Abstract 2168: Molecular pathway analysis of esophageal squamous cell differentiation versus carcinoma formation

Abstract

Abstract Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer and is characterized by high mortality. Our previous work analyzing candidate tumor associated genes in ESCC highlighted the important differences in mRNA expression between the normal esophageal and tumor epithelial compartments. However, to date there are limited studies examining expression changes that occur during esophageal squamous cell differentiation versus those associated with ESCC tumorigenesis. To address this issue, we microdissected the basal cell layer and differentiated cell layer from normal epithelium and compared these expression profiles with matched tumor samples in twelve patients using gene expression microarrays (Hu133A 2.0, Affymetrix, Inc.) and qRT-PCR for selected miRNAs. Genes and pathways of interest were determined using class comparison and pathway analyses. Pathway expression of BRCA1 in the DNA damage response pathway presented the most significant difference (P <0.00001) in normal differentiated cells compared to tumor differentiated cells, but no difference was present between normal basal cells and tumor peripheral cells. PDGF signaling was significant only in the normal basal vs. tumor comparison. Taken together, BRCA1 and PDGF expression suggest oncogenetic process differences in esophageal epithelial compartments. Basal cells presented with CCND1 and CDKN2A high expression and p53 low expression, implying that basal cells gene expression is closer to a pattern of tumorigenesis than that of differentiated cells. A typical “stem cell” pattern of CD44high/CD24low expression in normal basal cells vs. normal differentiated cells and tumor vs. normal comparisons indicated that the basal cell compartment may house progenitor or stem-like cells and tumor cells expression is indicative of this stem-like origin. Converse to our expectations, tumor peripheral vs. tumor center comparison revealed that the ESCC tumor clusters were essentially homogenous on the transcriptomic level. Overall, the preliminary results indicate that tumor profiles were closer to basal cells than differentiated cells, consistent with their rapid growth rate and less well differentiated morphology. Investigation of gene expression patterns in normal cell types and ESCC provides novel insight into the transcript profiles associated with normal development versus carcinogenesis. 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 2168.