Airway Progenitor Dysfunction Predicts Persistence of Bronchial Dysplasia Setting the Stage for Squamous Cell Lung Cancer

Squamous cell lung cancer arises from premalignant dysplasias characterized by squamous replacement of the normal mucociliary airway epithelium. Individuals with persistent, compared to regressive, dysplasias are at increased risk for lung cancer. Most studies have focused on genomic changes accrued in dysplasia, but the failure of normal epithelial repair has not been addressed. We hypothesized that basal progenitor cells, responsible for normal repair, are impaired in dysplasia.  Functional analysis of basal progenitors from dysplastic bronchial biopsies showed decreased self-renewal and multipotentiality compared to non-dysplastic biopsies. The stable prostacyclin analog iloprost, the only drug to have improved dysplasia in a clinical trial, also rescued progenitor function and reversed dysplasia in a subset of lesions. In a series of 32 dysplastic lesions followed in 19 subjects who underwent serial bronchoscopic biopsies, baseline progenitor function predicted dysplasia persistence or regression. Epithelial repair dysfunction is an early and potentially manipulable event in bronchial premalignancy.