Oral inflammation promotes oral squamous cell carcinoma invasion

// Cameron Goertzen 1 , Hayder Mahdi 1 , Catherine Laliberte 1, 3 , Tomer Meirson 2 , Denise Eymael 1 , Hava Gil-Henn 2 and Marco Magalhaes 1, 3, 4 1 Cancer Invasion and Metastasis Laboratory, Faculty of Dentistry, University of Toronto, Toronto, Canada 2 Cell Migration and Invasion Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel 3 Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, Toronto, Canada 4 Sunnybrook Health Sciences Centre, Toronto, Canada Correspondence to: Marco Magalhaes, email: marco.magalhaes@utoronto.ca Keywords: cancer; metastasis; inflammation; neutrophils; TNF Received: November 07, 2017      Accepted: May 07, 2018      Published: June 26, 2018 ABSTRACT Oral squamous cell carcinoma (OSCC) represents 95% of oral malignancies and invasion, and metastasis underlies disease morbidity and mortality. We recently established a direct link between oral inflammation and cancer invasion by showing that neutrophils increase OSCC invasion through a tumor necrosis factor (TNFα)-dependent mechanism. The objective of this study was to characterize OSCC-associated inflammation and to determine the molecular mechanisms underlying inflammation-mediated OSCC invasion. Our results showed a significant increase in neutrophil infiltration, the neutrophil-to-lymphocyte ratio in the OSCC microenvironment and increased inflammatory markers, particularly TNFα in saliva. We performed next-generation sequencing of the TNFα-treated OSCC cells and showed marked overexpression of over 180 genes distributed among clusters related to neutrophil recruitment, invasion, and invadopodia. At the molecular level, TNFα treatment increased phosphoinositide 3-kinase (PI3K)-mediated invadopodia formation and matrix metalloproteinase (MMP)-dependent invasion. We show here that TNFα promotes a pro-inflammatory and pro-invasion phenotype leading to the recruitment and activation of inflammatory cells in a paracrine mechanism. Increased TNFα in the tumor microenvironment tips the balance towards invasion leading to decreased overall survival and disease-free survival. This represents a significant advancement of oral cancer research and will support new treatment approaches to control OSCC invasion and metastasis.