality for men and women in the United States, with a high mortality rate and a five-year survival rate of less than 15%. Cancer ranks second as a cause of death for Americans after cardiovascular disease. The American Cancer Society (ACS) reported 171,900 new cases of lung cancer for 2003 (ACS, 2003). Peripheral adenocarcinoma (PAC) of the lung has increased dramatically over the last 20 years and is the leading histological type of lung cancer in smokers and nonsmokers in industrialized countries, including the United States. Among the four main histological lung cancer types (small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma), adenocarcinoma that is derived from small-airway epithelia with features of Clara cells accounts for about 35-40% of all lung cancer cases. Unlike other histological lung cancer types, adenocarcinoma also develops in a significant number of non-smokers.

Smoking remains the greatest contributor to the development of lung cancer, with 90% of all lung cancer cases estimated to be smoking related. Cigarette smoke contains about 4,000 toxic chemicals including the highly carcinogenic nitrosamine, 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK). NNK is the most potent carcinogen in laboratory animals and has therefore been implicated as a significant cause of tobacco-associated cancers in human.

Dietary and genetically determined factors appear to play an important role in modulating individual susceptibility to smoking-associated cancer and are closely linked to the chemoprevention approach.

Chemoprevention is defined as the use of naturally occurring or synthetic agents to prevent, inhibit or reverse the process of carcinogenesis. This relatively new approach of cancer prevention has precedence in other areas of medicine such as cardiovascular diseases.

Earlier studies have shown the presence of a β-adrenergic/cAMP growth-regulating pathway in PAC. Therefore, β-adrenergic stimulants in various drugs that are used for the treatment of chronic respiratory and cardiovascular diseases have been proposed as potential risk factors for the development of PAC. Furthermore, little is known about the downstream effectors of this pathway and their role in the regulation of proliferation of PAC and their normal cells of origin.

Using assays for the assessment of cAMP production, PKA activity, MAPK activation, CREB activation, and cell proliferation, we have identified a mitogenic pathway, which activates cAMP in cell lines derived from human peripheral adenocarcinomas that express features of Clara cells and their normal cells of origin, small airway epithelial cells (SAEC).

β -carotene and a substance contained in green and black tea, theophylline are widely believed to have cancer preventive effect. However, our current data show that each of these agents increases cAMP/PKA activity, ERK1/2 and CREB resulting in a significant growth stimulation of PAC and SAEC. Accordingly, and pending on the exact level targeted by a given chemopreventive agents, such treatments will likely promote the development of PAC. While some of these agents may inhibit the metabolic activation of tobacco carcinogens, such as NNK, former smokers who start chemoprevention will not benefit from such effects as they start chemopreventive treatment of after discontinuation of exposure to tobacco carcinogens. Currently, there is no agent that has been shown to be effective in preventing lung cancer. Accordingly, the most effective prevention of lung-cancer is never to smoke and to avoid exposure to second hand smoke.

Our study findings suggest that the widely advertised cancer preventive agents that currently are still tested by several laboratories as “chemopreventive” agents such as β-carotene and a substance contained in green and black tea, theophylline are unsafe to be used by smoker or by ex-smokers due to their tumor promoting effects via stimulation of cAMP on initiated cells of Clara cell lineage.

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