Beta-adrenergic activation of Epithelial-Mesenchymal Transition in ovarian cancer

The Epithelial-Mesenchymal Transition (EMT) is a key process in cancer metastasis whereby epithelial cells lose their polarity and cell-to-cell adhesion, and undergo morphologic changes, giving them a mesenchymal phenotype that allows them to migrate and invade other tissues. Our previous research has shown that beta-adrenergic signaling stimulates pathways involved in ovarian tumor progression, but the underlying mechanisms are not fully understood. We performed genome-wide transcriptome profiling of advanced stage ovarian carcinomas from 98 patients and compared those above versus below the median split on tumor norepinephrine level (NE) (median: 1.05pg/mg tumor). Patients were matched on age, BMI, cancer grade, stage, and histology. High-NE tumors showed increased expression of 694 genes by at least 25% and 124 by at least 50%. These included multiple genes related to EMT, as well as decreased expression of a variety of anti-metastatic genes. In ovarian cancer cell lines (SKOV3ip1 and HeyA8), exposure to stress-concentrations of NE increased transcription of SNAI2 and IL6, both of which regulate EMT. In an in vivo orthotopic mouse model of ovarian cancer, 3weeks of restraint stress significantly decreased the epithelial marker E Cadherin, increased mesenchymal markers N Cadherin and Vimentin, and up-regulated EMT mediators Snai1, Snai2, and Twist1. These results identify an additional pathway by which beta-adrenergic signaling can promote ovarian cancer progression by stimulating EMT gene expression programs that mediate metastasis