title: Endothelin-1 stimulates motility of head and neck squamous carcinoma cells by promoting stromal-epithelial interactions.
abstract: The invasion and migration of cancer cells is increasingly recognised to be influenced by factors derived from adjacent tumour-associated stroma. The contextual signals regulating stromal-tumour interactions, however, remain poorly understood. Here, we identify a role for endothelin-1 (ET-1), a mitogenic peptide elevated in a number of malignancies, in promoting pro-metastatic cross-talk between head and neck cancer cells and adjacent fibroblasts. We demonstrate that treatment of oral fibroblasts with ET-1 activates ADAM17-mediated release of epidermal growth factor receptor (EGFR) ligands, triggering EGFR signalling and increased motility in neighbouring head and neck cancer cells. ET-1-mediated paracrine transactivation of EGFR also increased cyclo-oxygenase-2 levels in the cancer cells, providing a molecular insight into the mechanisms by which the elevated levels of ET-1 observed in head and neck cancers may contribute to disease progression.
authors.affiliation: Oral Disease Research Group, School of Clinical Dentistry, University of Sheffield S10 2TA, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Hinsley
authors.forename: Stuart
authors.initials: S
authors.lastname: Hunt
authors.forename: Keith D
authors.initials: KD
authors.lastname: Hunter
authors.forename: Simon A
authors.initials: SA
authors.lastname: Whawell
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lambert
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009055:Mouth / Q000166:cytology / Q000378:metabolism; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human