Abstract 3661: Notch2 and Six1 are upregulated during progression of early-stage lung adenocarcinoma and define its unfavorable subset at advanced stages

Abstract

Abstract Lung adenocarcinoma (LA) often manifests as tumors with mainly lepidic growth (LG) pattern in which cancer cells replace alveolar cells, and is diagnosed, depending on the size of invasive foci, as in situ, minimally invasive, or invasive LA. This suggests that a subset of LAs undergoes malignant progression in this order. The present study examines how transcriptional aberrations during the early-stage of LA cells define the clinical phenotypes of advanced tumors. First, we comprehensively searched differentially expressed genes between preinvasive and invasive cancer cells in a single minimally invasive LA using laser capture microdissection and DNA microarrays, and successfully identified two transcription factors Notch2 and Six1 to be up-regulated in the invasive cancer cells from all of five minimally invasive LA tumors. These two molecules appeared to coordinately contribute to LA progression by inducing epithelial-mesenchymal transition and nuclear atypia, because exogenous Notch2 in NCI-H441 lung epithelial cells caused nuclei to enlarge and transactivated Six1, vimentin, and the TGF-β signal transducers Smad3 and Smad4. We then immunohistochemically stained 64 advanced LA tumors, and found that a third of them were double positive for Notch2 and Six1 in the invasive, but not in the LG component. The invasive potential was higher and 2-year disease-free survival rates were lower in tumors that were double-positive, than double negative in both components. These results suggested that paired up-regulation of Notch2 and Six1 during early LA progression persists in a considerable subset of advanced LAs and confers a more malignant phenotype on the subset. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3661. doi:1538-7445.AM2012-3661