Oral inflammation promotes oral squamous cell carcinoma invasion.

Cameron Goertzen,Denise Eymael,Hayder Mahdi,Hava Gil-Henn,Catherine Laliberte,Marco Magalhaes,Tomer Meirson

doi:10.18632/oncotarget.25540

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.

Highlights

Oral squamous cell carcinoma (OSCC) represents the majority of oral cancers, and the poor outcome of this disease is attributed to late detection and presence of metastasis at the time of diagnosis [1]
Our results show an increase in the overall inflammatory infiltrate from hyperkeratosis to dysplasia to OSCC samples (Figure 1A) as revealed through fluorescent immunohistochemistry (FIHC) IHC imaging (Figure 1B, Supplementary Figure 1A, 1B)
OSCC showed the highest density of inflammation for all cells except plasma cells and macrophages which were similar compared to dysplasia

Summary

Introduction

Oral squamous cell carcinoma (OSCC) represents the majority of oral cancers, and the poor outcome of this disease is attributed to late detection and presence of metastasis at the time of diagnosis [1]. For localized disease without metastasis, the 5-year survival rate is 80% but drops to 59% and 36% in regional and disseminated disease respectively [2]. This survival rate has not significantly improved in the last three decades emphasizing the need to better understand OSCC pathogenesis to increase patient survival and decrease morbidity [3]. We have established a new direct link between inflammation and oral cancer invasion by showing that neutrophils increase OSCC invasion, matrix degradation, and www.oncotarget.com invadopodia formation, independent of direct contact, through a TNFα-dependent mechanism [10]. It is crucial to investigate and understand the underlying processes of invadopodia formation in OSCC, the role of oral inflammation, in order to prevent invasion and metastasis

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Conclusion