Oral inflammation promotes oral squamous cell carcinoma invasion

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.

Salivary IL-17A, IL-17F, and TNF-αAre Associated with Disease Advancement in Patients with Oral and Oropharyngeal Cancer

“…The increase in TNF-α concentration correlated with higher T and N parameters was also confirmed by our study. Excessive TNF-α concentration in the tumor microenvironment shifts the balance towards invasion, resulting in a reduction in overall survival and disease-free survival [26]. Our study also showed an increase in TNF-α concentration in the saliva of patients with positive aerobic bacterial culture of oral swabs.…”

Oral Neutrophils: Underestimated Players in Oral Cancer

“…Cytokines and cytokine-coding mRNA in saliva are also shown to be predictors for OSCC progression ( 51 ). Goertzen et al showed that cancer patients have significantly increased pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-8 and TNF-α in saliva, as compared to controls ( 122 ). Salivary levels of IL-6 ( 118 , 119 ) may serve as oral cancer predictors ( 123 ).…”

Prevalence of human papillomavirus type 16 in persistent oral lesions arising in patients with tobacco, areca nut, and alcohol habits

“…Oral cancers are malignant lesions occurring within the oral cavity, and more than 90% of oral cancer cases are oral squamous cell carcinoma (OSCC) . The symptoms of early OSCC, precancer, and non‐cancer lesions cannot be differentiated visually and requires histopathological investigation for the diagnosis of lesions.…”

“…7 Oral cancers are malignant lesions occurring within the oral cavity, and more than 90% of oral cancer cases are oral squamous cell carcinoma (OSCC). 8 The symptoms of early OSCC, precancer, and non-cancer lesions cannot be differentiated visually and requires histopathological investigation for the diagnosis of lesions. HPV16 has been commonly reported in cases with HPV-positive head and neck cancer [9][10][11] and is frequently associated with oral cancer lesions in north Indian populations.…”