Squamous cell lung cancer (SCC) is the second leading cause of lung cancer death in the US with a 5-year survival rate of 16.8%. Since most SCC is diagnosed at a late stage, chemoprevention or early detection could improve survival. SCC develops through a series of histological alterations including dysplasia and carcinoma in situ. Previous studies have identified genetic changes in epithelial progenitor cells in dysplastic lesions. The goal of this project is to establish a correlation between specific genetic changes in epithelial progenitors and their function. A tissue stem cell is a progenitor cell that is capable of long-term self-renewal as well as differentiation to all the cell-types that make up a specific tissue and therefore is multipotential. Because the normal function of a progenitor cell is to repair and regenerate a native epithelium after injury, histologic changes in dysplasia led us hypothesize that “normal function of airway progenitors is altered in dysplasia”. To address this hypothesis we purified and established clonal cultures of basal progenitors from normal, moderate and severely dysplastic biopsies and compared their self-renewal and differentiation abilities. These analyses revealed that the self-renewal capacity of progenitor cells decreased as dysplasia grade increased. The progenitors from normal biopsies differentiated to all three cell-types (basal, secretory or mucin-secreting and ciliated) of the airways. In contrast, progenitors from dysplasia generated increased numbers of basal cells (p<0.05) and lacked secretory (p<0.001) and ciliated cells (p<0.001), suggesting that multipotential differentiation is impaired in dysplasia. Genetic analyses of dysplastic lesions and cultured dysplastic progenitors (n=4, histology grade ≥ 5.5) identified several mutations (p53, Notch 1, 2 and 3, FBXW7, and FGFR1) that have been previously reported in SCC. Thus, we demonstrate that we are able to culture airway stem/progenitor cells that recapitulate both the phenotypic and mutational characteristics of the lesions from which they originate. We propose that understanding the effect of these mutations in altered progenitor function will help to devise prevention as well as early detection strategies.
Citation Format: Moumit Ghosh, Ichiro Nakachi, Robert L. Keith, Daniel T. Merrick, Wilbur A. Franklin, York E. Miller. Malfunction and mutation of airway stem/progenitor cells in preneoplastic bronchial dysplasia. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B19.