Oral inflammation promotes oral squamous cell carcinoma invasion
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Cameron Goertzen1, Hayder Mahdi1, Catherine Laliberte1,3, Tomer Meirson2, Denise Eymael1, Hava Gil-Henn2 and Marco Magalhaes1,3,4
1Cancer Invasion and Metastasis Laboratory, Faculty of Dentistry, University of Toronto, Toronto, Canada
2Cell Migration and Invasion Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
3Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, Toronto, Canada
4Sunnybrook Health Sciences Centre, Toronto, Canada
Marco Magalhaes, email: [email protected]
Keywords: cancer; metastasis; inflammation; neutrophils; TNF
Received: November 07, 2017 Accepted: May 07, 2018 Published: June 26, 2018
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.
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