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: 1.05 pg/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, 3 weeks 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.