Abstract LB-250: Smoking reprograms human airway basal cells in vivo toward an embryonic stem cell-like molecular phenotype similar to that of lung adenocarcinoma
Authors: Shaykhiev Renat , Wang Rui , Zwick Rachel , Hackett Neil , Leung Roland , Moore Malcolm A.S. , Downey Robert J. , Strulovici-Barel Yael , Salit Jacqueline , Crystal Ronald 
Published: February 2011

Activation of the human embryonic stem cell (hESC)-like transcriptional program has been observed in various epithelial cancers, including lung adenocarcinomas, in association with tumor aggressiveness. We hypothesized that initial changes related to the acquisition of this “cancerous” hESC-like phenotype occur in the stem/progenitor cell compartment of healthy epithelia under the influence of a chronic carcinogenic stress as a step toward malignant tissue derangement. Given that cigarette smoking is capable of inducing molecular changes in the airway epithelium leading to lung cancer, we analyzed expression of hESC-specific genes in the freshly isolated large airway epithelium of healthy nonsmokers (LAE-NS; n=21) and healthy smokers (LAE-S; n=31) and in the pure basal cell (BC) populations obtained from the LAE-NS (BC-NS; n=4) and LAE-S (BC-S; n=4). Expression patterns were then compared to those in primary human lung adenocarcinoma samples (n=193) and pure human lung adenocarcinoma cells propagated as xenografts in the NOD/SCID/IL2Rg-null immunodeficient mice (n=4) using a list of 40 hESC-specific genes based on published meta-analysis of the hESC transcriptome. The microarray analysis revealed low-level constitutive expression of a subset of hESC-specific genes in the LAE-NS, with higher expression in the BC population. Smoking dramatically and selectively up-regulated hESC-specific gene expression in BC, an observation confirmed by massive parallel sequencing (RNA-Seq). Remarkably, 35% of known hESC-specific genes were found up-regulated in BC-S by both microarrays and RNA-Seq. The majority of these genes (71%) were not detected in nonsmokers’ BC indicative of their de novo induction by smoking. Strikingly, 82% of hESC-specific genes induced in BC-S were also significantly up-regulated in both primary human lung adenocarcinomas and xenograft-derived human lung adenocarcinoma cells. Clustering analysis identified a subgroup of lung adenocarcinoma samples (n=32; 6%) among 193 primary lung adenocarcinoma samples based on the high expression of hESC-specific signature found up-regulated in BC of healthy smokers. This subset of adenocarcinoma subjects exhibited distinct clinical/pathological characteristics, such as longer smoking history (p&lt;0.0002), lower lung function parameters such as FEV1 and DLCO (both p&lt;0.001), larger tumor size (p&lt;0.0002), more advanced tumor stage, poorer differentiation grade, and higher frequency of TP53 gene mutations (50% vs 23% in other adenocarcinoma subjects). Thus, prior to any clinical manifestations of lung cancer, cigarette smoking reprograms airway basal stem/progenitor cell population in vivo toward a lung cancer-associated hESC-like molecular state. The subset of lung adenocarcinomas highly expressing smoking-induced basal cell hESC-like gene signature have a distinct, aggressive clinical phenotype.

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 LB-250.