Abstract
In carcinogenesis, intercellular interactions within and between cell types are critical but remain poorly understood. We present a study on intercellular interactions between normal and premalignant epithelial cells and their functional relevance in the context of premalignant to malignant progression in Barrett’s esophagus. Using whole transcriptome profiling we found that in the presence of normal epithelial cells, dysplastic cells but not normal cells, exhibit marked down-regulation of a number of key signaling pathways, including the transforming growth factor beta (TGFβ) and epithelial growth factor (EGF). Functional assays revealed both cell types showed repressed proliferation and significant changes in motility (speed, displacement and directionality) as a result of interactions between the two cell types. Cellular interactions appear to be mediated through both direct cell-cell contact and secreted ligands. The findings of this study are important in that they reveal, for the first time, the effects of cellular communication on gene expression and cellular function between premalignant (dysplastic) epithelial cells and their normal counterparts.
Highlights
In carcinogenesis, intercellular interactions within and between cell types are critical but remain poorly understood
We found that heterotypic interactions between normal and dysplastic cells inhibited cellular proliferation and changed motility in both dysplastic and normal cells
Our findings suggest several signaling pathways, including TGF-β,epithelial growth factor (EGF), and their downstream genes as potential targets for further studies aimed at finding biomarkers for early diagnosis, detection and risk prediction in premalignant progression of Barrett’s esophagus
Summary
Intercellular interactions within and between cell types are critical but remain poorly understood. We present a study on intercellular interactions between normal and premalignant epithelial cells and their functional relevance in the context of premalignant to malignant progression in Barrett’s esophagus. Using whole transcriptome profiling we found that in the presence of normal epithelial cells, dysplastic cells but not normal cells, exhibit marked down-regulation of a number of key signaling pathways, including the transforming growth factor beta (TGFβ) and epithelial growth factor (EGF) Functional assays revealed both cell types showed repressed proliferation and significant changes in motility (speed, displacement and directionality) as a result of interactions between the two cell types. The Barrett’s epithelium can be safely visualized and biopsied during esophagogastroduodenoscopy This makes BE a suitable disease model to study premalignant to malignant progression with findings potentially relevant and generalizable to other types of cancer. Our findings suggest several signaling pathways, including TGF-β,EGF, and their downstream genes as potential targets for further studies aimed at finding biomarkers for early diagnosis, detection and risk prediction in premalignant progression of Barrett’s esophagus
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