Abstract 4299: Poor prognosis in smokers with non-small cell lung cancer correlates with the presence of a reparative progenitor cell population
Authors: Ooi Aik T. , Mah Vei H. , Nickerson Derek W. , Gilbert Jennifer L. , Ha Vi L. , Hegab Ahmed E. , Horvath Steve , Alavi Mohammad , Maresh Erin , Chia David , Gower Adam C. , Lenburg Marc E. , Spira Avrum , Walser Tonya , Wallace William D. , Dubinett Steven M. , Goodglick Lee , Gomperts Brigitte N. 
Published: February 2011

Abstract
Cigarette smoking is the most significant risk factor for the initiation and development of lung cancer. Tobacco exposure often results in chronic inflammation, tissue injury, and airway repair. A recent hypothesis demonstrates the presence of a stem/progenitor cell population that involved in airway epithelial repair. These cells may be tumor-initiating cells in lung cancer, and subsequently may be involved in tumor recurrence and metastasis. In the airway epithelium, cells that express keratin (K) 5 and its intermediate filament binding partner K14 are considered to be progenitor cells in the adult large airways at steady state and during airway epithelial repair.
In order to identify subpopulations of airway epithelial stem/progenitor cells under steady state conditions, normal repair, aberrant repair with premalignant lesions, and lung cancer, and their respective correlation with injury and prognosis, we used immunostaining on mouse and human lung tissues, along with a human lung cancer tissue microarray. We found K5 and K14 expression in the steady state submucosal glands and gland ducts. In the basal layer of normal airway pseudostratified columnar epithelium, only K5 expression was prominent while K14 expression was absent. In a heterotopic, syngeneic, murine tracheal transplant model of repairing airway epithelium, we identified a population of K14+ progenitor epithelial cells that was temporally involved in normal repair after injury. Dysregulated repair resulted in persistence of K14+ cells in the airway epithelium of premalignant lesions.
In human patients (n = 399), the presence of K14+ cells in non-small cell lung cancer (NSCLC) predicted poorer outcomes (P = 0.004) especially in patients who are smokers (P = 0.001). The predictive value was more pronounced in current smokers (P = 0.01) compared to former smokers (P = 0.04). In never smokers, the presence of K14+ cells had no predictive value for outcome. We found that the presence of K14+ cells in the primary tumors of current smokers was associated with metastatic disease (P = 0.02). We further found that non-adenocarcinoma NSCLCs from current smokers with metastases had a higher percentage of K14+ cells in the primary tumor sites. (P = 0.004). Examination of K14 expression in distant metastatic sites revealed a significant increase in the number of K14-expressing cells in metastases compared to the primary sites in squamous lung cancer, but not in other histologic subtypes.
Our data propose that dysregulated repair after injury leads to a self-renewing K14+ progenitor cell population in premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis with the strongest predictive value in smokers, where it correlated with metastasis. This suggests that reparative K14+ progenitor cells are the putative tumor-initiating cells in this subgroup of smokers with NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4299.