Preclinical Model for Prevention of NSCLC in Former Smokers
D.V.M., Justus Liebig University, Giessen, Germany
Ph.D. College of Veterinary Medicine, Hannover, Germany
Faculty Web Page
Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers; smoking is the most significant risk factor for the development of all types of lung cancer. Smoking cessation decreases the risk of lung cancer; however, smokers who quit usually do so after years of smoking, at which time gene mutations caused by tobacco carcinogens are already evident.
Of the three types of NSCLC, peripheral pulmonary adenocarcinoma (PAC) is the most common. There are two phenotypically different types of PAC: PAC with features of bronchiolar Clara cells (PACC) and PAC with features of alveolar type II cells (PAC-type II). In previous studies, Dr. Schuller found that NNK, a potent tobacco carcinogen, causes PACC to develop in hamsters, but NNK causes PAC-type II to develop in mice.
Dr. Schuller’s recent data, along with published evidence, suggest that the growth of human and murine (mouse and rat) PAC-type II cells is controlled by the epidermal growth factor receptor (EGF-r) pathway, and agents that increase intracellular cyclic AMP (cAMP) can inhibit this pathway. The data further indicate that human and hamster PACC is controlled by beta-adrenergic receptors, which are stimulated by beta-adrenergic agonists or agents that increase cAMP. In turn, this leads to transactivation of the EGF receptor and membarne estrogen recptors. Cyclic AMP is an important molecule that controls many biological processes, including cell proliferation.
These data indicate that because adenocarcinomas of either lineage can develop in humans, it is possible that agents with strong chemopreventive effects via stimulation of cAMP in murine models may, in humans, selectively promote adenocarcinomas derived from PACC cells.
In preclinical studies, murine models are widely used to test the efficacy of novel chemopreventive agents. Dr. Schuller’s study documents the need for the re-evaluation of published extrapolations of rodent chemoprevention data to human lung cancer, considering similarities in tumor phenotype, cell lineage, and expression of regulatory pathways between the human disease and the animal models.
In conjunction with published evidence, Dr. Schuller’s data also suggest that some widely-advertised cancer preventive agents may be unsafe for smokers and former smokers due to these agents’ selective promoting effects on initiated cells of PACC lineage.