Chronic inflammation in the lung is a known risk factor for lung cancer, a virtually fatal disease with no effective therapy. However, the molecular mechanisms underlying tumor-promoting effects of chronic inflammation remain enigmatic. The long-term objective of this proposal is to determine the molecular mechanisms through which chronic inflammation promotes lung cancer. The asbestos model of lung injury is well established in our laboratory and it serves as a paradigm for inducing the initial events that lead to carcinogenesis. Cigarette smoke is a potent inducer of inflammation in the lung and increases the oncogenic potential of asbestos by unknown mechanisms. Bronchioalveolar stem cells (BASCs) have been identified as the putative cells of origin in lung adenocarcinoma. The anatomic location of the BASC niche precisely coincides with asbestos-induced lesion development. Accordingly, the central hypothesis of this proposal is that cigarette smoke augments the pro-neoplastic effects of asbestos and that inhibition of the p53 tumor suppressor protein enhances inflammation and dysregulates proliferation of BASCs thereby increasing the synergistic effects of asbestos and cigarette smoke in lung tumorigenesis. To directly test our hypothesis, we will use two independent, but complementary approaches that utilize in vivo mouse models of lung cancer and in vitro cell culture of BASCs. First, we will determine lung tumorigenesis in wild-type and p53R172H (a dominant negative mutant) knockin mice after inhalation exposure to asbestos and cigarette smoke. Second, we will measure activation of pro-inflammatory transcription factors, levels of pro-inflammatory cytokines and markers of cell proliferation at sites of lesion development in wild-type and p53R172H knockin mice exposed to asbestos and cigarette smoke. Third, we will determine inflammatory mediator-dependent mechanisms of bronchoalveolar stem cell proliferation. Finally, we will reduce inflammation and evaluate tumorigenesis induced by cigarette smoke and asbestos. These studies will determine whether BASCs are the targets of the oncogenic effects of chronic inflammation induced by mixed asbestos- cigarette smoke inhalation exposures and further characterize the underlying molecular mechanisms with an emphasis on transcriptional programming governed by crosstalk between inflammatory signals and p53. Determining the role of chronic inflammation in the acquisition of a malignant phenotype by a lung stem cell may provide novel insight into the pathogenesis and treatment of lung cancer. Most lung cancers in humans are associated with cigarette smoking, which induces lung inflammation. Inhaled asbestos, also an established human lung carcinogen, induces chronic inflammation in the lung and interacts synergistically with cigarette smoke in lung tumorigenesis. The focus of this proposal is upon the molecular mechanisms through which cigarette smoke amplifies lung carcinogenesis associated with inhaled asbestos.
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